4,719 Matching Annotations
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    1. 9

      Case#: Patient 9, Gender N/A, Onset at 3-4 months. Death around 1-2 years, Southeast Asian

      DiseaseAssertion: Pompe disease

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0001252, HP:0001270, HP:0001640, HP:0005165

      Muscular hypotonia, Motor delay, Cardiomegaly, Shortened PR interval)

      CaseHPOFreeText: BVH, Ejection fraction 10%, Creatine kinase levels 1,010u/l

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: No GAA measurement . Ejection fraction 10%, Creatine kinase levels 1,010u/l

      PCR of all exons was performed and subsequently subjected to capillary Sanger sequencing in both directions

      Variant: NM_000152.5(GAA):c.1941C>G (p.Cys647Trp)

      ClinVar: 550327

      CAID: N/A

      gnomAD: Highes population MAF = 0.0001427 (Others)

      ParentalGenotype: Both parents were carriers for the viariant c.1941C>G (p.Cys647Trp)

      PreviouslyPublished: N/A

    1. c.1143delC(p.Ala382Leufs*10)

      Case58

      HPOsFreeText: See Group Phenotypes


      CasePreviousTesting: Sanger sequencing

      CaseMethod1: Sanger sequencing and PCR Amplification

      CaseMethod2: Whole Exome Sequencing (WES)

      CaseGenotypingMethod: Patients were previously confirmed with Pompe disease by Sanger sequencing to capture the pathogenic variants. The process was repeated as part of the study taking care to amplify the coding regions and exon/intron boundaries to compare with the WES results afterwards.


      Variant1: NM_000152.4:c.1143delC (p.Ala382Leufs*10)

      CAID: 370263 https://www.ncbi.nlm.nih.gov/clinvar/variation/370263/

      gnomAD: European (Non-Finnish) 8.946e-6, Overall 4.031e-6 http://gnomad.broadinstitute.org/variant/17-78082353-AC-A


      Variant2: NM_000152.4:c.-32-13T>G

      ClinVar: 4027 https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

      gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G


      CaseAddInfo: Adult Late Onset Pompe Disease

    2. c.1933G > A(p.Asp645Asn)

      Case32

      HPOsFreeText: See Group Phenotypes


      CasePreviousTesting: Sanger sequencing

      CaseMethod1: Sanger sequencing and PCR Amplification

      CaseMethod2: Whole Exome Sequencing (WES)

      CaseGenotypingMethod: Patients were previously confirmed with Pompe disease by Sanger sequencing to capture the pathogenic variants. The process was repeated as part of the study taking care to amplify the coding regions and exon/intron boundaries to compare with the WES results afterwards.


      Variant: NM_000152.4:c.1933G>A (p.Asp645Asn)

      ClinVar: 188728 https://www.ncbi.nlm.nih.gov/clinvar/variation/188728/

      gnomAD: African 6.599e-5, Overall 8.250e-6 http://gnomad.broadinstitute.org/variant/17-78086719-G-A


      CaseAddInfo: Infantile Onset Pompe Disease, Patient is homozygous for this variant, 1 more patient has the same genotype

    3. c.2560C > T(p.Arg854*)

      Case21

      HPOsFreeText: See Group Phenotypes


      CasePreviousTesting: Sanger sequencing

      CaseMethod1: Sanger sequencing and PCR Amplification

      CaseMethod2: Whole Exome Sequencing (WES)

      CaseGenotypingMethod: Patients were previously confirmed with Pompe disease by Sanger sequencing to capture the pathogenic variants. The process was repeated as part of the study taking care to amplify the coding regions and exon/intron boundaries to compare with the WES results afterwards.


      Variant1: NM_000152.4:c.2560C>T (p.Arg854*)

      ClinVar: 4034 https://www.ncbi.nlm.nih.gov/clinvar/variation/4034/

      gnomAD: African 1.891e-3, Overall 2.090e-4 http://gnomad.broadinstitute.org/variant/17-78092070-C-T


      Variant2: NM_000152.4:c.1129G>C (p.Gly377Arg)

      ClinVar: 497033 https://www.ncbi.nlm.nih.gov/clinvar/variation/497033/

      gnomAD: European (Non-Finnish) 2.356e-5, Overall 1.072e-5 http://gnomad.broadinstitute.org/variant/17-78082341-G-C


      CaseAddInfo: Infantile Onset Pompe Disease

    1. CaseOPTPD-1: Female, Taiwan, Birth diagnosis

      HPOsFreeText: GAA (MS/MS) enzyme activity at 1.47 umol/hr/L

      GenotypingMethod: GAA Gene Sequencing and PCR Amplification


      Variant1: NM_000152.4:c.1726G>A (p.Gly576Ser)

      ClinVar: 92467 https://www.ncbi.nlm.nih.gov/clinvar/variation/92467/

      gnomAD: East Asian 0.1427, Overall 0.01700 http://gnomad.broadinstitute.org/variant/17-78085871-G-A


      Variant2: NM_000152.4:c.546+5G>T

      ClinVar: 557811 https://www.ncbi.nlm.nih.gov/clinvar/variation/557811/

      gnomAD: East Asian 4.978e-4, Overall 3.824e-5 http://gnomad.broadinstitute.org/variant/17-78078936-G-T


      CaseAddInfo: One Pompe Mutation allele and Two Pseudodeficency Mutation alleles, Nomenclature indicates patient is homozygous for Variant 1 and Variant 2 is in cis with only one copy, 2 other patients have the same genotype

    2. CaseIP2-4: Female, Taiwan, Birth diagnosis

      HPOsFreeText: GAA (MS/MS) enzyme activity at 0.08 umol/hr/L, Serum CK at 385 U/L

      GenotypingMethod: GAA Gene Sequencing and PCR Amplification


      Variant1: NM_000152.4:c.1194+2T>C

      ClinVar: 370077 https://www.ncbi.nlm.nih.gov/clinvar/variation/370077/

      gnomAD: Not in gnomAD


      Variant2: NM_000152.4:c.1935C>A (p.Asp645Glu)

      ClinVar: 4029 https://www.ncbi.nlm.nih.gov/clinvar/variation/4029/

      gnomAD: East Asian 1.729e-3, Overall 1.240e-4 http://gnomad.broadinstitute.org/variant/17-78086721-C-A


      Variant3: NM_000152.4:c.1726G>A (p.Gly576Ser)

      ClinVar: 92467 https://www.ncbi.nlm.nih.gov/clinvar/variation/92467/

      gnomAD: East Asian 0.1427, Overall 0.01700 http://gnomad.broadinstitute.org/variant/17-78085871-G-A


      CaseAddInfo: Infantile Onset Pompe Disease, Nomenclature indicates Variant 1 and 2 are in trans, also that Variant 3 is in cis with only one of them

    3. CaseLP2-10: Male, Taiwan, Birth diagnosis

      HPOsFreeText: GAA (MS/MS) enzyme activity at 0.06 umol/hr/L, Serum CK at 670 U/L

      GenotypingMethod: GAA Gene Sequencing and PCR Amplification


      Variant1: NM_000152.4:c.752C>T (p.Ser251Leu)

      ClinVar: 325781 https://www.ncbi.nlm.nih.gov/clinvar/variation/325781/

      gnomAD: East Asian 2.760e-3, Overall 3.540e-4 http://gnomad.broadinstitute.org/variant/17-78081415-C-T


      Variant2: NM_000152.4:c.761C>T (p.Ser254Leu)

      ClinVar: 325782 https://www.ncbi.nlm.nih.gov/clinvar/variation/325782/

      gnomAD: East Asian 2.759e-3, Overall 1.947e-4 http://gnomad.broadinstitute.org/variant/17-78081424-C-T


      Variant3: NM_000152.4:c.2662G>T (p.Glu888Ter)

      ClinVar: 578595 https://www.ncbi.nlm.nih.gov/clinvar/variation/578595/

      gnomAD: East Asian 2.719e-4, Overall 1.998e-5 http://gnomad.broadinstitute.org/variant/17-78092467-G-T


      CaseAddInfo: Late Onset Pompe Disease, Nomenclature indicates Variants 1 and 2 are in cis

    4. CaseOPOPD-62: Female, Taiwan, Birth diagnosis

      HPOsFreeText: GAA (MS/MS) enzyme activity at 0.85 umol/hr/L

      GenotypingMethod: GAA Gene Sequencing and PCR Amplification

      Variant1: NM_000152.4:c.1726G>A (p.Gly576Ser)

      ClinVar: 92467 https://www.ncbi.nlm.nih.gov/clinvar/variation/92467/

      gnomAD: East Asian 0.1427, Overall 0.01700 http://gnomad.broadinstitute.org/variant/17-78085871-G-A

      Variant2: NM_000152.4:c.2024_2026delACA (p.Asn675del)

      ClinVar: 189006 https://www.ncbi.nlm.nih.gov/clinvar/variation/189006/

      gnomAD: East Asian 1.106e-4, Overall 8.275e-6 http://gnomad.broadinstitute.org/variant/17-78086806-CACA-C

      CaseAddInfo: One Pompe Mutation allele and One Pseudodeficency Mutation allele, 3 other people have this genotype

    1. 4

      Patient 4: Male, 37yo at diagnosis, 41yo at ERT

      CasePresentingHPOs:

      HPOsFreeText: anti rh-GAA antibodies titre = neg, enzyme (μmol/g/h) = 2.1 (3-20), mobility aid required before and after ERT

      CaseNotHPOs:

      NotHPOsFreeText: NIV not used

      CaseAddInfo: 10yr disease duration

      CasePMIDs:

      CasePreviousTesting: same as group

      CaseGenotypingMethod: same as group

      Variant: NM_000152.4(GAA):c.1437G>A (p.Lys479=)

      ClinVar: 188044, https://www.ncbi.nlm.nih.gov/clinvar/variation/188044/

      gnomAD: n/a

    2. 17

      Patient17: Male, 34yo at diagnosis and ERT

      CasePresentingHPOs:

      HPOsFreeText: anti rh-GAA antibodies titre = 1:800, enzyme (μmol/g/h) = 0.75 (3-20), NIV required only after ERT began

      CaseNotHPOs:

      NotHPOsFreeText: mobility aid not required

      CaseAddInfo: 17yr disease duration, variants in trans

      CasePMIDs:

      CasePreviousTesting: same as group

      CaseGenotypingMethod: same as group

      Variant1: NM_000152.4(GAA):c.-32-13T>G

      Clinvar: 4027, https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

      gnomAD: 0.003582, http://exac.broadinstitute.org/variant/17-78078341-T-G

      Variant2: NM_001079803.2(GAA):c.896T>C (p.Leu299Pro)

      ClinVar: 180144, https://www.ncbi.nlm.nih.gov/clinvar/variation/180144/

      gnomAD: n/a

    1. 5

      Patient5: Female

      CasePresentingHPOs: HP:0004887, HP:0002194, HP:0001522

      HPOsFreeText: ERT dosage = 20 mg/kg/2 w, CRIM positive

      CaseNotHPOs:

      NotHPOsFreeText:

      CaseAddInfo: Symptom onset at 2mo, diagnosis and ERT at 4mo, ERT lasted for 1mo, ventilation required at 3mo, died at 5mo, variants in trans

      CasePMIDs: 21763167, 11738358

      CasePreviousTesting: same as group

      CaseGenotypingMethod: same as group

      Variant1: NM_000152.4(GAA):c.784G>A (p.Glu262Lys)

      ClinVar: 188806, https://www.ncbi.nlm.nih.gov/clinvar/variation/188806/

      gnomAD: 1.66e-05, http://exac.broadinstitute.org/variant/17-78081447-G-A

      Variant2: NM_000152.4(GAA):c.1802C>T (p.Ser601Leu)

      ClinVar: 194154, https://www.ncbi.nlm.nih.gov/clinvar/variation/194154/

      gnomAD: 0.00003187, http://gnomad.broadinstitute.org/variant/17-78086424-C-T

    2. 13

      Patient13: Female

      CasePresentingHPOs:

      HPOsFreeText: ERT dosage = 20mg/kg/2w, HCM reversal, CRIM positive, able to run and climb stairs, can speak well

      CaseNotHPOs: HP:0004887, HP:0009046

      NotHPOsFreeText:

      CaseAddInfo: Symptom onset at 2mo, diagnosis at 6mo, ERT at 8mo, ERT lasted for 111mo, currently 10yo

      CasePMIDs: 14695532, 14972326

      CasePreviousTesting: same as group

      CaseGenotypingMethod: same as group

      Variant: NM_000152.4(GAA):c.1064T>C (p.Leu355Pro)

      ClinVar: 284093, https://www.ncbi.nlm.nih.gov/clinvar/variation/284093/

      gnomAD: 8.304e-06, http://exac.broadinstitute.org/variant/17-78082197-T-C

    1. LOPD-18

      CaseLOPD-18: 2 weeks diagnosis

      HPOsFreeText: GAA activity 2.9 (nmol · h−1 · mg−1), Mean percentage of normal 4.0%

      GenotypingMethod: Newborn Screening Panels


      Variant1: NM_000152.4:c.-32-13T>G

      ClinVar: 4027 http://www.ncbi.nlm.nih.gov/clinvar/variation/4027

      gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G


      Variant2: NM_000152.4:c.2188G>T (p.Glu730Ter)

      ClinVar: 495665 https://www.ncbi.nlm.nih.gov/clinvar/variation/495665/

      gnomAD: Not in gnomAD


      CaseAddInfo: Late Onset Pompe Disease

    2. PD/VOUS-2

      CasePD/VOUS-2: 2 weeks diagnosis

      HPOsFreeText: GAA activity 16.6 (nmol · h−1 · mg−1), Mean percentage of normal 23.3%

      GenotypingMethod: Newborn Screening Panels


      Variant1: NM_000152.4:c.1726G>A (p.Gly576Ser)

      ClinVar: 92467 https://www.ncbi.nlm.nih.gov/clinvar/variation/92467/

      gnomAD: East Asian 0.1427, Overall 0.01700 http://gnomad.broadinstitute.org/variant/17-78085871-G-A


      Variant2: NM_000152.4:c.2065G>A (p.Glu689Lys)

      ClinVar: 4030 https://www.ncbi.nlm.nih.gov/clinvar/variation/4030/

      gnomAD: East Asian 0.2355, Overall 0.05524 http://gnomad.broadinstitute.org/variant/17-78087041-G-A


      Variant3: NM_000152.4:c.2069C>T (p.Pro690Leu)

      ClinVar: 424308 https://www.ncbi.nlm.nih.gov/clinvar/variation/424308/

      gnomAD: East Asian 1.077e-4, Overall 2.337e-5 http://gnomad.broadinstitute.org/variant/17-78087045-C-T


      CaseAddInfo: Patient has one pseudodeficency allele and one allele of uncertain significance, Nomenclature claims Variant 1 and 2 are in cis

    3. LOPD-14

      CaseLOPD-14: 2 weeks diagnosis

      HPOsFreeText: GAA activity 3.0 (nmol · h−1 · mg−1), Mean percentage of normal 4.2%

      GenotypingMethod: Newborn Screening Panels


      Variant1: NM_000152.4:c.-32-13T>G

      ClinVar: 4027 http://www.ncbi.nlm.nih.gov/clinvar/variation/4027

      gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G


      Variant2: NM_000152.4:c.2509C>T (p.Arg837Cys)

      ClinVar: 456408 https://www.ncbi.nlm.nih.gov/clinvar/variation/456408/

      gnomAD: European (Non-Finnish) 4.676e-5, Overall 2.487e-5 http://gnomad.broadinstitute.org/variant/17-78092019-C-T


      CaseAddInfo: Late Onset Pompe Disease

    1. 5/F

      Patient5: female

      CasePresentingHPOs: HP:0001270

      HPOsFreeText: CRIM negative, Anti-rh GGA antibodies maximum titer = 1:25.600, infusion associated reaction, heat normalization

      CaseNotHPOs: HP:0004887, HP:0025156, HP:0001371

      CaseAddInfo: homozygous variants in trans, symptom onset and diagnosis at 1yo, ERT at 2yo. Died due to infusion reaction with ERT.

      CasePreviousTesting: same as group

      CaseGenotypingMethod: same as group

      Variant: NM_000152.4(GAA):c.236_246delCCACACAGTGC (p.Pro79Argfs)

      ClinVar: 371302, https://www.ncbi.nlm.nih.gov/clinvar/variation/371302/

      gnomAD: n/a

    2. 13/F

      Patient13: female

      CasePresentingHPOs: HP:0004887, HP:0011471, HP:0001270, HP:0002546, HP:0000365

      HPOsFreeText: CRIM positive, tracheostomy, partial heart normalization

      CaseNotHPOs: HP:0001371

      NotHPOsFreeText: infusion associated reaction

      CaseAddInfo: variants in trans, symptom onset at 6yo, diagnosis and ERT at 11yo

      CasePreviousTesting: same as group

      CaseGenotypingMethod: same as group

      Variant1: NM_000152.4(GAA):c.236_246delCCACACAGTGC (p.Pro79Argfs)

      ClinVar: 371302, https://www.ncbi.nlm.nih.gov/clinvar/variation/371302/

      gnomAD: n/a

      Variant2: NM_000152.4(GAA):c.1927G>A (p.Gly643Arg)

      ClinVar: 4023, https://www.ncbi.nlm.nih.gov/clinvar/variation/4023/

      gnomAD: 5.884e-05, http://exac.broadinstitute.org/variant/17-78086713-G-A

    1. 20 mg/kg (N = 16)

      Case14HPOsFreeText: 20 mg/kg GAA treatment, GAA activity at 0.1 umol/h/L, GAA activity at 33% lower limit of normal

      CaseAddInfo: Late Onset Pompe Disease


      CaseGenotypingMethod: Method not described, only that the diagnosis was "confirmed … based on 2 GAA gene mutations"


      Variant1: NM_000152.4:c.-32-13T>G

      ClinVar: 4027 https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

      gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 https://gnomad.broadinstitute.org/variant/17-78078341-T-G


      Variant2: NM_000152.4:c.1441T>C (p.Trp481Arg)

      ClinVar: 189007 https://www.ncbi.nlm.nih.gov/clinvar/variation/189007/

      gnomAD: African 8.031e-5, Overall 2.126e-5 https://gnomad.broadinstitute.org/variant/17-78084529-T-C


      CaseAddInfo:

    1. 2/a

      Case#: 2/a, age 20, age 14 (report)

      DiseaseAssertion: Pompe Disease

      FamilyInfo: Family 2, no further information

      CasePresenting HPOs:HP:0002878, HP:0012378, HP:0003546, HP:0001324 (Respiratory failure, fatigue, exercise intolerance, muscle weakness)

      CaseHPOFreeText: valvular myopathy, biopsy with vacuolar myopathy with PAS +

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: single gene sequencing/analysis, 64.47 NaG/AaGIA, 92.28% inhibition of GAA; NaG/AaGIA above 40 and %INH above 87 are in the affected range

      Variants:

      Variant 1:NM_000152.5(GAA):c.377G>A (p.Trp126Ter)

      ClinVar: 932904

      Variant 2: NM_000152.5(GAA):c.1655T>C (p.Leu552Pro)

      ClinVar: 279811

      ParentalGenotypes: N/A

      PreviouslyPublished: N/A

    1. P10a

      Patient10: Female, 75yo

      CasePresentingHPOs: HP:0000822

      HPOsFreeText: LOPD

      CaseNotHPOs:

      NotHPOsFreeText:

      CaseAddInfo: 5yr follow-up MRI, 40yr disease duration, ERT lasted 103mo

      CasePMIDs: PMID: 25614309

      CasePreviousTesting: same as group

      CaseGenotypingMethod: same as group

      Variant1: NM_000152.4(GAA):c.-32-13T>G

      Clinvar: 4027, https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

      gnomAD: 0.003582, http://exac.broadinstitute.org/variant/17-78078341-T-G

      Variant2: NC_000017.11:g.(?80118193)(80118357_?)del (del exon 18)

      ClinVar: 456368, https://www.ncbi.nlm.nih.gov/clinvar/variation/456368/

      gnomAD: n/a

    1. PD04

      Patient4: Female, southern China

      CasePresentingHPOs:

      HPOsFreeText: IOPD

      CaseNotHPOs:

      NotHPOsFreeText:

      CaseAddInfo:

      CasePMIDs:

      CasePreviousTesting: same as group

      CaseGenotypingMethod: same as group

      Variant1: NM_000152.4(GAA):c.1935C>A (p.Asp645Glu)

      ClinVar: 4029, https://www.ncbi.nlm.nih.gov/clinvar/variation/4029/

      gnomAD: 0.0001721, http://exac.broadinstitute.org/variant/17-78086721-C-A

      Variant2: NM_000152.4(GAA):c.2185delC (p.Leu729Trpfs) **this is not the same protein transcript listed in paper (p.Thr729fsX8) but I could not find this in clinvar or allele registry)

      ClinVar: 370552, https://www.ncbi.nlm.nih.gov/clinvar/variation/370552/https://www.ncbi.nlm.nih.gov/clinvar/variation/370552/

      gnomAD: n/a

    1. P2

      PatientF3P2: Female, 36 years diagnosis, European and Native American

      CasePresentingHPOs: HP:0003236, HP:0012378, HP:0003547, HP:0009113, HP:0002910 (Increased serum CK, Fatigue, Shoulder weakness, Weak diaphragm, Increased transaminases)

      HPOsFreeText: Decline in energy and strength reported with each of her four pregnancies most prominent after her youngest daughter's diagnosis of IOPD, Subsequent enzyme assay indicated deficient GAA activity via a dried blood spot (2.2 pmol/punch/hr, control >3.88 pmol/punch/hr), Pulmonary functioning tests (PFTs) showed a decrease in forced vital capacity (FVC) from 93% predicted seated to 72% predicted supine, Laboratory results demonstrated an elevated CK level of 490 U/L (control 30–220 U/L) and mild elevation of transaminases with AST of 83 U/L (control 15–41 U/L) and ALT of 60 U/L (control 14–54 U/L)

      CaseAddInfo: Mother of proband F3P1, found to have minimally symptomatic LOPD

    1. 4-year-old Japanese girl

      Case1: Female, 4 years old, Japanese

      DiseaseAssertion: Thrombocytopenia

      FamilyInfo: 4-generation pedigree available

      ParentalGenotype: See Figure 1 A for parents in the pedigree

      CasePresentingHPOs: HP:0004406, HP:0000979

      (Recurrent epistaxis, purpura)

      CaseHPOFreeText: Mild bleeding tendency

      CaseNotHPOs: N/A

      CaseNotHPOsFreeText: N/A

      ProteinExpression: Flow cytometry showed reduced expression levels

      PlateletAggregation: Platelet aggregation induced by ADP and collagen was markedly reduced but agglutination induced by ristocetin was within the normal range.

      CasePreviousTesting: Direct sequencing analysis around T2231 in exon 14 of the ITGB3 gene. Genomic DNA extracted from the affected and unaffected individuals of the pedigree were amplified by PCR and sequenced (See Figure 2)

      Gene: ITGB3

      Variant: NM_000212.2:c.2231T>C (p.Leu744Pro)

      LegacyVariant: p.Leu718Pro

      ClinVar: 50229

      CAiD: CA143712

      gnomAD: N/A

    1. The patient is a Caucasian 43-year old female

      Case1: Female, 43 years old, Caucasian

      DiseaseAssertion: Thrombasthenia

      FamilyInfo: Pedigree found in Fig. 2B

      ParentalGenotype: See Pedigree Fig 2B

      CasePresentingHPOs: HP:0000132 (Menorrhagia)

      CaseHPOFreeText: Severe and frequent mucocutaneous hemorrhages, intra-peritoneal bleeding

      CaseNotHPOs: N/A

      CaseNotHPOsFreeText: N/A

      ProteinExpression: 25% decrease of GPIbα and a reduced mean value of side scatter in the patient’s platelets.

      PlateletAggregation: Platelet aggregation was markedly reduced in response to ADP, epinephrine, collagen, and arachidonic acid but agglutination induced by ristocetin was normal

      CasePreviousTesting: Screening for mutations was carried out by direct sequencing of PCR-amplified overlapping fragments of reversed transcribed αIIb and β3 mRNA.

      Gene: ITGB3

      Variant: NM_000212.2:c.2231T>C (p.Leu744Pro)

      LegacyVariant: (p.Leu718Pro)

      ClinVar: 50229

      CAiD: CA143712

      gnomAD: N/A

    1. Case#: Downes_2019_BSS, male, age unknown, South-Asian ancestry reported

      DiseaseAssertion: BSS

      FamilyInfo: NR

      ParentalGenotype: NR

      CasePresentingHPOs: NR

      PlateletAggregation: NR

      CaseHPOFreeText: NR

      CaseNotHPOs:

      CaseNotHPOFreeText:

      ProteinExpression: NR

      CasePreviousTesting:

      GenotypingMethod: HTS panel described in supplementary table 3

      PreviouslyPublished:

      Gene: ITGA2B

      Variant: homozygous c.1005_1013del (p.His335_Leu338delinsGln)

      HGVS: NM_000419.5(ITGA2B):c.1005_1013del

      ClinVarID: 626948

      CAID:

      gnomAD: not found in v.2.1.1

      MultipleGeneVariants:

    1. dentification of ACO2 variants in individuals with ION Cohorts including about 1000 molecularly undiagnosed ION individuals from France, Germany, Italy, Spain, Belgium and the UK were screened by targeted sequencing for the presence of ACO2 variants. Among individuals with a single ACO2 variant, we selected cases with an MAF lower than 0.0001, whereas in individuals with biallelic heterozygous composite or homozygous variants, we selected the cases with an MAF lower than 0.005 for each variant. This led to the identification of 50 individuals harbouring 1 of 43 different heterozygous mutations, among which 29 were novel, as well as 11 individuals with biallelic mutations, among which 8 were novel. A compilation of these variants and the associated amino acid changes are displayed on ACO2 primary sequence and 3D structure in Fig. 1A and C and listed in the Supplementary Table 1. Notably, four dominant variants p.(Arg474Gly), p.(Trp603Ser), p.(Ser669Leu) and p.(Arg671Trp) were identified in two unrelated individuals and p.(Arg671Gln) in four unrelated individuals, while one recessive variant, p.(Leu74Val), with an MAF value of 0.00369, was found in five unrelated ROA individuals, and also formerly described in eight individuals with syndromic ACO2 presentations. This p.(Leu74Val) variant was associated once with p.(Gly661Arg) in the P56 individual, a combination already reported in an ROA family.6 Segregation analysis was performed where available. In DOA cases, all affected relatives carried the variant, whereas some relatives in the families of patients P6, P8, P9, P13 and P33 carrying the variant were asymptomatic, as occasionally observed in families with OPA1 mutations.15,41 Moreover, segregation analysis revealed de novo mutations in the P15 and P18 index cases. Analysis of the types of mutations identified in ACO2 (Fig. 1B) revealed that two-third of all variants were missense mutations, irrespective of the dominant or recessive mode of inheritance, while nonsense, frame-shift, splice-site mutations and deletions accounted together for the third part of all mutations identified, without significant difference between the distribution of the mutation types between dominant and recessive cases (P-value: 0.80). Notably, the identification of null alleles in dominant cases suggests that ACO2 haploinsufficiency contributes mainly to DOA pathophysiology.

      Case: Charif Patient #60, 7yo at report, 6yo at dx, male, European

      CasePresentingHPOs:

      CasePresentingHPOsFreeText: inherited optic neuropathy/dominant optic atrophy; BCVA= OD:0.25, OS:0.08; central scotoma; ODS: temporal atrophy

      CaseNOTHPOs:

      CaseNOTHPOSFreeText: other symptoms

      CasePreviousTesting:

      CaseGenotypingMethod: ACO2 mutations were screened using resequencing gene panels dedicated to the molecular diagnosis of IONs or of mitochondrial inherited diseases. All candidate pathogenic variants were validated by Sanger sequencing

      Variant: NM_001098.2 c.525+1G>A; c.220C>G p.(Leu74Val) compound heterozygous

      ClinVarID: or CAID: 1470169

      AddCaseInfo: no segregation data

      PreviouslyPublished: n/a

      VariantEvidence: n/a

    2. Identification of ACO2 variants in individuals with ION Cohorts including about 1000 molecularly undiagnosed ION individuals from France, Germany, Italy, Spain, Belgium and the UK were screened by targeted sequencing for the presence of ACO2 variants. Among individuals with a single ACO2 variant, we selected cases with an MAF lower than 0.0001, whereas in individuals with biallelic heterozygous composite or homozygous variants, we selected the cases with an MAF lower than 0.005 for each variant. This led to the identification of 50 individuals harbouring 1 of 43 different heterozygous mutations, among which 29 were novel, as well as 11 individuals with biallelic mutations, among which 8 were novel. A compilation of these variants and the associated amino acid changes are displayed on ACO2 primary sequence and 3D structure in Fig. 1A and C and listed in the Supplementary Table 1. Notably, four dominant variants p.(Arg474Gly), p.(Trp603Ser), p.(Ser669Leu) and p.(Arg671Trp) were identified in two unrelated individuals and p.(Arg671Gln) in four unrelated individuals, while one recessive variant, p.(Leu74Val), with an MAF value of 0.00369, was found in five unrelated ROA individuals, and also formerly described in eight individuals with syndromic ACO2 presentations. This p.(Leu74Val) variant was associated once with p.(Gly661Arg) in the P56 individual, a combination already reported in an ROA family.6 Segregation analysis was performed where available. In DOA cases, all affected relatives carried the variant, whereas some relatives in the families of patients P6, P8, P9, P13 and P33 carrying the variant were asymptomatic, as occasionally observed in families with OPA1 mutations.15,41 Moreover, segregation analysis revealed de novo mutations in the P15 and P18 index cases. Analysis of the types of mutations identified in ACO2 (Fig. 1B) revealed that two-third of all variants were missense mutations, irrespective of the dominant or recessive mode of inheritance, while nonsense, frame-shift, splice-site mutations and deletions accounted together for the third part of all mutations identified, without significant difference between the distribution of the mutation types between dominant and recessive cases (P-value: 0.80). Notably, the identification of null alleles in dominant cases suggests that ACO2 haploinsufficiency contributes mainly to DOA pathophysiology.

      Case: Charif Patient #1, 25yo at report, female, European

      CasePresentingHPOs:

      CasePresentingHPOsFreeText: inherited optic neuropathy/dominant optic atrophy; BCVA= OD:0.5, OS:0.63; ODS: diffuse loss;

      CaseNOTHPOs:

      CaseNOTHPOSFreeText: other symptoms

      CasePreviousTesting:

      CaseGenotypingMethod: ACO2 mutations were screened using resequencing gene panels dedicated to the molecular diagnosis of IONs or of mitochondrial inherited diseases. All candidate pathogenic variants were validated by Sanger sequencing

      Variant: NM_001098.2 c.172C>T p.(Arg58*) heterozygous

      ClinVarID: or CAID: 441075

      AddCaseInfo: no segregation data

      PreviouslyPublished: n/a

      VariantEvidence: n/a

    1. KMP 15

      Case#: KMP 15, female, 82 yrs, East Slovakia

      DiseaseAssertion: HCM

      FamilyInfo: yes

      CasePresentingHPOs: n/a

      CaseHPOFreeText: symptomatic, LVOTO yes; LVEF 60%; NYHA III.; ICD yes; ECG; echocardiography;

      CaseNotHPOs: n/a

      CaseNotHPOFreeText: n/a

      CasePreviousTesting: Additional Sanger sequencing of exons 12, 24, 25 of MYBPC3, exon 12 NEBL, exons 12, 20, 21 of SCN5A, exon 7 of TNNI3, and exon 9 of TNNT2 gene

      CaseGenotypingMethod: Sanger sequencing;

      Variant: NM_000257.4(MYH7):c.2734A>G (p.Lys912Glu)

      ClinVar: 520267 https://www.ncbi.nlm.nih.gov/clinvar/variation/520267/

      CAID: n/a

      gnomAD: absent

    1. Case#: Consequence 7 Table 1 in Data Supplement (1 cases)

      DiseaseAssertion: HCM

      FamilyInfo: N/A

      CasePresentingHPOs: N/A

      CaseHPOFreeText: Cardiac magnetic resonance imaging, BSA, NYHA functional class, obstructive HCM, atrial fibrillation, coronary artery disease, NSVT, Syncope, SCD family hitory, wall thickness

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: Additional oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing for MYBPC3, TMP1, TNNC1, TNNI2, TNNI3, TNNT2, ACTC1, MYL3

      CaseGenotypingMethod: oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing

      Variant: NM_000257.4(MYH7):c.1608G>T (p.Glu536Asp)

      ClinVar: 177671 https://www.ncbi.nlm.nih.gov/clinvar/variation/177671/

      CAID: n/a

      gnomAD: absent

    2. Case#: Consequence 16 Table 1 in Data Supplement (1 cases)

      DiseaseAssertion: HCM

      FamilyInfo: N/A

      CasePresentingHPOs: N/A

      CaseHPOFreeText: Cardiac magnetic resonance imaging, BSA, NYHA functional class, obstructive HCM, atrial fibrillation, coronary artery disease, NSVT, Syncope, SCD family hitory, wall thickness

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: Additional oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing for MYBPC3, TMP1, TNNC1, TNNI2, TNNI3, TNNT2, ACTC1, MYL3

      CaseGenotypingMethod: oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing

      Variant: NM_000257.4(MYH7):c.5135G>A (p.Arg1712Gln)

      ClinVar: 36642 https://www.ncbi.nlm.nih.gov/clinvar/variation/36642/

      CAID: n/a

      gnomAD: 0.00004657 European (non-Finnish) https://gnomad.broadinstitute.org/variant/14-23884860-C-T

    3. Case#: Consequence 5 Table 1 in Data Supplement (1 cases)

      DiseaseAssertion: HCM

      FamilyInfo: N/A

      CasePresentingHPOs: N/A

      CaseHPOFreeText: Cardiac magnetic resonance imaging, BSA, NYHA functional class, obstructive HCM, atrial fibrillation, coronary artery disease, NSVT, Syncope, SCD family hitory, wall thickness

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: Additional oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing for MYBPC3, TMP1, TNNC1, TNNI2, TNNI3, TNNT2, ACTC1, MYL3

      CaseGenotypingMethod: oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing

      Variant: NM_000257.4(MYH7):c.2198G>T (p.Gly733Val)

      ClinVar: 181177 https://www.ncbi.nlm.nih.gov/clinvar/variation/181177/

      CAID: n/a

      gnomAD: absent

    4. Case#: Consequence 8 Table 1 in Data Supplement (1 cases)

      DiseaseAssertion: HCM

      FamilyInfo: N/A

      CasePresentingHPOs: N/A

      CaseHPOFreeText: Cardiac magnetic resonance imaging, BSA, NYHA functional class, obstructive HCM, atrial fibrillation, coronary artery disease, NSVT, Syncope, SCD family hitory, wall thickness

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: Additional oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing for MYBPC3, TMP1, TNNC1, TNNI2, TNNI3, TNNT2, ACTC1, MYL3

      CaseGenotypingMethod: oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing

      Variant: NM_000257.4(MYH7):c.2539A>G (p.Lys847Glu)

      ClinVar: 177757 https://www.ncbi.nlm.nih.gov/clinvar/variation/177757/

      CAID: n/a

      gnomAD: absent

    5. Case#: Consequence 2 Table 1 in Data Supplement (1 case)

      DiseaseAssertion: HCM

      FamilyInfo: N/A

      CasePresentingHPOs: N/A

      CaseHPOFreeText: Cardiac magnetic resonance imaging, BSA, NYHA functional class, obstructive HCM, atrial fibrillation, coronary artery disease, NSVT, Syncope, SCD family hitory, wall thickness

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: Additional oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing for MYBPC3, TMP1, TNNC1, TNNI2, TNNI3, TNNT2, ACTC1, MYL3

      CaseGenotypingMethod: oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing

      Variant: NM_000257.4(MYH7):c.5135G>A (p.Arg1712Gln)

      ClinVar: 36642 https://www.ncbi.nlm.nih.gov/clinvar/variation/36642/

      CAID: n/a

      gnomAD: 0.00004657 European (non-Finnish) https://gnomad.broadinstitute.org/variant/14-23884860-C-T

    1. Q380RR628PA8, A20, L14Mild, survival beyond age 35, no mental retardation

      Case#: Patient #17, Brazilian

      DiseaseAssertion: MPS1, mild

      FamilyInfo:

      CasePresentingHPOs:

      CaseHPOFreeText: survival beyond age 35

      CaseNotHPOs:

      CaseNotHPOFreeText: mental retardation

      GenotypingMethod:

      PreviouslyPublished:

      Variant: Q380R; R628P (also A8, A20, L14)

      ClinVar: 1064675

      CAID:

      SupplementalData:

    1. The differential diagnosis of neurodegenerative disorders with atrophy of the cerebral and cerebellar cortex and cerebellar vermis is broad even in young age groups; concomitant occurrence of degeneration of the retina points to lysosomal storage disorders, mitochondrial disorders, defects of carbohydrate glycosylation, and infantile neuroaxonal dystrophy.1–4 We hereby report on the identification of a tricarboxylic acid (TCA) cycle defect manifesting in infancy by the degeneration of the cerebrum, cerebellum, and retina. The subjects of this study were eight individuals, two males and six females, originating from two unrelated families of Arab Muslim origin (Figure 1). Their clinical data are summarized in Table 1. All were born following an uneventful pregnancy and delivery and had normal birth weights, head circumferences, and Apgar scores. Symptoms were first noted at 2–6 months of age and included variable appearance of truncal hyptonia, head bobbing, athetosis, generalized seizures, and ophthalmologic abnormalities that included strabismus, nystagmus, abnormal eye movements, and abnormal pursuit. The course was characterized by failure to thrive, gradual evolution of severe muscle wasting despite satisfactory oral intake, worsening of the hypotonia, attenuating deep tendon reflexes until complete areflexia was reached, progressive microcephaly, variable forms of seizures that were typically triggered by intercurrent febrile illnesses and were partly responsive to anticonvulsants, and failure to gain developmental milestones, culminating in profound psychomotor retardation. A distinctive feature was the appearance of head bobbing and athetoid movements of the upper limbs along with horizontal nystagmus when the individuals were held at the upright position. Visual tracking, normal at the newborn period, steadily deteriorated with the gradual evolution of bilateral optic atrophy. Visual evoked potentials in early infancy were normal, but the electroretinogram responses became critically reduced over the first two years of life, indicating severe retinal dystrophy. Similarly, auditory brain responses declined steadily, reflecting sensorineural hearing loss of variable severity. EEG disclosed generalized or focal spike and wave activity and slow background compatible with nonspecific encephalopathy. Electrophysiologic assessment of peripheral muscles and nerves performed in individual V-2 at 2 years revealed a normal electromyogram and a mild decrease of peripheral sensory and motor velocity suggesting demyelination. Taken together with the gradual disappearance of tendon reflexes, this finding indicates an evolving peripheral demyelinating neuropathy. Figure 1. Open in a new tab Pedigrees of the Two Families (A) Family A and (B) Family B. Affected individuals are represented by filled symbols.Table 1. Clinical Features of Affected Individuals Family A Family B IV-3 IV-5 V-2 V-5 V-7 III-1 III-2 III-3 Sex m f f f m f f f Current age (years) 18 13 7 3 0.5 9 8 2 Birth weight (centile) 2,900 g (10) 3,700 g (75) 2,700 g (10) 2,800 g (15) 3,700 g (75) 3,220 g (25) 3,450 g (50) 2,750 g (10) Birth head circumference (centile) 35 cm (40) 35 cm (50) 35 cm (50) 34 cm (25) 35 cm (40) 34.5 cm (40) 35 cm (50) 34 cm (25) Initial manifestations (age at presentation) H, A (5 months) H, A (6 months) H, A (2 months) H, E (4 months) H, E (3 months) H, S (3 months) A, H (5 months) A, E (5 months) Current weight (centile) 25 kg (−5 SD) 26 kg (−4 SD) 11 kg (−5 SD) 9 kg (−4 SD) 7.7 kg (25) 13 kg (−6 SD) 12 kg (−6 SD) 8 kg (−4 SD) Current head circumference (centile) 47 cm (−5 SD) 49.5 cm (−3 SD) 46.5 cm (−3.5 SD) 46.5 cm (5) 42.7 cm (25) 48.5 cm (−2.5 SD) 48 cm (3) 45.5 cm (5) Global DD/MR profound severe profound profound moderate profound profound severe Current motor skills no intentional movements crawls, rolls sits with support does not roll rolls, does not sit lift head when supine does not role does not role roles both sides Current cognitive skills vegetative state, no smile smile, recognize family smile, recognize family smile, recognize family smile, recognize family no eye contact, does not recognize family no eye contact, responds to auditory stimuli smile, recognize family Ataxia yes yes yes yes very mild yes yes yes Seizures generalized generalized focal and generalized focal and generalized no generalized myoclonic and focal focal and generalized no Retinal dystrophy (age at diagnosis) not evaluated severe (4 years) severe (1 year) severe (1 year) not evaluated profound (2 years) profound (1.5 years) moderate (1.5 years) ophthalmology optic atrophy, strabismus optic atrophy, strabismus optic atrophy, nystagmus optic atrophy, nystagmus, strabismus strabismus optic atrophy, nystagmus optic atrophy, nystagmus optic atrophy, nystagmus, strabismus Initial MR scan (age) not done normal (11 months) mild CoA (3 months) mild CoA (frontal and temporal) (11 months) normal (in utero, 30 weeks) CoA (frontal and temporal) mild thinning of CC (7 months) CoA abnormal WM (16 months) normal (in utero, 31 weeks) Last MR scan (age) not done severe CeA, moderate CoA (frontal and temporal), abnormal periventricular WM signal (12 years) severe CeA, moderate CoA (frontal and temporal), thin CC abnormal WM signal (4 years) severe CeA, moderate CoA (frontal and temporal), thin CC, abnormal WM signal (2.5 years) not done not done mild CoA and CeA (1y) Tendon reflexes absent brisk absent absent normal absent decreased absent Other severe scoliosis moderate SNHL severe SNHL (hearing aids) Open in a new tab The following abbreviations are used: A, ataxia/athetoid movements; H, hypotonia; E, eye abnormalities; S, seizures; HC, head circumference; DD, developmental delay; MR, mental retardation; CoA, cortical atrophy; CeA, cerebellar atrophy; WM, white matter; CC, corpus callosum; SNHL, sensorineural hearing loss.During gestation and throughout the first 6 months, brain MRI was typically normal. Thereafter, repeated MR scans (Figure 2) displayed progressive cerebellar atrophy of both hemispheres and the vermis. In addition, symmetric cortical atrophy gradually evolved, affecting mainly the frontal and temporal lobes along with a striking thinning of the corpus callosum. White matter abnormalities, indicated by T2 and fluid-attenuated inversion recovery (FLAIR) periventricular hyperintense signals, were first noted during the second year of life. Taken together, these serial MR scans revealed generalized progressive brain atrophy affecting primarily the cerebellum and to a lesser extent the white matter and the frontal and parietal lobes of the cerebral cortex. Figure 2. Open in a new tab Representative MRI Findings (A) T2-weighted, coronal section image of individual V-2 at 3 months shows a normal cerebellum and mild cortical atrophy. (B) T1-weighted, coronal section scan of the same individual at 4 years displays severe atrophy of the cerebellar hemispheres (arrowheads) and the vermis (arrows). (C) T1-weighted, coronal section image of individual IV-5 at 12 years shows enlarged cerebellar folia and reduced volume indicating generalized (vermian and hemispheral) atrophy. Note also the mild cortical atrophy and visible sulci. (D) Cortical atrophy and white matter abnormal signals (arrows) demonstrated by FLAIR image of coronal section in the same individual. (E) Moderate cortical atrophy, very thin corpus callosum (arrow), and cerebellar atrophy (arrowhead) in a T1-weighted, sagital section of individual V-5 at 2.5 years. (F) FLAIR image, axial section of individual V-5 displaying frontal and temporal cortical atrophy compared with relatively preserved occipital cortex. The abnormal periventricular white matter signal (arrow) is consistent with dysmyelination.

      Case#: Spiegel Patient V-2 (proband not designated, so was chosen), female, 7yo at report, Arab Muslin origin

      DiseaseAssertion: Infantile Cerebellar-Retinal Degeneration

      FamilyInfo: All eight individuals were homozygous for the mutation; ten parents and one of the healthy sibs were heterozygous, and three healthy sibs were homozygous for the normal allele. 3 additional affected individuals are deceased, so it is possible that they were not genotyped and that may be the reason for the discrepancy in the count.

      CasePresentingHPOs: HP:0000648, HP:0000639, HP:0012736, HP:0001252, HP:0001251, HP:0002194, HP:0100543, HP:0007359, HP:0002197, HP:0000556, HP:0002120, HP:0001272, HP:0033725, HP:0002500, HP:0001284, HP:0000407

      CaseHPOFreeText: birth weight= 2,700 g (10th centile); birth head circumference= 35 cm (50th centile); initial manifestations: hypotonia and ataxia at 2 months; current weight= 11 kg (−5 SD); current head circumference= 46.5 cm (−3.5 SD); current motor skills= does not roll; current cognitive skills= smile, recognize family; focal and generalized seizures; severe retinal dystrophy dx at 1yo; mild cortical atrophy on MR scan at 3mo; severe cerebellar atrophy, moderate cortical atrophy (frontal and temporal), thin corpus callosum, abnormal white matter signal last MR scan at 4 yo; moderate sensorineural hearing loss

      CaseNotHPOs:

      CaseNotHPOFreeText:

      GenotypingMethod: homozygosity mapping, WES

      PreviouslyPublished: n/a

      Variant: c.336C>G in ACO2 [MIM 100850] (NM_001098.2), which causes p.Ser112Arg (NP_001089.1). homozygous

      ClinVar: 29584

      FunctionalEvidence: Specific aconitase activity in the individuals' lymphoblasts was severely reduced. Under restrictive conditions, the mutant human ACO2 failed to complement a yeast ACO1 deletion strain, whereas the wild-type human ACO2 succeeded,

      AdditionalInfo: 2 "unrelated" families reported, but "Affected individuals of both unrelated clans shared a similar homozygous haplotype, indicating that Ser112Arg is a founder mutation in this population" so will count the segregations as one family

      SupplementalData: n/a

    1. 926T > C and 121–1G > A in one case

      Case: Haagerup II:8

      CasePresentingHPOs:

      CasePresentingHPOsFreeText: not specified

      CaseNOTHPOs:

      CaseNOTHPOSFreeText: not specified

      CasePreviousTesting: same as group

      CaseGenotypingMethod: same as group

      Variants: c926T>C and c121-1G>A

      ClinVarID: or CAID: ClinVarID: 8426; ClinVarID: 859435

      gnomAD: 2/129174 European (non-Finnish) alleles at a frequency of 0.00001548 with no homozygotes; 4/112000 European (non-Finnish) alleles at a frequency of 0.00003571 with no homozygotes

      AddCaseInfo:

      PreviouslyPublished: no

      VariantEvidence: predicted but variant was proven to segregate with disease; predicted to delete all of exon 3

    1. 4H-Sc.236C>T (p.A79V)c.1882C>T (p.R628*)This report

      Case#: Kwak Patient #4, 2yo at dx

      DiseaseAssertion: Hurler-Scheie

      FamilyInfo:

      CasePresentingHPOs: HP:0000280, HP:0007957, HP:0100790, HP:0000924, HP:0001627, HP:0001433

      CaseHPOFreeText: IDUA activity=6.5 nmol/mg protein/hr, uGAGs=202.8 CPC unit/g creatinine

      CaseNotHPOs:

      CaseNotHPOFreeText:

      PreviouslyPublished:

      Variant: c.236C>T (p.A79V); c.1882C>T (p.R628*)-Path in ClinVar

      ClinVar: 1458769; 550421

      CAID:

      SupplementalData: supplemental file contains phenotype information

    1. The ethnic background of these families was as follows: northern European (two), Czech, Spanish, Portuguese (two), Indian, and Honduran. Genomic DNA was extracted from blood leukocytes using the Puregene Genomic DNA Isolation kit (Gentra Systems, Minneapolis, Minnesota). Exons 2–8 of the cathepsin K gene (14) were amplified from genomic DNA of Pycno patients by PCR, isolated, and sequenced by cycle sequencing with an ABI 377 Sequencer (Perkin-Elmer Corp., Norwalk, Conneticut, USA).

      Case: Family 2

      CasePresentingHPOs:

      CasePresentingHPOsFreeText: not specified

      CaseNOTHPOs:

      CaseNOTHPOSFreeText: not specified

      CasePreviousTesting: none

      CaseGenotypingMethod: Exons 2-8 were amplified by PCR and sequenced.

      Variant: Q190X

      ClinVarID: or CAID: ClinVarID: 371328

      gnomAD: The variant is reported in 1/30616 South Asian alleles at a frequency of 0.00003266, with no homozygotes in gnomAD v2.1.1.

      AddCaseInfo:

      PreviouslyPublished:

      VariantEvidence: none

    1. Here, we report an international multicenter cohort of 16 patients (of whom 7 are newly diagnosed) with biallelic pathogenic variants in ACO2 gene.

      Sharkia Proband A-3, onset at 5 weeks old, 5yo at report, Caucasian, American, male. Patient A3 has

      Variant: c.590A>G and c.172C>T

      CaseHPO: HP:0001252, HP:0001251, HP:0001250, HP:0002120, HP:0001272, HP:0000648, HP:0000512, HP:0012736, HP:0001508, HP:0000252, HP:0030890

  2. Nov 2026
    1. patient (V-1)

      Case#: V-1; male; age 28; Chinese family

      DiseaseAssertion: Hypertrophic cardiomyopathy

      FamilyInfo: V-1 is part of a large consanguineous HCM pedigree. Family segregation information was reported for the MYBPC3 variant. V-1 died suddenly at age 29

      CasePresentingHPOs: HP:0001712 HP:0005144 HP:0032092

      CaseHPOFreeText: Left ventricular hypertrophy; increased interventricular septal thickness; left ventricular outflow tract obstruction

      Genotyping Method: Sanger sequencing and next-generation sequencing

      Variant: c.3624delC, missense

      ClinVar: 42727

      CAID: CA014493

    1. 12-year-old boy

      Case1: Male, 12, China

      DiseaseAssertion: Hypertrophic cardiomyopathy

      FamilyInfo: parents where not consanguineous, both carried variants.

      ParentalTesting: sanger sequencing showed c.1789C>T variant in patients paternal grandmother, and c.3033delG from maternal grandmother

      CasePresentingHPOs: HP:0001962 HP:0002094 HP:0001279 HP:0001712 “Palpitations, Dyspnea, Syncope, Left ventricular hypertrophy”

      CaseHPOFreeText: symptoms lasted about a year, ECG showed sinus arrhythmia, high left ventricle voltage

      CaseNotHPOs: “the patient had no skeletal muscle disease or mental retardation. The diagnosis of glycogen storage disease was also excluded.”

      CaseNotHPOFreeText: no other family members diagnosed with heart disease

      CasePreviousTesting: diagnosed 3 months before presentation with HCM, no prior genetic testing, but there was echocardiogram and ecg testing.

      Genotyping Method: Sanger and NGS

      FunctionalAnalysis: no functional analysis preformed

      Variant: c.1789C>T (p.Arg597Trp), c.3033delG (p.Gln1012Serfs*8)

      ClinVar: NM_000256.3(MYBPC3):c.1789C>T (p.Arg597Trp),

      CAID: no results

      gnomAD: no results

      AdditionalInfo: treated with metoprolol, at 3 moth follow up lvot decreased

    1. 8 of 570 probands and 25 relatives

      Case#: cohort annotation with 8 probands and 25 relatives that are carriers.

      DiseaseAssertion: Pathogenic MYBPC3 c.2149–1G>A variant associated with hypertrophic cardiomyopathy

      FamilyInfo: Eight unrelated probands, all male, with 45 relatives, 25 where carriers of the variant, 12 had HCM and 13 where unaffected

      ParentalTesting: not reported

      CasePresentingHPOs: HP:0001712 HP:0002094 HP:0001279 HP:0100749 HP:0001962 HP:0001649 “Left ventricular hypertrophy, Dyspnea, syncope, Chest pain, Palpitations, Tachycardia CaseHPOFreeText:HCM with variable expression with men diagnosed younger then women

      CaseNotHPOs:not reported

      CaseNotHPOFreeText: not reported

      CasePreviousTesting: not reported

      Genotyping Method: Sanger sequencing

      FunctionalAnalysis: rna analysis shows abnormal transcript, suggesting founder effect.

      Variant: MYBPC3 NM_000256.3:c.2149–1G>A

      ClinVar: 177814

      CAID: not reported

      gnomAD:not reported

      AdditionalInfo: HCM penetrance increased with age and was highest in males over 30

    1. A total of 28 patients

      Case#: 28 patients, 21 retrospectives, 7 prospectives.

      DiseaseAssertion: patients had reported unsolved metabolic condition, possible mitochondrial disorder. Onset ranged from prenatal to 7 years, study ranged from 1 year to 29, 9 patients died

      FamilyInfo:individual family histories not summerized

      ParentalTesting:all reported varients confirmed via sanger sequencing on parents, though most had proband only sequencing.

      CasePresentingHPOs: “motor developmental delay, intellectual disability, developmental regression, muscle weakness, dystonia, choreoathetosis, ataxia, tremor, nystagmus, strabismus, Epilepsy, Brain atrophy CaseHPOFreeText: mri showed brain atrophy in 10, white matter injury in 6, hypo/aplasia of the corpus collosum in 3, mitochondrial hypoplasia in 5, myofibular disorganization in 2.

      CaseNotHPOs: not reported

      CaseNotHPOFreeText: not reported

      CasePreviousTesting: retrospective patients had mtdna investigations done without diagnosis

      Genotyping Method: WES and Sanger

      FunctionalAnalysis: reported for selected finding such as impaired adp/atp transports for a variant slc25a4, no cohort wide analysis

      Variant: heterogenous findings across the cohort genes read included SLC25A4, POLG, SPATA5, NDUFB11, SMN1, MYH2, LMNA, TSPOAP1, CACNA1A, ALS2, SCN2A, EPG5, NKX1-2, ATRX, ABCC6, and MYBPC3. Though for the cardiomyopathy purposes, c.1828G > A, p.(Asp610Asn) c.1543_1545delAAC, p.(Asn515del)

      ClinVar: 2247822

      CAID: not reported

      gnomAD: not reported

      AdditionalInfo: WES diagnostic yield was 16/28, 4 patients where diagnosed via MD. The paper suggests WES as a first step for children though there where sensitivity limitations.

    1. A 27-year-old man

      Case#:1 Male, 27, no reported ethnicity

      DiseaseAssertion: sinus tachycardia, signs of hypertrophy of both atria and ventricles

      FamilyInfo: proband had a sister who died at 15 days of age due to a congenital heart disease (transposition of the great arteries). No other relative was diagnosed with cardiomyopathy of other cardiac disease before 50 years of age

      ParentalTesting: family history was unremarkable. Parents were not consanguineous.

      CasePresentingHPOs: HP:0001639, HP:0001644, HP:0200128, HP:0004308 "Hypertrophic cardiomyopathy, Dilated cardiomyopathy, Biventricular hypertrophy, Ventricular arrhythmia <br /> CaseHPOFreeText: Dilated cardiomyopathy recorded at age of 4, Severe respiratory infection led to circulatory decompensation and acute femoral thrombosis"

      CaseNotHPOs: none reported

      CaseNotHPOFreeText: no evidence of myeloproliferative disease was found when bone marrow trepanobiopsy was preformed.

      CasePreviousTesting: dcm diagnosis at age 4, Whole exome sequencing (WES)

      Genotyping Method: WES, NGS, & Sanger

      FunctionalAnalysis: none reported

      Variant: chr11:g.47357432_47357458del, ENST00000545968.1: c.2711_2737del, p.2711_2737del

      ClinVar: VCV000978729.2

      gnomAD: ENSG00000134571.12

  3. Oct 2026
    1. A 19-year-old woman was diagnosed with a reduced coagulation factor VIII activity of 30% after bleeding complications from wisdom tooth surgery

      Case: Female, 19 y.o., ethnicity unknown.

      DiseaseAssertion: VWD2N

      FamilyInfo: Proband has one older symptomatic sister who shares an identical compound heterozygous genotype, presenting with a mild bleeding tendency, reduced FVIII activity (20-30%), and severely reduced FVIII binding (<2%). The family features one younger unaffected sister who tested negative for both variants, and an unaffected carrier mother. Both parents had normal factor VIII, and there was no male relative with reduced factor VIII or bleeding symptoms.

      ParentalGenotype(s): Mother is heterozygous for the c.2561G>A (p.R854Q) variant, negative for the c.2402G>A (p.S801N) variant, and has normal baseline factor VIII levels, confirming the sisters' variants are in trans. Father unavailable/not tested.

      CasePresentingHPOs: HP:0004846 (Prolonged bleeding after surgery), HP:0003645 (Prolonged partial thromboplastin time).

      CaseHPOFreeText: Index patient experienced bleeding complications following wisdom tooth surgery. Factor VIII binding activity is reduced at 32%. Reduced coagulation factor VIII activity (30%). Prolonged activated partial thromboplastin time (aPTT) of 37 seconds.

      CaseNOTHPOs: HP:0001873 (Thrombocytopenia), HP:0012147 (Reduced quantity of von Willebrand factor), HP:0030130 (Impaired von Willebrand factor collagen binding activity).

      CaseNOTHPOFreeText: Normal vWF antigen (vWF:Ag) levels (101%), normal vWF activity (116%), normal vWF-collagen-binding activity (104%), normal vWF multimer distribution structures, normal hemoglobin level (128 g/L), and normal Prothrombin Time (PT/QUICK) of 83%.

      CasePreviousTesting: Siblings did not carry any known mutations in the F8 gene or the LMAN1 and MCFD2 genes (which encode for endoplasmic reticulum carrier proteins of coagulation factors V and VIII).

      GenotypingMethod: Direct sequence analysis of VWF exons 18-20.

      PreviouslyPublished: NA.

      Gene: VWF

      HGNCID: HGNC:12726

      Variant: Heterozygous c.2561G>A (p.R854Q) and heterozygous c.2402G>A (p.S801N).

      HGVS: (1) NM_000552.5:c.2561G>A (p.Arg854Gln) (2) NM_000552.5:c.2402G>A (p.Ser801Asn)

      ClinVarID: (1) 296 (2) NA

      CAID: (1) NA (2) CA383522023

      gnomAD: (1) MAF of 0.005974 in the European (non-Finnish) population https://gnomad.broadinstitute.org/variant/12-6034812-C-T?dataset=gnomad_r4

      (2) MAF of 0.00001098 in the South Asian population https://gnomad.broadinstitute.org/variant/12-6044331-C-T?dataset=gnomad_r4

    1. 38-year-old obese (BMI = 44) man

      Case1: 38, Male

      FamilyInfo: ”identification of nine additional heterozygous carriers of the p.V79I mutation, none of whom fulfilled the diagnostic criteria for HCM” Pedigree in Figure 1, and Table 1 gives identifiers in variant carriers.

      CasePresentingHPOs:HP:0030148

      CaseHPOFreeText: “Echocardiography demonstrated asymmetrical septal ventricular hypertrophy…and left atrial dilation”

      CaseNotHPOs:HP:0001279, HP:0000822

      CaseNotHPOFreeText: ”He was asymptomatic and had never experienced cardiac symptoms, systemic hypertension, or syncope.”

      Genotyping Method:Genotyping of 11 sarcomere genes

      Variant:(c.235G > A), p.V79I

      ClinVar:CA013672

    1. 35 year-old asymptomatic Caucasian female

      Case1: 35, Female, Caucasian

      DiseaseAssertion: Patient was asymptomatic

      FamilyInfo: “ significant family history of hypertrophic cardiomyopathy (HCM), including sudden cardiac death of unknown cause in one son and HCM in two other children”

      CaseHPOFreeText: “extensive, diffuse, poorly demarcated LGE throughout the LV ventricle”

      CaseNotHPOFreeText: “CMR showed normal left ventricular (LV) systolic function…and normal wall thickness ”

      CasePreviousTesting:

      Genotyping Method: Subsequent genotyping

      Variant: c.305G>A (p.Arg102Gln)

      ClinVar:CA004273

    1. n 8-year-old girl with a 2-year history of progressive shortness of breath on exertion

      Case1: 8 year old female

      DiseaseAssertion: Heart failure

      FamilyInfo: “ no family history of sudden cardiac death or cardiomyopathy” Pedigree in Figure 5.

      ParentalTesting: Variant not found in parents

      CasePresentingHPOs:HP:0010741, HP:0001723

      CaseHPOFreeText: “biatrial enlargement of ST-segment depression in the inferior and lateral precordial leads” “Echocardiography revealed the enlargement of both atria…slight pericardial effusion, and a LV ejection fraction of 55%”

      CaseNotHPOFreeText: “LV global longitudinal strain measured by speckle-tracking echocardiography was normal” “Late gadolinium enhancement was negative.” “no evidence of pulmonary embolism, anomalous pulmonary venous drainage, or pulmonary arteriovenous fistulas” “The following laboratory findings were normal: thyroid function, liver chemistry tests, rheumatic disease antibody levels, troponin I, creatinine, and blood urea nitrogen levels, white blood cell count, urine analysis, D-dimer levels, hepatitis panel screening, and serum free light chain concentrations; HIV antibody levels were negative.”

      Genotyping Method: Next generation sequencing

      Variant: c.574C > T p.R192C)

      ClinVar:CA021951

    1. proband (individual II.11 in Tables 1 and 2 and Fig. 1a) presented with dyspnea on exertion, palpitations and exercise intolerance at 53 years of age

      Case1: Female, 53

      DiseaseAssertion: Restrictive Cardiomyopathy

      FamilyInfo:Pedigree in Fig 1. shows “ The proband (II.11) has five siblings and three nieces with cardiomyopathy,” “the proband’s two oldest siblings were diagnosed with idiopathic DCM”

      CasePresentingHPOs: HP:0002094, HP:0001962, HP:0031329, HP:0001688, HP:0001709

      CaseHPOFreeText:”Echocardiography revealed massive biatrial enlargement (Fig. 2a) and markedly abnormal diastolic function” “she had mild hypertrophy localized to the mid-septum” “progressive atrial enlargement”

      CaseNotHPOs:HP:0012436,

      CaseNotHPOFreeText: “with no systolic anterior motion of the anterior mitral valve leaflet or left ventricular outflow tract obstruction” “The sample was negative for eosinophilic infiltrate, myocarditis, sarcoidosis, amyloidosis and hemochromatosis.”

      CasePreviousTesting: Sequenced TNNT2, TTN, MYL3, MYBPC, MYL2, MYH7, ACTC1, TPM1, and TNNI3

      Genotyping Method: PCR

      Variant: c.266T>A (p.Ile89Asn)

      ClinVar:CA004157

      gnomAD: To be found

      AdditionalInfo: Autosomal Dominant trait, heterozygous missense mutation in TNNT2

    1. 21-year-old professional soccer player

      Case1: 21, Male

      DiseaseAssertion: To be found

      FamilyInfo: No remarkable family history.

      CasePresentingHPOs: HP:0003401, HP:0410173, HP:0001688

      CaseHPOFreeText: "arietal ischemic lesions, elevated high-sensitivity I troponin, left ventricle (LV) dilation, apical hypokinesia, apical thrombus, and multifocal nonischemic late gadolinium enhancement with edema" " elevated N-terminal pro–B-type natriuretic peptide and low c-reactive protein"

      CaseNotHPOs: HP:0001297, HP:0012819

      CaseNotHPOFreeText: "A cardioembolic stroke due to myocarditis with an LV thrombus was assumed" “Ischemic heart disease was considered unlikely at presentation” “Cardiac sarcoidosis was considered but was not supported” “Autoimmune myocarditis and other systemic inflammatory causes were also considered” “Giant cell myocarditis was considered to be unlikely”

      CasePreviousTesting:

      Genotyping Method: Whole genome sequencing

      Variant: c.1484G>A; p.Arg495Gln

      ClinVar: CA010464

      gnomAD: To be found

    1. CasePT-104: United States

      CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

      HPOsFreeText: N/A

      CaseNotHPOs: HP:0001650, HP:0001658 (Aortic valve stenosis, Myocardial infarction)

      NotHPOsFreeText: N/A

      CaseAddInfo:


      CaseGenotypingMethod: DNA was collected from the participants using blood samples. 18 genes suspected on contributing to HCM were targeted and sequenced. The variants were then located and filtered for pathogenicity.


      Variant: NM_000257.3:c.4399C>G (p.Leu1467Val)

      ClinVar: 43015 https://www.ncbi.nlm.nih.gov/clinvar/variation/43015/

      gnomAD: South Asian 1.111e-3, Overall 1.352e-4 https://gnomad.broadinstitute.org/variant/14-23886482-G-C

    1. 1

      Case1: Male, 0.5 yr onset, 2.5 yr diagnosis, 10.04 yr report

      CasePresentingHPOs: HP:0001371 (Contractures)

      HPOsFreeText: Wheelchair used, FVC z-score sitting -0.25 (97% pred), FVC z-score supine -1.12 (87% pred), 65% MRC Scale, 530 CK U/l, 9.1 GAA activity (nmol/h/mg)^h from cultured fibroblasts

      NotHPOsFreeText: No respiratory support

    2. 7

      Case7: Male, 1 yr onset, 2 yr diagnosis, 13.7 yr report

      CasePresentingHPOs: HP:0002650 (Scoliosis)

      HPOsFreeText: Respiratory support at night, FVC z-score sitting -4.08 (54% pred), FVC z-score supine -5.4 (39% pred), 87% MRC Scale, 548 CK U/l, 17.9 GAA activity (nmol/h/mg)^h from cultured fibroblasts

      NotHPOsFreeText: No wheelchair used

    1. Patient 5

      Case5: Female, Caucasian, United States, 2 months onset and diagnosis, 0.4 years report

      CasePresentingHPOs: HP:0011968, HP:0011469, HP:0012378, HP:0004347, HP:0010453 (Feeding difficulties, Nasal regurgitation, Fatigue, Weakness of muscles of respiration, Pelvic bone asymmetry)

      HPOsFreeText: Difficulty in lying supine while eating, sleeping and self-limited gasping episodes was observed, PT evaluation showed mild consistent asymmetry with increased lateral head tilt to the right, Tendency towards flexion/abduction/external rotation positioning of lower extremities was noted, Slight lateral thigh grooves reflected early IT band tightness with decreased posterior weight shift and propping on forearms in prone, AIMS score was at 10th percentile for chronological age and 25th to 50th percentile for corrected age, ALT 27 U/L (Normal 5–40 U/L), AST 36 U/L (Normal 15–41 U/L), ALP 352 U/L (Normal 24–170 U/L), Urinary Glc4 4.1 mmol/mol creatinine (Normal ≤8.3 mmol/mol creatinine)

      CaseNotHPOs: HP:0002033, HP:0002015, HP:0004323, HP:0003808 (Poor suck, Poor swallowing, Abnormality of body weight, Abnormal muscle tone)

      NotHPOsFreeText: CK levels, ECG, and ECHO have consistently been within normal limits, Had normal passive ranges of motion and appropriate weight bearing through lower extremities in supported standing

    2. Patient 4

      Case4: Female, Caucasian, United States, 1 month onset, 6 months diagnosis, 1.1 years report

      CasePresentingHPOs: HP:0003236, HP:0012378, HP:0006589, HP:0003725 (Increased serum CK, Fatigue, Flaring of lower rib cage, Firm muscles)

      HPOsFreeText: HyperCKemia present in the first month (505 IU/L; Normal 30–279 IU/L) but normalized spontaneously at 4 months (188 IU/L), PT assessment revealed subtle motor signs including preferred position of ring sitting with hips in flexion/abduction/external rotation and bilateral IT band tightness, Imbalanced trunk flexion, Decreased use of abdominals and excessive use of spinal extension, Asymmetry was noted in reaching objects in prone and weight shifting with lateral flexion and shortening on the left at the neck and trunk, AIMS score was at the 25th percentile and GMFM was 22.14%, Urinary Glc4 4.8 mmol/mol creatinine (Normal ≤8.3 mmol/mol creatinine)

      CaseNotHPOs: HP:0003690 (Limb muscle weakness)

      NotHPOsFreeText: She had no head lag when pulled to sit and the ability to transfer objects and bring them to midline

    3. Patient 1

      Case1: Male, Caucasian, United States, Birth onset

      CasePresentingHPOs: HP:0008872, HP:0002100, HP:0001508, HP:0008947, HP:0001655, HP:0003236, HP:0200136, HP:0001290, HP:0002835, HP:0002194 (Feeding difficulties in infancy, Recurrent aspiration pneumonia, Poor weight gain, Infantile muscular hypotonia, Patent foramen ovale, Increased serum CK, Oropharyngeal dysphagia, Low muscle tone, Aspiration, Delayed gross motor development)

      HPOsFreeText: HyperCKemia was present since the early neonatal period (378 IU/L, day 8 of life; N: 60–305 IU/L), ERT at a dose of 20 mg/kg every 2 weeks was initiated at age 1 month, CK levels were normalized on ERT by age 4 months (80 IU/L), Flexion/abduction/ external rotation positioning of lower extremities, iliotibial (IT) band tightness, lack of independent sitting, AIMS score between 10th and 25th percentile, GMFM at 23.16%, At age 23 months, he had achieved significant motor milestones; started sitting with support at 10 months and without support at 12 months, pulled to stand at 12 months, walked at 15 months and could feed himself with an immature pincer grasp. Swallow study was normal, ALT 26 U/L (Normal 5–40 U/L), AST 45 U/L (Normal 15–41 U/L), ALP 211 U/L (Normal 24–170 U/L), Urinary Glc4 3.7 mmol/mol creatinine (Normal ≤8.3 mmol/mol creatinine)

      CaseNotHPOs: HP:0011675, HP:0002910 (ECG abnormality, Elevated hepatic transaminases)

      NotHPOsFreetext:

      CaseAddInfo: Older brother of Patient 2, Late-Onset Pompe Disease

    4. Patient 2

      Case2: Male, Caucasian, United States, Birth onset

      CasePresentingHPOs: HP:0001290, HP:0200136, HP:0002033, HP:0003236, HP:0001655, HP:0002058, HP:0002194, HP:0002421, HP:0000467, HP:0002015 (Generalized hypotonia, Oral-pharyngeal dysphagia, Poor suck, Increased serum CK, Patent foramen ovale, Myopathic face, Delayed gross motor development, Poor head control, Neck muscle weakness, Dysphagia)

      HPOsFreeText: hyperCKemia at 435 IU/L on day of life 4, Patent foramen ovale detected at birth by ECHO but resolved spontaneously, PT evaluation at age 2 months revealed flexion/abduction/external rotation positioning of lower extremities with tightness bilaterally in hip flexors, hamstrings, and IT bands, Had a tendency to remain on toes when held in supported standing with additional support required for weight bearing through lower extremities, Had difficulty lifting his head in prone, with asymmetric head lift to 45 degrees, and an inability to maintain head in midline when supine, AIMS score at age 2 months was between 10–25th percentile, ALT 41 U/L (Normal 5–40 U/L), AST 33 U/L (Normal 15–41 U/L), ALP 239 U/L (Normal 24–170 U/L), Urinary Glc4 4.5 mmol/mol creatinine (Normal ≤8.3 mmol/mol creatinine)

      CaseNotHPOs: HP:0011016 (Abnormality of urine glucose concentration)

      NotHPOsFreeText:

      CaseAddInfo: Younger brother of Patient 1, Late-Onset Pompe Disease

    5. Patient 7

      Case7: Female, Caucasian, United States, 6 months diagnosis, 8 months report

      CasePresentingHPOs: HP:0001643, HP:0006699, HP:0006682, HP:0003722, HP:0008969 (Patent ductus arteriosus, Premature atrial contractions, Premature ventricular contractions, Neck flexor weakness, Leg muscle stiffness)

      HPOsFreeText: At 6 months head lag during pull to sit was noted, Had predominant overall flexion position of lower extremities with a tendency towards hip flexion/abduction/external rotation, with lateral thigh grooves suggestive of bilateral IT band tightness, AIMS score was between 10th and 25th percentile for chronological age and 50th percentile for her corrected age adjusted for prematurity while GMFM score was 16.55%, ALT 37 U/L (Normal 5–40 U/L), AST 53 U/L (Normal 15–41 U/L), ALP 174 U/L (Normal 24–170 U/L)

      CaseNotHPOs: HP:0003236, HP:0001712, HP:0001290 (Increased serum CK, Left ventricular hypertrophy, Decreased muscle tone)

      NotHPOsFreeText: Other evaluations including pulmonary, speech, and swallow were normal

    6. Patient 6

      Case6: Male, Caucasian, United States, 1 month onset, 6 months diagnosis, 8 months report

      CasePresentingHPOs: HP:0003236, HP:0001655, HP:0003701, HP:0006589, HP:0003093, (Increased serum CK, Patent foramen ovale, Proximal muscle weakness, Flaring of lower rib cage, Limited hip extension,

      HPOsFreeText: HyperCKemia was noticed in the first month (438 U/L; Normal 60–305) but normalized spontaneously by age 6 months, flexion/abduction/external rotation positioning of lower extremities and with bilateral IT band tightness was revealed at the same time, also had decreased active use of abdominal oblique muscles with a lack of active trunk rotation, Decreased active use of lower abdominal muscles with inability to achieve a posterior pelvic tilt in supine, AIMS score was at 1st percentile for age and GMFM was at 12.3%, ALT 30 U/L (Normal 5–40 U/L), AST 90 U/L (Normal 15–41 U/L), ALP 249 U/L (Normal 24–170 U/L), Urinary Glc4 2.6 mmol/mol creatinine (Normal ≤8.3 mmol/mol creatinine)

      CaseNotHPOs: HP:0001712, HP:0001290 (Left ventricular hypertrophy, Decreased muscle tone)

      NotHPOsFreeText: Other evaluations including cardiac, pulmonary, speech, and swallow were normal

    1. one confirmed LOPD patient

      Case1: Female, 55 years report, 25 years onset, Brazil, African

      CasePresentingHPOs: HP:0003325, HP:0003236, HP:0003148, HP:0100284, HP:0011807, HP:0003326, HP:0008994, HP:0002527, HP:0003551, HP:0002015, HP:0000822, HP:0000819, HP:0003119, HP:0003707, HP:0003391, HP:0003327, HP:0001315, HP:0002515, HP:0010546 (Limb-girlde muscle weakness, Increased serum CK, Elevated serum acid phosphatase, EMG: myotonic discharges, Type 1 muscle fiber atrophy, Myalgia, Proximal muscle weakness in lower limbs, Falls, Difficulty climbing stairs, Dysphagia, Hypertension, Diabetes mellitus, Dyslipidemia, Calf muscle pseudohypertrophy, Gowers sign, Axial muscle weakness, Reduced deep tendon reflexes, Waddling gait, Muscle fibrillation)

      HPOsFreeText: Serum CK 1467 U/L (normal: ≤ 200U/L), NaG/AaGIA ratio 40.4, %INH 87.2, GAA activity 4.2% from dried blood spot, Falls occurring mainly when walking for long distances, Normal Mini-Mental State Examination score (27/30), Mild symmetrical weakness in proximal muscles in the lower limbs (Medical Research Council grade 4), Needle electromyography revealed motor unit potentials with low amplitude and short duration in the iliopsoas muscle associated with fibrillation and short myotonic discharge potentials in lumbar paraspinal muscles

      CaseNotHPOs: HP:0001270 (Motor delay)

      NotHPOsFreeText: Muscle biopsy with the absence of vacuolar myopathy

      CaseAddInfo: Late-Onset Pompe Disease, One sister diagnosed with LOPD based on low GAA activity and shared genetic variants but no other known relatives with the condition

    1. 3

      Case3: Male, 19 years report, Italy

      CasePresentingHPOs: HP:0003551 (Difficulty climbing stairs)

      HPOsFreeText: Height is 1.78 m, Weight is 60 kg, BMI is 18.9 kg/cm2, 7 years on ERT, Forced Vital Capacity at 107%

      CaseNotHPOs: HP:0002098 (Respiratory distress)

      NotHPOsFreeText: Nocturnal non-invasive ventilation

      CaseAddInfo: Late Onset Pompe Disease

    2. 1

      Case1: Female, 46 years report, Italy

      CasePresentingHPOs: HP:0003551 (Difficulty climbing stairs)

      HPOsFreeText: Height is 1.64 m, Weight is 50 kg, BMI is 18.6 kg/cm2, 2 years on ERT, Forced Vital Capacity at 108%

      CaseNotHPOs: HP:0002098 (Respiratory distress)

      NotHPOsFreeText: Nocturnal non-invasive ventilation

      CaseAddInfo: Late Onset Pompe Disease

    1. II

      CaseII: Adult onset, 71 years diagnosis

      CasePresentingHPOs: HP:0003701, HP:0003326, HP:0003236, HP:0003198 (Proximal muscle weakness, Myalgia, Increased serum CK, Myopathy)

      HPOsFreeText: Plasma CK 5–10× Normal, GAA activity from dried blood spot: 0%, 6-Minute Walking Test: 40 min, Forced Vital Capacity Seated: 850 (22%)

      CaseNotHPOs: HP:0002795 (Abnormal respiration)

      CaseAddInfo: Late-Onset Pompe Disease

    2. 1

      CaseV,1: Adolescent onset, 42 years diagnosis

      CasePresentingHPOs: HP:0003701, HP:0003236, HP:0003388, HP:0003326 (Proximal muscle weakness, Increased serum CK, Easy fatigability, Myalgia)

      HPOsFreeText: Plasma CK 5-10× Normal, Vacuoles in histology, 6-Minute Walking Test: 135 min, Forced Vital Capacity Seated: 950 (20%), GAA activity from dried blood spot: 0.20%

      CaseNotHPOs: HP:0002795 (Abnormal respiration)

      CaseAddInfo: Late-Onset Pompe Disease

    3. 3

      CaseV,3: Child onset, 45 years diagnosis

      CasePresentingHPOs: HP:0003701, HP:0003236 (Proximal muscle weakness, Increased serum CK)

      HPOsFreeText: Plasma CK 2.5-5× Normal, GAA activity from dried blood spot: 0.08%, 6-Minute Walking Test: 566 min

      CaseNotHPOs: HP:0002795 (Abnormal respiration)

      CaseAddInfo: Late-Onset Pompe Disease

    4. III

      CaseIII: Adult onset, 63 years diagnosis

      CasePresentingHPOs: HP:0003701, HP:0003388, HP:0003236, HP:0003198, HP:0002460, HP:0002015 (Proximal muscle weakness, Easy fatigability, Increased serum CK, Myopathy, Distal muscle weakness, Dysphagia)

      HPOsFreeText: Plasma CK 2.5–5× Normal, GAA activity from muscle: 11.7%

      CaseNotHPOs: HP:0002795 (Abnormal respiration)

      CaseAddInfo: Late-Onset Pompe Disease

    5. I

      CaseI: Early adult onset, 49 years diagnosis

      CasePresentingHPOs: HP:0003701, HP:0003388, HP:0003236, HP:0003198 (Proximal muscle weakness, Easy fatigability, Increased serum CK, Myopathy)

      HPOsFreeText: Plasma CK 5–10× Normal, GAA activity from lymphocytes: 14.2%

      CaseNotHPOs: HP:0002795 (Abnormal respiration)

      CaseAddInfo: Late-Onset Pompe Disease

    6. 2

      CaseV,2: Adult onset, 33 years diagnosis

      CasePresentingHPOs: HP:0003701, HP:0003236, HP:0003388 (Proximal muscle weakness, Increased serum CK, Easy fatigability)

      HPOsFreeText: Plasma CK 5-10× Normal, 6-Minute Walking Test: 566 min, Forced Vital Capacity Seated: 3000 (90%), GAA activity from dried blood spot: 0.20%

      CaseNotHPOs: HP:0002795 (Abnormal respiration)

      CaseAddInfo: Late-Onset Pompe Disease

    1. 9

      Case9: Male, 40 years onset, 45 years diagnosis, 74 years report, France

      CasePresentingHPOs: HP:0002540, HP:0002878, HP:0004887 (Inability to walk, Respiratory failure, Respiratory failure requiring assisted ventilation)

      HPOsFreeText: Lost ambulation at 50 years, Started invasive ventilation at 67 years, Started ERT given every other week at a dose of 20 mg/kg at 70 years for 43 months, Peak Anti-rhGAA antibodies at 1:409,600, Time off ventilation stayed constant at 0 min, Total Motor Function Measure from 29 to 26, 6MWT stayed constant at 0 meters

      CaseNotHPOs: HP:0030148 (Heart murmur)

      NotHPOsFreeText: No adverse reaction to ERT was recorded

      CaseAddInfo: Late Onset Pompe Disease

    2. 12

      Case12: Male, 35 years onset, 50 years diagnosis, 61 years report, France

      CasePresentingHPOs: HP:0002540, HP:0002878, HP:0004887 (Inability to walk, Respiratory failure, Respiratory failure requiring assisted ventilation)

      HPOsFreeText: Lost ambulation at 48 years, Started invasive ventilation at 35 years, Started ERT given every other week at a dose of 20 mg/kg at 56 years for 49 months, Peak Anti-rhGAA antibodies at 1:1600, FVC at 0 (L / % expected), MIP at 22 (cm H2O), MEP at 28 (cm H2O), Time off ventilation stayed constant at 0 min, 6MWT stayed constant at 0 meters

      CaseNotHPOs: HP:0030148 (Heart murmur)

      NotHPOsFreeText: No adverse reaction to ERT was recorded

      CaseAddInfo: Late Onset Pompe Disease

    3. 3

      Case3: Male, 28 years onset, 30 years diagnosis, 69 years report, France

      CasePresentingHPOs: HP:0002540, HP:0002878, HP:0004887, HP:0002093 (Inability to walk, Respiratory failure, Respiratory failure requiring assisted ventilation, Respiratory insufficency)

      HPOsFreeText: Lost ambulation at 58 years, Started invasive ventilation at 28 years, Started ERT given every other week at a dose of 20 mg/kg at 68 years for 11 months, Peak Anti-rhGAA antibodies at 1:1600, FVC at 0.45/13 (L / % expected), MIP at 17 (cm H2O), MEP at 29 (cm H2O), Time off ventilation stayed constant at 0, Total Motor Function Measure from 31 to 27

      CaseNotHPOs: HP:0030148 (Heart murmur)

      NotHPOsFreeText: No adverse reaction to ERT was recorded

      CaseAddInfo: Late Onset Pompe Disease, Patient died before publication

    1. 62-year-old man

      Case1: Male, 62 years report

      CasePresentingHPOs: HP:0002091, HP:0002878, HP:0003701, HP:0040047, HP:0002098, HP:0100786, HP:0006510, HP:0005978, HP:0000822, HP:0003124, HP:0001677, HP:0003236, HP:0004324, HP:0002329, HP:0030207, HP:0002098, HP:0040047, HP:0100750, HP:0002097, HP:0007269, HP:0040046 (Restrictive lung disease, Respiratory failure, Proximal muscle weakness, Abnormality of the right hemidiaphragm, Shortness of breath, Hypersomnia, Chronic obstructive pulmonary disease, Diabetes mellitus Type II, Hypertension, Hypercholesterolemia, Coronary artery disease, Elevated serum creatine kinase, Increased body weight, Drowsiness, Paradoxical respiration, Respiratory distress, Abnormality of the right hemidiaphragm, Atelectasis, Emphysema, Spinal muscular atrophy, Abnormality of the left hemidiaphragm)

      HPOsFreeText: Hypercapnic respiratory failure, Chronic phrenic neuropathy bilaterally, Long history of apparently idiopathic right hemidiaphragm paralysis, Underwent muscle biopsy and electromyography, both of which showed nonspecific myopathic features associated with mild denervation, On presentation, the patient's vital signs were a temperature of 36.5 °C (97.7 °F); heart rate, 94 beats/minute; blood pressure, 104/70 mm Hg; respiratory rate, 22 breaths/minute; oxygen saturation, 90% when receiving 2 L of supplemental oxygen per minute; and body mass index, 29.9 kg/m2, Decreased air entry bilaterally, Laboratory values were: Hemoglobin, 120 g/L; platelets, 279 × 109/L; white blood cells, 7.7 × 109/L; sodium, 140 mmol/L; potassium, 5.1 mmol/L; bicarbonate, 40 mmol/L; serum urea nitrogen, 3.6 mmol/L; creatinine, 70.7 μmol/L; and calcium, 2.48 mmol/L, Fatty atrophy of rotator cuff musculature, Tests for resting room-air arterial blood gases showed a pH of 7.29; PCO2, 89.4 mm Hg; PO2, 67.6 mm Hg; and serum bicarbonate, 43 mmol/L, Right diaphragm paralysis, Electromyography showed complete absence of phrenic compound muscle action potentials bilaterally. No activation of motor unit potentials was seen within the diaphragm, either with respiration or with volitional effort. Ultrasonography showed that the left hemidiaphragm was hyperechoic, 0.14 cm thick at functional residual capacity (FRC), with a thickening ratio of 1.1 (the thickening ratio is thickness at total lung capacity/thickness at FRC). The right hemidiaphragm was hyperechoic, 0.15 cm thick at FRC, with thickening ratio of 0.9. (Normal thickness is >0.15 cm, normal thickening ratio is >1.2.) The aldolase concentration was slightly increased at 9 U/L (reference level, <7.7 U/L). To complete the evaluation for rarer causes of diaphragmatic dysfunction, neurology services requested testing for inherited neuropathies. Three weeks later, the patient's serum GAA level was 1.0 nmol/mL/hour (reference level, >7.4 nmol/mL/hour)

      CaseNotHPOs: HP:0003549 (Abnormality of connective tissue)

      NotHPOsFreeText: The following tests were within reference range: creatine kinase, thyroid function tests, erythrocyte sedimentation rate, serum and protein electrophoresis, antinuclear antibody profile, and anti-Jo antibodies

      CaseAddInfo: Ex-Smoker with 40–80 pack-years of smoking, Medications at presentation to facility included aspirin, clopidogrel, simvastatin, diltiazem, sitagliptin, metformin, budesonide and formoterol inhaler, tiotropium bromide inhaler, and albuterol inhaler

    1. 1

      Case1: Female, 12 years report, 3 years onset, 12 years diagnosis

      CasePresentingHPOs: HP:0003325, HP:0002093, HP:0002650 (Limb-girdle muscle weakness, Respiratory insufficiency, Scoliosis)

      HPOsFreeText: 730 CK (U/L), Normal Heart, 0 GAA activity (µmol/L/h), Showed respiratory involvement and required nocturnal non-invasive ventilation, An ambulant patient with 284 m six minute walk distance at the time of diagnosis

      CaseNotHPOs: HP:0003457, HP:0001627 (EMG abnormality, Abnormality of the heart)

      NotHPOsFreeText: Muscle weakness confined to limb-girdle muscles

    1. 4

      Case4: 0.5 years diagnosis, Germany

      CasePresentingHPOs: HP:0031185, HP:0001635, HP:0001252, HP:0001324, HP:0003236, HP:0001639 (Increased NT-proBNP level, Cardiac failure, Muscular hypotonia, Muscle weakness, Increased serum CK, Hypertrophic cardiomyopathy)

      HPOsFreeText: 3924 BNP (pg/ml), 7.68 IVS (d) z score, 6.42 IVS (s) z score, Heart Failure at NYHA Class 3

      NotHPOsFreeText: No left-ventricular outflow tract obstruction

      CaseAddInfo: Infantile-Onset Pompe Disease

    1. 1117

      Case1117: Male, 35 years onset, Welsh/English, Caucasian

      CasePresentingHPOs: HP:0003560, HP:0005110 (Muscular dystrophy, Atrial fibrillation)

      HPOsFreeText: 1,000 –2000's CK level, Immunohistochemistry: dystrophin, sarcoglycans, merosin

      CaseNotHPOs: HP:0009051, HP:0002540 (Increased muscle glycogen content, Non-ambulatory)

    1. Patient Number 3

      Case3: Male, 35 years report, 5 years onset, Algeria, African

      CasePresentingHPOs: HP:0003323, HP:0003749, HP:0002355, HP:0007340, HP:0008956, HP:0003484, HP:0003236, HP:0003198 (Progressive muscle weakness, Pelvic girdle muscle weakness, Difficulty walking, Lower limb muscle weakness, Proximal lower limb amyotrophy, Upper limb muscle weakness, Increased serum CK, Myopathy)

      HPOsFreeText: At grade 3 of Vignos and Walton scales, CK rate was 5 times the normal value and AST and ALT were normal, EMG was compatible with a myopathic disorder, GAA activity measured in leukocytes was significantly decreased

      CaseNotHPOs: HP:0003115, HP:0003116, HP:0001270, HP:0001290, HP:0002240, HP:0001640, HP:0005952, HP:0002540 (Abnormal ECG, Abnormal echocardiography, Motor delay, Generalized hypotonia, Hepatomegaly, Cardiomegaly, Decreased pulmonary function, Non-ambulatory)

    1. 15

      Patient15: Male, 21 years report, 2 years onset

      CasePresentingHPOs: N/A

      HPOsFreeText: GAA activity 4.7% from a dried blood spot

      CaseNotHPOs: HP:0002098, HP:0001324, HP:0001640, HP:0002240 (Respiratory distress, Muscle weakness, Cardiomegaly, Hepatomegaly)

      NotHPOsFreeText: No wheelchair needed, Respiratory Assistance not needed

      CaseAddInfo: LOPD

    1. The affected patient

      Case1: Male, French-Canadian, 18 years onset, 54 years diagnosis and report

      CasePresentingHPOs: HP:0008994, HP:0000822, HP:0003119, HP:0004398, HP:0007185, HP:0009109, HP:0002094, HP:0012764, HP:0002098 (Proximal muscle weakness in lower limbs, High blood pressure, dyslipidemia, Peptic ulcer, Loss of consciousness, Denervation of the diaphragm, Dyspnea, Orthopnea, Shortness of breath)

      HPOsFreeText: Dependent on continuous positive airway pressure or bilevel positive airway pressure when he is lying flat or sleeping because of previous intubation and tracheostomy, GAA activity measured from dried blood spot was 0.87 pmol/h/punch (Normal 4.96 - 27.3)

      CaseAddInfo: Late Onset Pompe Disease, The patient’s mother had six miscarriages and died at age 75 of lung cancer and his father died of cardiac problems in his early sixties, It appears that no other family members, including his parents and two siblings, were affected, patient had a previous appendectomy, He has no allergies, stopped smoking in 2002, and denied any alcohol or drug use

    1. 10

      Case9: No assertion made on age, gender or ethnicity

      DiseaseAssertion: Glanzmann thrombasthenia

      FamilyInfo: N/A

      ParentalGenotype: The identified variants were heterozygote in parents.

      CasePresentingHPOs: HP:0005542

      (Prolonged clotting time)

      CaseHPOFreeText: Bleeding time greater than 20 minutes and hematocrit of 38.1%

      CaseNotHPOs: N/A

      CaseNotHPOsFreeText: N/A

      ProteinExpression: N/A

      PlateletAggregation: N/A

      CasePreviousTesting: Genetic study of patient was conducted using direct sequencing of entire coding and exon-intron boundaries of the ITGA2B and ITGB3 genes.

      Gene: ITGA2B

      Variant: NM_000419.3:c.1392A>G (p.Pro464Pro)

      LegacyVariant: N/A

      ClinVar: N/A

      CAiD: CA500273575

      gnomAD: https://gnomad.broadinstitute.org/variant/17-42458248-T-C

    2. 3

      Case3: No assertion made on age, gender or ethnicity

      DiseaseAssertion: Glanzmann thrombasthenia

      FamilyInfo: N/A

      ParentalGenotype: The identified variants were heterozygote in parents.

      CasePresentingHPOs: HP:0000978, HP:0005542

      (Easy bruising, prolonged clotting time)

      CaseHPOFreeText: Bleeding time greater than 20 minutes,

      CaseNotHPOs: N/A

      CaseNotHPOsFreeText: N/A

      ProteinExpression: N/A

      CasePreviousTesting: Genetic study of patient was conducted using direct sequencing of entire coding and exon-intron boundaries of the ITGA2B and ITGB3 genes.

      Gene: ITGB3

      Variant: NM_000212.2:c.401del (p. Glu134GlyfsTer10)

      LegacyVariant: N/A

      ClinVar: N/A

      CAiD: CA915940222

      gnomAD: N/A

    1. RL

      Case4: Patient RL

      DiseaseAssertion: Glanzmann thrombasthenia

      FamilyInfo: N/A

      ParentalGenotype: N/A

      CasePresentingHPOs:

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOsFreeText: N/A

      ProteinExpression: N/A

      PlateletAggregation: N/A

      CasePreviousTesting: The amplification of DNA fragments using PCR and their electrophoretic migration through a denaturing gradient was used to scan the entire coding region, splice site junctions and promoter regions of the GPIIb and GPIIIa genes for all 20 patients in this study

      Gene: ITGA2B

      Variant: NM_000419.3:c.1544+1G>A

      LegacyVariant: N/A

      ClinVar: 2895

      CAiD: CA10575473

      gnomAD: N/A

    2. ProSsyl

      Case11: Patient Ssyl

      DiseaseAssertion: Glanzmann thrombasthenia

      FamilyInfo: N/A

      ParentalGenotype: N/A

      CasePresentingHPOs: N/A

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOsFreeText: N/A

      ProteinExpression: N/A

      PlateletAggregation: N/A

      CasePreviousTesting: The amplification of DNA fragments using PCR and their electrophoretic migration through a denaturing gradient was used to scan the entire coding region, splice site junctions and promoter regions of the GPIIb and GPIIIa genes for all 20 patients in this study

      Gene: ITGB3

      Variant: NM_000212.2:c.1955A>T (p.His652Leu)

      LegacyVariant: (p.His626Leu)

      ClinVar: N/A

      CAiD: CA400032927

      gnomAD: N/A

    1. Supplementary Table S1 & S2 Proband and Variant Information:

      Case20: GT23, Male, 19, French

      DiseaseAssertion: Glanzmann thrombasthenia

      FamilyInfo: N/A

      ParentalGenotype: N/A

      CasePresentingHPOs: HP:0000978, HP:0000225, HP:0000421

      (Easy bruising, gingival bleeding, epistaxis)

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOsFreeText: N/A

      ProteinExpression: Flow cytometry showed <5% expression of αIIbβ3 (See Supplementary Table 1)

      PlateletAggregation: Absent platelet aggregation (See Supplementary Table 1)

      CasePreviousTesting: Sanger sequencing of ITGA2B and ITGB3

      Gene: ITGB3

      Variant: NM_000212.2:c.1031A>C (p.Tyr344Ser)

      LegacyVariant: N/A

      ClinVar: N/A

      CAiD: CA400025814

      gnomAD: N/A

    2. Supplementary Table S1 & S2 Proband and Variant Information:

      Case6: GT7, Female, 19, French

      DiseaseAssertion: Glanzmann thrombasthenia

      FamilyInfo: 1 brother, that is all the information Supp table S1 gives us

      ParentalGenotype: N/A

      CasePresentingHPOs: HP:0000978 and HP:0000421

      (Easy bruising and epistaxis)

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOsFreeText: N/A

      ProteinExpression: Flow cytometry showed <10-15% expression of αIIbβ3 (See Supplementary Table 1)

      PlateletAggregation: Absent ADP but some response with other agonists (See Supplementary Table 1)

      CasePreviousTesting: Sanger sequencing of ITGA2B and ITGB3

      Gene: ITGB3

      Variant: NM_000212.2:c.187C>T (p.Arg63Cys) and NM_000212.2:c.505C>T (p.Arg169Ter)

      LegacyVariant: N/A

      ClinVar: 631774

      CAiD: CA8622892 and CA291224658

      gnomAD: MAF in the East Asian population is 0.00005012 http://gnomad.broadinstitute.org/variant/17-45360741-C-T

    3. Supplementary Table S1 & S2 Proband and Variant Information:

      Case9: GT10, Male, 45, French and Italian

      DiseaseAssertion: Glanzmann thrombasthenia

      FamilyInfo: N/A

      ParentalGenotype: N/A

      CasePresentingHPOs: N/A

      CaseHPOFreeText: Mild lifelong bleeding

      CaseNotHPOs: N/A

      CaseNotHPOsFreeText: N/A

      ProteinExpression: Flow cytometry showed 30-50% variant expression of αIIbβ3 (See Supplementary Table 1)

      PlateletAggregation: Residual platelet aggregation (See Supplementary Table 1)

      CasePreviousTesting: Sanger sequencing of ITGA2B and ITGB3

      Gene: ITGA2B

      Variant: NM_000419.3:c.1440-13_1440-1del (p.Arg480Serfs*106) and NM_000419.3:c.3077G>A (p.Arg1026Gln)

      LegacyVariant: N/A

      ClinVar: 50232

      CAiD: CA913184940 and CA10575572

      gnomAD: MAF in the European (non-Finnish) population 0.00006482 http://gnomad.broadinstitute.org/variant/17-45363676-T-C and MAF in the European (non-Finnish) population is 0.000008801 http://gnomad.broadinstitute.org/variant/17-42449775-C-T

    4. Supplementary Table S1 & S2 Proband and Variant Information:

      Case10: GT11, Female, 54, French and German

      DiseaseAssertion: Glanzmann thrombasthenia

      FamilyInfo: N/A

      ParentalGenotype: N/A

      CasePresentingHPOs: HP:0000421, HP:0000225, HP:0000132

      (Epistaxis, gingival bleeding, menorrhagia)

      CaseHPOFreeText: Spontaneous bruising

      CaseNotHPOs: N/A

      CaseNotHPOsFreeText: N/A

      ProteinExpression: Flow cytometry showed 10-15% variant expression of αIIbβ3 (See Supplementary Table 1)

      PlateletAggregation: Absent platelet aggregation (See Supplementary Table 1)

      CasePreviousTesting: Sanger sequencing of ITGA2B and ITGB3

      Gene: ITGA2B

      Variant: NM_000419.3:c.1073G>A (p.Arg358His) and NM_000419.3:c.1234G>A (p.Gly412Arg)

      LegacyVariant: N/A

      ClinVar: 2896 and 381748

      CAiD: CA115839 and CA8603182

      gnomAD: MAF in the Latino population is 0.0001453 http://gnomad.broadinstitute.org/variant/17-42458406-C-T

    5. Supplementary Table S1 & S2 Proband and Variant Information:

      Case54: GT54, Male, 33, Argintinian/Italian

      DiseaseAssertion: Glanzmann thrombasthenia

      FamilyInfo: N/A

      ParentalGenotype: N/A

      CasePresentingHPOs: HP:0000225, HP:0006298

      (Gingival bleeding, bleeding following tooth extraction)

      CaseHPOFreeText: Hematomas

      CaseNotHPOs: N/A

      CaseNotHPOsFreeText: N/A

      ProteinExpression: Flow cytometry showed <5% expression of αIIbβ3 (See Supplementary Table 1)

      PlateletAggregation: Absent platelet aggregation (See Supplementary Table 1)

      CasePreviousTesting: Sanger sequencing of ITGA2B and ITGB3

      Gene: ITGB3

      Variant: NM_000212.2:c.2014+1G>A and a "LR deletion variant" as mentioned in Sup Table 1

      LegacyVariant: N/A

      ClinVar: N/A

      CAiD: CA400033055

      gnomAD: N/A

    1. 1CabGT-1

      Case1: (Proband CabGT-1) Male, age not specified, China

      DiseaseAssertion: Glanzmann thrombasthenia

      FamilyInfo: N/A

      ParentalGenotype: N/A

      CasePresentingHPOs: N/A

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      ProteinExpression: Surface expression detected by flow cytometry showed <5% GPIIb and <5% GPIIIa

      Platelet Aggregation: N/A

      CasePreviousTesting: Promoter and exon sequences of aIIb and b3 genes were amplified and directly sequence

      Gene: ITGA2B

      Variant: NM_000419.3:c.531T>A (p.Cys177Ter)

      LegacyVariant: N/A

      ClinVar: N/A

      CAiD: CA290955739

      gnomAD N/A

    2. 7CabGT-7

      Case7: (Proband CabGT-7) Female, age not specified, Caucasian

      DiseaseAssertion: Glanzmann thrombasthenia

      FamilyInfo: N/A

      ParentalGenotype: N/A

      CasePresentingHPOs: N/A

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      ProteinExpression: Flow cytometry showed <5% GPIIb and 11% GPIIIa surface expression

      Platelet Aggregation: N/A

      CasePreviousTesting: Promoter and exon sequences of aIIb and b3 genes were amplified and directly sequence

      Gene: ITGA2B

      Variant: The first variant was found to be: NM_000419.3:c.1563T>A (p.Cys521Ter) and they did not find the second mutation

      LegacyVariant: N/A

      ClinVar: N/A

      CAiD: CA290950094

      gnomAD N/A

    3. 3CabGT-3

      Case3: (Proband CabGT-3), Male, age not specified, European Caucasian

      DiseaseAssertion: Glanzmann thrombasthenia

      FamilyInfo: N/A

      ParentalGenotype: N/A

      CasePresentingHPOs: N/A

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      ProteinExpression: N/A

      Platelet Aggregation: N/A

      CasePreviousTesting: Promoter and exon sequences of aIIb and b3 genes were amplified and directly sequence

      Gene: ITGA2B

      Variant: NM_000419.3:c.1214T>C (p.Ile405Thr) and c.1442-13_1442-1del, which is not showing up in CAR (Unregistered Variant?)

      LegacyVariant: N/A

      ClinVar: N/A

      CAiD: CA290950815 (p.Ile405Thr)

      gnomAD N/A

    4. 9CabGT-9

      Case9: (Proband CabGT-9), Female, age not specified, Kuwait

      DiseaseAssertion: Glanzmann thrombasthenia

      FamilyInfo: N/A

      ParentalGenotype: N/A

      CasePresentingHPOs: N/A

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      ProteinExpression: N/A

      Platelet Aggregation: N/A

      CasePreviousTesting: Promoter and exon sequences of aIIb and b3 genes were amplified and directly sequence

      Gene: ITGA2B

      Variant: NM_000419.3:c.1879-2A>G

      LegacyVariant: N/A

      ClinVar: N/A

      CAiD: CA290949031

      gnomAD N/A

    1. Supplementary Table S1:

      Case41: GT48, French, gender and age not specified here at this time

      DiseaseAssertion: Glanzmann thrombasthenia type I

      FamilyInfo: N/A

      ParentalGenotype: N/A

      CasePresentingHPOs: N/A

      CaseHPOFreeText: All patients had a life-long history of mucocutaneous bleeding

      CaseNotHPOs: N/A

      CaseNotHPOsFreeText: N/A

      ProteinExpression: All patients in this study met the clinical and platelet function requirements for GT-- this includes an absent or strongly reduced expression of alphaIIbBeta3 in platelets

      PlateletAggregation: All patients in this study met the clinical and platelet function requirements for GT-- this includes absent or severely reduced platelet aggregation with at least three physiological agonists

      CasePreviousTesting: Sanger sequencing was performed. Sanger sequencing ensured coverage of all exons and splice sties of the ITGA2B and ITGB3 genes and extended 300-500 bp into the introns as well as including the UTR. They sequenced 416 bp upstream of the ITGA2B promoter and 463 bp upstream of the ITGB3 promoter. In total they sequenced 51.2% of the ITGA2B gene and 19.4% of the larger ITGB3 gene

      Gene: ITGB3

      Variant: NM_000212.2:c.1094A>G (p.Asn365Ser) and NM_000212.2:c.1522del (p.Gln508SerfsTer161)

      LegacyVariant: N/A

      ClinVar: N/A

      CAiD: CA400026292 and CA772541579

      gnomAD: N/A

    2. Supplementary Table S1:

      Case23: GT26, French, gender and age not specified

      DiseaseAssertion: Glanzmann thrombasthenia type I

      FamilyInfo: N/A

      ParentalGenotype: N/A

      CasePresentingHPOs: N/A

      CaseHPOFreeText: All patients had a life-long history of mucocutaneous bleeding

      CaseNotHPOs: N/A

      CaseNotHPOsFreeText: N/A

      ProteinExpression: All patients in this study met the clinical and platelet function requirements for GT-- this includes an absent or strongly reduced expression of alphaIIbBeta3 in platelets

      PlateletAggregation: All patients in this study met the clinical and platelet function requirements for GT-- this includes absent or severely reduced platelet aggregation with at least three physiological agonists

      CasePreviousTesting: Sanger sequencing was performed. Sanger sequencing ensured coverage of all exons and splice sties of the ITGA2B and ITGB3 genes and extended 300-500 bp into the introns as well as including the UTR. They sequenced 416 bp upstream of the ITGA2B promoter and 463 bp upstream of the ITGB3 promoter. In total they sequenced 51.2% of the ITGA2B gene and 19.4% of the larger ITGB3 gene

      Gene: ITGA2B

      Variant: NM_000419.3:c.1073G>A (p.Arg358His)

      LegacyVariant: N/A

      ClinVar: 2896

      CAiD: CA115839

      gnomAD: N/A

    3. Supplementary Table S1:

      Case10: GT11, French/German, age and gender not specified

      DiseaseAssertion: Glanzmann thrombasthenia type I

      FamilyInfo: N/A

      ParentalGenotype: N/A

      CasePresentingHPOs: N/A

      CaseHPOFreeText: All patients had a life-long history of mucocutaneous bleeding

      CaseNotHPOs: N/A

      CaseNotHPOsFreeText: N/A

      ProteinExpression: All patients in this study met the clinical and platelet function requirements for GT-- this includes an absent or strongly reduced expression of alphaIIbBeta3 in platelets

      PlateletAggregation: All patients in this study met the clinical and platelet function requirements for GT-- this includes absent or severely reduced platelet aggregation with at least three physiological agonists

      CasePreviousTesting: Sanger sequencing was performed. Sanger sequencing ensured coverage of all exons and splice sties of the ITGA2B and ITGB3 genes and extended 300-500 bp into the introns as well as including the UTR. They sequenced 416 bp upstream of the ITGA2B promoter and 463 bp upstream of the ITGB3 promoter. In total they sequenced 51.2% of the ITGA2B gene and 19.4% of the larger ITGB3 gene

      Gene: ITGA2B

      Variant: NM_000419.3:c.1073G>A (p.Arg385His) NM_000419.3:c.1234G>A (p.Gly412Arg)

      LegacyVariant: N/A

      ClinVar: 2896 and 381748

      CAiD: CA115839 and CA8603182

      gnomAD: MAF in the Latino population for (p.Gly412Arg) is 0.0001453 https://gnomad.broadinstitute.org/variant/17-42458406-C-T

    4. Supplementary Table S1:

      Case65: GT76, French, gender and age are not specified

      DiseaseAssertion: Glanzmann thrombasthenia type I

      FamilyInfo: N/A

      ParentalGenotype: N/A

      CasePresentingHPOs: N/A

      CaseHPOFreeText: All patients had a life-long history of mucocutaneous bleeding

      CaseNotHPOs: N/A

      CaseNotHPOsFreeText: N/A

      ProteinExpression: All patients in this study met the clinical and platelet function requirements for GT-- this includes an absent or strongly reduced expression of alphaIIbBeta3 in platelets

      PlateletAggregation: All patients in this study met the clinical and platelet function requirements for GT-- this includes absent or severely reduced platelet aggregation with at least three physiological agonists

      CasePreviousTesting: Sanger sequencing was performed. Sanger sequencing ensured coverage of all exons and splice sties of the ITGA2B and ITGB3 genes and extended 300-500 bp into the introns as well as including the UTR. They sequenced 416 bp upstream of the ITGA2B promoter and 463 bp upstream of the ITGB3 promoter. In total they sequenced 51.2% of the ITGA2B gene and 19.4% of the larger ITGB3 gene

      Gene: ITGA2B

      Variant: NM_000419.3:c.2421G>A (p.Trp807Ter)

      LegacyVariant: N/A

      ClinVar: N/A

      CAiD: CA399796017

      gnomAD: N/A

    5. Supplementary Table S1:

      Case47: GT54, Arg/Italian, gender and age not specified

      DiseaseAssertion: Glanzmann thrombasthenia type I

      FamilyInfo: N/A

      ParentalGenotype: N/A

      CasePresentingHPOs: N/A

      CaseHPOFreeText: All patients had a life-long history of mucocutaneous bleeding

      CaseNotHPOs: N/A

      CaseNotHPOsFreeText: N/A

      ProteinExpression: All patients in this study met the clinical and platelet function requirements for GT-- this includes an absent or strongly reduced expression of alphaIIbBeta3 in platelets

      PlateletAggregation: All patients in this study met the clinical and platelet function requirements for GT-- this includes absent or severely reduced platelet aggregation with at least three physiological agonists

      CasePreviousTesting: Sanger sequencing was performed. Sanger sequencing ensured coverage of all exons and splice sties of the ITGA2B and ITGB3 genes and extended 300-500 bp into the introns as well as including the UTR. They sequenced 416 bp upstream of the ITGA2B promoter and 463 bp upstream of the ITGB3 promoter. In total they sequenced 51.2% of the ITGA2B gene and 19.4% of the larger ITGB3 gene

      Gene: ITGB3

      Variant: NM_000212.2:c.2014+5G>A and the other variant is a "LR deletion" which is all thats mentioned

      LegacyVariant: N/A

      ClinVar: N/A

      CAiD: CA915940701

      gnomAD: N/A

    1. F1P1

      Case1: Patient F1P1, Male, 11 years old, Tunisian

      DiseaseAssertion: Glanzmann thrombasthenia type I

      FamilyInfo: Table 1 states there is a family history of bleeding (we have minimal to no specific info on this)

      ParentalGenotype: N/A

      CasePresentingHPOs: HP:0000225, HP:0000978

      (Gingival bleeding, easy bruising)

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOsFreeText: N/A

      ProteinExpression: N/A

      PlateletAggregation: GT diagnosis was based on absent platelet aggregation induced by ADP, collagen, and TRAP and subnormal or cyclical ristocetin induced agglutination

      CasePreviousTesting: Using PCR they successfully amplified 20 DNA fragments for the ITGA2B gene (covering more than 48% of the ITGA2B gene constituting 30 exons) and15 DNA fragments of theITGB3gene (covering 15 exons)

      Gene: ITGB3

      Variant: NM_000212.2:c.176T>C (p.Leu59Pro) and NM_000212.2:c.1143A>C (p.Val381Val) and NM_000212.2:c.1545G>A (p.Arg515Arg) and the other variant stated here is g.41037G>C which I am marking as an Unknown Variant-- biocurator should look at this and determine variant

      LegacyVariant: N/A

      ClinVar: 13558 (p.Leu59Pro), 255535 (p.Val381Val), 255537 (p.Arg515Arg)

      CAiD: CA123235 (p.Leu59Pro), CA8623175 (p.Val381Val), CA8623284 (p.Arg515Arg)

      gnomAD: MAF in the Ashkenazi Jewish population is 0.1565 https://gnomad.broadinstitute.org/variant/17-45360730-T-C for (p.Leu59Pro) and MAF in the East Asian population is 0.5857 https://gnomad.broadinstitute.org/variant/17-45368337-A-C for (p.Val381Val) and MAF in the East Asian population for (p.Arg515Arg) is 0.3455 https://gnomad.broadinstitute.org/variant/17-45369789-G-A

    1. 6

      Case6: Female, Iraq, age not specified

      DiseaseAssertion: Glanzmann thrombasthenia

      FamilyInfo: Table 1 mentions family history available for the proband, however no specific details about family provided in paper

      ParentalGenotype: N/A

      CasePresentingHPOs: HP:0000421, HP:0000225, HP:0000132, HP:0031364

      (Epistaxis, gingival bleeding, menorrhagia, ecchymosis)

      CaseHPOFreeText: Post-partum bleeding

      CaseNotHPOs: N/A

      CaseNotHPOsFreeText: N/A

      ProteinExpression: N/A

      PlateletAggregation: N/A

      CasePreviousTesting: N/A

      Gene: ITGB3

      Variant: NM_000212.2:c.2031_2041del (p.Asp677Glufs)

      LegacyVariant: (p.Asp651Glufs*3)

      ClinVar: N/A

      CAiD: CA915940605

      gnomAD: N/A

    2. 13

      Case13: Female, Iraq, age not specified

      DiseaseAssertion: Glanzmann thrombasthenia

      FamilyInfo: Table 1 mentions family history available for the proband, however no specific details about family provided in paper

      ParentalGenotype: N/A

      CasePresentingHPOs: HP:0000421, HP:0000225, HP:0031364, HP:0000132, HP:0002239, HP:0002573

      (Epistaxis, gingival bleeding, ecchymosis, menorrhagia, gastrointestinal bleeding, rectal bleeding)

      CaseHPOFreeText: Haemarthrosis, DIC

      CaseNotHPOs: N/A

      CaseNotHPOsFreeText: N/A

      ProteinExpression: N/A

      PlateletAggregation: N/A

      CasePreviousTesting: N/A

      Gene: ITGB3

      Variant: NM_000212.2:c.2031_2041del (p.Asp677Glufs)

      LegacyVariant: (p.Asp651Glufs*3)

      ClinVar: N/A

      CAiD: CA915940605

      gnomAD: N/A

    3. 14

      Case14: Female, Arab, age not specified

      DiseaseAssertion: Glanzmann thrombasthenia

      FamilyInfo: Table 1 mentions family history available for the proband, however no specific details about family provided in paper

      ParentalGenotype: N/A

      CasePresentingHPOs: HP:0000421, HP:0000225, HP:0031364, HP:0000132

      (Epistaxis, gingival bleeding, ecchymosis, menorrhagia)

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOsFreeText: N/A

      ProteinExpression: N/A

      PlateletAggregation: N/A

      CasePreviousTesting: N/A

      Gene: ITGA2B

      Variant: NM_000419.3:c.409-2_419del

      LegacyVariant: N/A

      ClinVar: 2889

      CAiD: CA10575471

      gnomAD: N/A

    4. 16

      Case16: Male, Arab, age not specified

      DiseaseAssertion: Glanzmann thrombasthenia

      FamilyInfo: Table 1 mentions family history available for the proband, however no specific details about family provided in paper

      ParentalGenotype: N/A

      CasePresentingHPOs: N/A

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOsFreeText: N/A

      ProteinExpression: N/A

      CasePreviousTesting: N/A

      Gene: ITGA2B

      Variant: NM_000419.3:c.409-2_419del

      LegacyVariant: N/A

      ClinVar: 2889

      CAiD: CA10575471

      gnomAD: N/A

    1. M/10

      Case2: Male, 10 years old, Andra Pradesh India

      DiseaseAssertion: Glanzmann thrombasthenia

      FamilyInfo: N/A

      ParentalGenotype: N/A

      CasePresentingHPOs: HP:0000421, HP:0031364, HP:0002239, HP:0000225

      (Epistaxis, ecchymosis, GI bleeding, gingival bleeding)

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOsFreeText: N/A

      ProteinExpression: See Table 1 for values

      PlateletAggregation: See Table 1 for values

      CasePreviousTesting: PCR amplification of ITAG2B and ITGB3

      Gene: ITGA2B

      Variant: NM_000419.3:c.475G>A (p.Gly159Ser)

      LegacyVariant: (p.Gly128Ser)

      ClinVar: N/A

      CAiD: CA8603454

      gnomAD: MAF in the South Asian population is 0.00003267 https://gnomad.broadinstitute.org/variant/17-42463018-C-T

    2. M/13

      Case1: Male, 13 years old, Andra Pradesh India

      DiseaseAssertion: Glanzmann thrombasthenia

      FamilyInfo: N/A

      ParentalGenotype: N/A

      CasePresentingHPOs: HP:0006298, HP:0000421, HP:0000967, HP:0002239, HP:0000225

      (Prolonged bleeding after dental extraction, epistaxis, petechiae, GI bleeding, gingival bleeding)

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOsFreeText: N/A

      ProteinExpression: See Table 1 for values

      PlateletAggregation: See Table 1 for values

      CasePreviousTesting: PCR amplification of ITAG2B and ITGB3

      Gene: ITGA2B

      Variant: NM_000419.3:c.48G>A (p.Trp16Ter)

      LegacyVariant: N/A

      ClinVar: N/A

      CAiD: CA399807046

      gnomAD: N/A

    1. .

      Case4: No gender, age, or ethnicity provided. Patient followed in Germany

      DiseaseAssertion: Glanzmann thrombasthenia

      FamilyInfo: N/A

      ParentalGenotype: N/A

      CasePresentingHPOs: N/A

      CaseHPOFreeText: Severe bleeding

      CaseNotHPOs: N/A

      CaseNotHPOsFreeText: N/A

      ProteinExpression: N/A

      PlateletAggregation: Minimal information, not specific enough

      CasePreviousTesting: Sanger sequencing identified disease-causing variants in 18 out of 20 patients (Probands 6 and 14 excluded) with istoantibodies to αIIbβ3. The mutations were evenly distributed between ITGB3 and ITGA2B.

      Gene: ITGB3

      Variant: NM_000212.2:c.1717T>C (p.Cys573Arg)

      LegacyVariant: N/A

      ClinVar: N/A

      CAiD: CA400032387

      gnomAD: N/A

    1. The French patient who is the object of this study is now an elderly male with a lifelong but mild bleeding disorder

      Case1: Male, French, age not specified

      DiseaseAssertion: Glanzmann thrombasthenia

      FamilyInfo: N/A "Has no surviving close relatives"

      ParentalGenotype:

      CasePresentingHPOs: HP:0002239 (GI bleeding)

      CaseHPOFreeText: Hemorrhage

      CaseNotHPOs: HP:0000421, HP:0000225

      (Epistaxis, gingival bleeding)

      CaseNotHPOsFreeText: N/A

      ProteinExpression:

      PlateletAggregation: Total lack of platelet aggregation in response to physiologic agonists and also defective clot retraction

      CasePreviousTesting: Direct sequencing of all exons and splice sites of ITGA2B was performed and sequencing of the 15 exons, splice sites, and promoter of ITGB3 was also performed

      Gene: ITGA2B

      Variant: NM_000419.3:c.1413C>G (p.Tyr471Ter) and NM_000419.3:c.1882C>T (p.Arg628Ter)

      LegacyVariant: N/A

      ClinVar: N/A

      CAiD: CA290950376 and CA399801310

      gnomAD: MAF in European (non-Finnish) population 0.000008791 http://gnomad.broadinstitute.org/variant/17-42457994-G-C and MAF in the Latino population is 0.00003983 http://gnomad.broadinstitute.org/variant/17-42456075-G-A

    1. M8

      Case16: (M8) Male, 47 years old, French Gypsy

      DiseaseAssertion: Glanzmann thrombasthenia

      FamilyInfo: N/A

      ParentalGenotype: N/A

      CasePresentingHPOs: N/A

      CaseHPOFreeText: Mucocutaneous bleeding

      CaseNotHPOs: N/A

      ProteinExpression: Failed to express alphaIIbbeta3 on the surface of their platelets

      Platelet Aggregation: Absent platelet aggregation to all agonists (no mention for which agonists or response to ristocetin)

      CasePreviousTesting: All the information we are given is "mutation screening of the ITGA2B and ITGB3 genes" the method for sequencing etc. was not stated

      Gene: ITGA2B

      Variant: NM_000419.3:c.1544+1G>A

      LegacyVariant: N/A

      ClinVar: 2895

      CAiD: CA10575473

      gnomAD N/A

    1. Supplementary Tables 1 and 2 combined information:

      Case20a: GT20a, Male, 30 years old

      DiseaseAssertion: Glanzmann thrombasthenia

      FamilyInfo: Family information available in Table1 (brother of GT20b)

      ParentalGenotype: Parents are consanguineous, no other genotype information available

      CasePresentingHPOs: HP:0000225

      (Gingival bleeding)

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOsFreeText: N/A

      ProteinExpression: Showed <5% of αIIbβ3 expression measured by flow cytometry

      PlateletAggregation: Platelet aggregation showed no response to ADP and collagen but normal response to ristocetin

      CasePreviousTesting: All exons from ITGA2B and ITGB3 genes were amplified by PCR using intronic primers. DNA sequencing was determined by Sanger sequencing.

      Gene: ITGA2B

      Variant: NM_000419.3:c.1882C>T (p.Arg628Ter)

      LegacyVariant: N/A

      ClinVar: N/A

      CAiD: CA399801310

      gnomAD: MAF in Latino population: 0.00003983 https://gnomad.broadinstitute.org/variant/17-42456075-G-A

    2. Supplementary Tables 1 and 2 combined information:

      Case42: GT42, Female, 9 years old

      DiseaseAssertion: Glanzmann thrombasthenia

      FamilyInfo: Not available per supplementary table 1

      ParentalGenotype: Parents are consanguineous, no other genotype information available

      CasePresentingHPOs: HP:0000978, HP:0000979, HP:0031364, HP:0000421

      (Bruising, purpura, ecchymosis, epistaxis)

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOsFreeText: N/A

      ProteinExpression: Showed <5% of αIIbβ3 expression measured by flow cytometry

      PlateletAggregation: Platelet aggregation showed no response to ADP and collagen but normal response to ristocetin

      CasePreviousTesting: All exons from ITGA2B and ITGB3 genes were amplified by PCR using intronic primers. DNA sequencing was determined by Sanger sequencing.

      Gene: ITGB3

      Variant: NM_000212.2:c.1300del (p.Gln434fs) Note in google doc to ask

      LegacyVariant: N/A

      ClinVar: N/A

      CAiD: CA915940256

      gnomAD: N/A

    1. Supplemental Table S1:

      Cases6-11: Males and Females from India/Pakistan, ages not specified

      DiseaseAssertion: Glanzmann thrombasthenia

      FamilyInfo: N/A

      ParentalGenotype: N/A

      CasePresentingHPOs: N/A

      CaseHPOFreeText: Moderate to severe bleeding tendency in these patients

      CaseNotHPOs: N/A

      CaseNotHPOsFreeText: N/A

      ProteinExpression: <5% αIIbβ3 expression

      PlateletAggregation: Absent platelet aggregation (all the information that is provided in Supp. Table S1)

      CasePreviousTesting: Sanger sequencing of exons, splice sites and untranslated regions of the ITGA2B and ITGB3 genes was performed

      Gene: ITGA2B

      Variant: NM_000419.3:c.1652G>A (p.Arg551Gln)

      LegacyVariant: N/A

      ClinVar: N/A

      CAiD: CA8602986

      gnomAD: MAF in the South Asian population is 0.00006536 https://gnomad.broadinstitute.org/variant/17-42457470-C-T

      PreviouslyPublished: PMID: 19172520 and 26896847

    2. Supplemental Table S1:

      Cases 13-18: Males and Females, from Sweden, France and Germany and other places, ages are not specified

      DiseaseAssertion: Glanzmann thrombasthenia

      FamilyInfo: N/A

      ParentalGenotype: N/A

      CasePresentingHPOs: N/A

      CaseHPOFreeText: Moderate to severe bleeding when data was available

      CaseNotHPOs: N/A

      CaseNotHPOsFreeText: N/A

      ProteinExpression: 5%/<5% when homozygous αIIbβ3 expression

      PlateletAggregation: Absent platelet aggregation (all the information that is provided in Supp. Table S1)

      CasePreviousTesting: Sanger sequencing of exons, splice sites and untranslated regions of the ITGA2B and ITGB3 genes was performed

      Gene: ITGA2B

      Variant: NM_000419.3:c.1787T>C (p.Ile596Thr)

      LegacyVariant: N/A

      ClinVar: 2900

      CAiD: CA115846

      gnomAD: MAF in the European non finnish pop is 0.0001325 https://gnomad.broadinstitute.org/variant/17-42457148-A-G

      PreviouslyPublished: PMID: 9215749, 9734640, 20020534, 22513797, 25373348

    1. The proband, a 35-year old woman from southern Italy,

      Case1: Female, 35 years old, Italian

      DiseaseAssertion: Macrothromocytopenia

      FamilyInfo: See Supp. Fig S1 for pedigree

      ParentalGenotype: See Supp. Fig S1 for pedigree

      CasePresentingHPOs: N/A

      CaseHPOFreeText: Life-long moderate to severe bleeding, mainly mucocutaneous

      CaseNotHPOs: N/A

      CaseNotHPOsFreeText: No abnormalities in blood clotting

      ProteinExpression: Flow cytometry showed mild reduction of surface αIb β3

      PlateletAggregation: Impaired platelet aggregation to physiological agonists but not to ristocetin,

      CasePreviousTesting: ITGA2B and ITGB3 were amplified and sequenced

      Gene: ITBG3

      Variant: NM_000212.2:c.2134+1G>C

      LegacyVariant: N/A

      ClinVar: 50228

      CAiD: CA143711

      gnomAD: N/A

    1. B

      Case2: Patient ID B, Male, 16 years old, ethnicity not specified

      DiseaseAssertion: Glanzmann thrombasthenia

      FamilyInfo: Table 1 asserts family information is provided; however, minimal information

      ParentalGenotype: N/A

      CasePresentingHPOs: HP:0004406, HP:0000225

      (Recurrent epsitaxis, gingival bleeding)

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOsFreeText: N/A

      ProteinExpression: N/A

      PlateletAggregation: Defective response to ADP, adrenaline, collagen, arachidonic acid, and normal response to ristocetin

      CasePreviousTesting: Exon PCR was used to amplify a;; coding regions of the ITGA2B and ITGB3 genes. PCR products were purified and Sanger sequenced. Segregation using parental samples was undertaken when available.

      Gene: ITGA2B

      Variant: NM_000419.3:c.641T>G (p.Leu214Arg)

      LegacyVariant: N/A

      ClinVar: N/A

      CAiD: CA399805518

      gnomAD: MAF in South Asian population 0.00003266 http://gnomad.broadinstitute.org/variant/17-42462561-A-C

    2. O

      Case15: Patient ID O, Female, 7 years old, ethnicity not specified

      DiseaseAssertion: Glanzmann thrombasthenia

      FamilyInfo: N/A

      ParentalGenotype: N/A

      CasePresentingHPOs: HP:0004406, HP:0000225

      (Recurrent epistaxis, gingival bleeding)

      CaseHPOFreeText: N/A

      CaseNotHPOs: HP:0000967, HP:0000979, HP:0000978, HP:0002239, HP:0002239, HP:0000790, HP:0005261, HP:0002248

      (Petechiae, purpura, easy bruising, GI bleeding, intracranial hemorrhage, hematuria, hemarthrosis, hematemesis)

      CaseNotHPOsFreeText: Hemorrhage after dental, hemorrhage after trauma, ear bleeding, hematoma

      ProteinExpression: N/A

      PlateletAggregation: Defective response to ADP, adrenaline, collagen, arachidonic acid, and normal response to ristocetin

      CasePreviousTesting: Exon PCR was used to amplify coding regions of the ITGA2B and ITGB3 genes. PCR products were purified and Sanger sequenced. Segregation using parental samples was undertaken when available

      Gene: ITGB3

      Variant: NM_000212.2:c.2080C>T (p.Gln694Ter)

      LegacyVariant: N/A

      ClinVar: N/A

      CAiD: CA400033218

      gnomAD: N/A

    3. H

      Case8: Patient ID H, Female, 8 years old, ethnicity not specified

      DiseaseAssertion: Glanzmann thrombasthenia

      FamilyInfo: N/A (Table 1 does mention family history of bleeding)

      ParentalGenotype: N/A (Parents are consangenous)

      CasePresentingHPOs: HP:0000978, HP:0004406, HP:0000225, HP:0002239, HP:0005261

      (Easy bruising, recurrent epistaxis, gingival bleeding, GI bleeding, hemarthrosis)

      CaseHPOFreeText: Hemorrhage after dental, hemorrhage after trauma, ear bleeding

      CaseNotHPOs: HP:0000967, HP:0000979, HP:0002239, HP:0000790, HP:0002248

      (Petechiae, purpura, intracranial hemorrhage, hematuria, hematemesis)

      CaseNotHPOsFreeText: Hematoma

      ProteinExpression: N/A

      PlateletAggregation: Defective response to ADP, adrenaline, collagen, arachidonic acid, and normal response to ristocetin

      CasePreviousTesting: Exon PCR was used to amplify a;; coding regions of the ITGA2B and ITGB3 genes. PCR products were purified and Sanger sequenced. Segregation using parental samples was undertaken when available.

      Gene: ITGA2B

      Variant: NM_000419.3:c.1652G>A

      LegacyVariant: N/A

      ClinVar: N/A

      CAiD: CA8602986

      gnomAD: MAF in South Asian population is 0.00006536 http://gnomad.broadinstitute.org/variant/17-42457470-C-T

      PreviouslyPublished: PMID: 19172520

    1. 1

      Case1: Male, 3.5 years old, Indian

      DiseaseAssertion: Glanzmann thrombasthenia

      FamilyInfo: N/A

      ParentalGenotype: N/A

      CasePresentingHPOs: (HP:0000421 Epistaxis)

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      ProteinExpression: Diagnosis of GT was made on the basis of quantitive determination of receptor count by flow cytometric analysis of GPIIb-IIIa

      PlateletAggregation: Diagnosis of GT was made on the basis of impaired platelet aggregation (platelet aggregation was tested against ristocetin, ADP, collagen, epinephrine and arachidonic acid)

      CasePreviousTesting: Multiplex PCR by using GPIIb primers and CSGE analysis were performed

      Gene: ITGA2B

      Variant: NM_000419.3:c.1286G>A (p.Asp396Asn)

      LegacyVariant: (p.Asp365Asn)

      ClinVar: N/A

      CAiD: CA399803675

      gnomAD: N/A

    1. ET

      Case31: Patient ET

      DiseaseAssertion: Glanzmann thrombasthenia

      FamilyInfo: N/A

      ParentalGenotype: N/A

      CasePresentingHPOs: HP:0000978, HP:0000421, HP:0000132

      (Bruising, epistaxis, menorrhagia)

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOsFreeText: N/A

      ProteinExpression: N/A

      PlateletAggregation: N/A

      CasePreviousTesting: N/A

      Gene: ITGB3

      Variant: NM_000212.2:c.719G>A (p.Arg240Gln)

      LegacyVariant: N/A

      ClinVar: 13553

      CAiD: CA123224

      gnomAD: N/A

      PreviouslyPublished: Reference 52

    2. 6FL

      Case6: Patient FL (found in the GT database) gender and age are not specified

      DiseaseAssertion: Glanzmann thrombasthenia

      FamilyInfo: N/A

      ParentalGenotype: N/A

      CasePresentingHPOs: HP:0000978, HP:0006298 Bruising and prolonged bleeding after tooth extraction

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOsFreeText: N/A

      ProteinExpression: 7-10% GPIIIa and GPIIb surface expression

      PlateletAggregation: N/A

      CasePreviousTesting: N/A

      Gene: ITGA2B

      Variant: NM_000419.3:c.1063G>A (p.Glu355Lys)

      LegacyVariant: (p.Glu324Lys)

      ClinVar: 2899

      CAiD: CA115844

      gnomAD: MAF in the European (non-Finnish) population is 0.00001978 https://gnomad.broadinstitute.org/variant/17-42461008-C-T

      PreviouslyPublished: Reference 17 in this article

    1. GT-63

      Case51: (GT-63) Female, age or ethnicity not specified

      DiseaseAssertion: Glanzmann thrombasthenia

      FamilyInfo: N/A

      ParentalGenotype: N/A

      CasePresentingHPOs: N/A

      CaseHPOFreeText: Bleeding severity: Severe (See Supplementary Table 3)

      CaseNotHPOs: N/A

      CaseNotHPOsFreeText: N/A

      ProteinExpression: Flow cytometry performed and CD41 and CD61 were observed (See Supplementary Table 3)

      PlateletAggregation: Minimal information (See Supplementary Table 3)

      CasePreviousTesting: DNA was extracted from peripheral blood samples from patients and family members, and Sanger sequencing and PCR was performed. Samples were processed for targeted sequencing using the available SHGp heme panel of 393 genes.

      Gene: ITGA2B

      Variant: NM_000419.3:c.558C>G (p.Tyr186Ter)

      LegacyVariant: N/A

      ClinVar: N/A

      CAiD: CA399805728

      gnomAD: N/A

    2. GT-50

      Case40: (GT-50) Male, age or ethnicity not specified

      DiseaseAssertion: Glanzmann thrombasthenia

      FamilyInfo: Proband GT49-GT52 are related

      ParentalGenotype: N/A

      CasePresentingHPOs: N/A

      CaseHPOFreeText: Bleeding severity: Information not available (See Supplementary Table 3)

      CaseNotHPOs: N/A

      CaseNotHPOsFreeText: N/A

      ProteinExpression: Flow cytometry performed and CD41 and CD61 were observed (See Supplementary Table 3)

      PlateletAggregation: Minimal information (See Supplementary Table 3)

      CasePreviousTesting: DNA was extracted from peripheral blood samples from patients and family members, and Sanger sequencing and PCR was performed. Samples were processed for targeted sequencing using the available SHGp heme panel of 393 genes.

      Gene: ITGB3

      Variant: NM_000212.2:c.2113del (p.Leu705Cysfs*4)

      LegacyVariant: N/A

      ClinVar: N/A

      CAiD: CA8623443

      gnomAD: MAF in East Asian population: 0.0001087 http://gnomad.broadinstitute.org/variant/17-45380183-TC-T

    1. TA

      Case12: Patient TA, gender, age and ethnicity not specified

      DiseaseAssertion: Glanzmann thrombasthenia type I

      FamilyInfo: His son is Patient TE

      ParentalGenotype: N/A

      CasePresentingHPOs: N/A

      CaseHPOFreeText: Bleeding symptoms were evaluated by examining available hospital records. Mild bleeders were defined as those who had minor symptoms, such as epistaxis or gum bleeds, and moderate bleeders suffered, in addition, from bleeding complications after surgery and trauma. Severe bleeders were defined as those with a history of spontaneous or life-threatening hemorrhages, such as gastrointestinal bleeding, or who had repeated episodes requiring platelet transfusion. See Table 1.

      CaseNotHPOs: N/A

      CaseNotHPOsFreeText: N/A

      ProteinExpression: See Table 6

      PlateletAggregation: See Table 6

      CasePreviousTesting: To ascertain the mutations, we sequenced the coding regions of the αIIb and β3 subunits including the exon/intron boundaries

      Gene: ITGA2B and ITGB3

      Variant: ITGA2B variant: NM_000419.3:c.3060G>A and ITGB3 variant: NM_000212.2:c.856G>A (p.Gly286Arg)

      LegacyVariant: N/A

      ClinVar: N/A

      CAiD: CA500261104 and CA400020688

      gnomAD: MAF in the European (non-Finnish) population is 0.00001760 https://gnomad.broadinstitute.org/variant/17-45364514-G-A for the ITGB3 variant

    2. OK

      Case1: Patient OK, gender, age, ethnicity not specified

      DiseaseAssertion: Glanzmann thrombasthenia type I

      FamilyInfo: N/A

      ParentalGenotype: N/A

      CasePresentingHPOs: N/A

      CaseHPOFreeText: Bleeding symptoms were evaluated by examining available hospital records. Mild bleeders were defined as those who had minor symptoms, such as epistaxis or gum bleeds, and moderate bleeders suffered, in addition, from bleeding complications after surgery and trauma. Severe bleeders were defined as those with a history of spontaneous or life-threatening hemorrhages, such as gastrointestinal bleeding, or who had repeated episodes requiring platelet transfusion. See Table 1.

      CaseNotHPOs: N/A

      CaseNotHPOsFreeText: N/A

      ProteinExpression: See Table 6

      PlateletAggregation: See Table 6

      CasePreviousTesting: To ascertain the mutations, we sequenced the coding regions of the αIIb and β3 subunits including the exon/intron boundaries

      Gene: ITGA2B

      Variant: NM_000419.3:c.620C>T (p.T207I)

      LegacyVariant: N/A

      ClinVar: N/A

      CAiD: CA399805570

      gnomAD: N/A

    1. Patientstudies.

      Case1: Female, 14 years old, German

      DiseaseAssertion: Glanzmann thrombasthenia

      FamilyInfo: N/A

      ParentalGenotype: N/A

      CasePresentingHPOs: HP:0000978 (Bruising)

      CaseHPOFreeText: Severe hemorrhage after tonsillectomy, bleeding after shedding off her deciduous teeth, prolonged cutaneous bleeding time > 20 minutes

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      ProteinExpression: Flow cytometry revealed that the proband expressed only 7-10% of GPIIb-IIIa on the platelet surface

      PlateletAggregation: Absent aggregation in response to ADP, collagen, epinephrine, and arachidonic acid but normal platelet aggregation in response to ristocetin

      CasePreviousTesting: Sequence analysis of PCR amplifeid platelet GPIIb mRNA was performed

      Gene: ITGA2B

      Variant: NM_000419.3:c.1073G>A (p.Arg358His)

      LegacyVariant: (p.Arg327His)

      ClinVar: 2896

      CAiD: CA115839

      gnomAD: N/A

    1. M4

      Case4: Patient M4, Male, French Gypsy, age is not specified

      DiseaseAssertion: Glanzmann thrombasthenia

      FamilyInfo: See Figure 2 for pedigree It shows this patient is unaffected

      ParentalGenotype: Unaffected parents see pedigree Fig 2

      CasePresentingHPOs: N/A

      CaseHPOFreeText: France, GT is particularly frequent in the Gypsy population, mainly represented by the Manouche tribe. Their clinical phenotype is the same as for classic type I disease, with a moderate and occasional severe bleeding syndrome

      CaseNotHPOs: N/A

      CaseNotHPOsFreeText: N/A

      ProteinExpression: Flow cytometry analysis has shown that these patients' surface expresses <5% of normal GPIIIa and GPIIb levels (we are not given an exact value for each proband)

      PlateletAggregation: "Absent platelet aggregation" this is all the information we are given for platelet aggregation

      CasePreviousTesting: N/A

      Gene: ITGA2B

      Variant: NM_000419.3:c.1544+1G>A

      LegacyVariant: N/A

      ClinVar: 2895

      CAiD: CA10575473

      gnomAD: N/A

  4. www.researchgate.net www.researchgate.net
    1. Patient 2

      Case2: Patient 2, Male, 4 years old

      DiseaseAssertion: Glanzmann thrombasthenia

      FamilyInfo: Affected brother is Patient 1

      ParentalGenotype: Mother and father revealed heterozygosity for c.1878G>C mutation. (Parents are consanguineous)

      CasePresentingHPOs: HP:0000967 (Petechiae)

      CaseHPOFreeText: Hematomas, prolonged in vitro bleeding time

      CaseNotHPOs: N/A

      CaseNotHPOsFreeText: N/A

      ProteinExpression: Flow cytometry analysis revealed that there was 109 of GPIIb/IIIa expression for Patient 2

      PlateletAggregation: All patients' platelets showed severely reduced platelet aggregation after stimulation with collagen and ADP in contrast to the normal range (See Table 1). Stimulation with epinephrine and arachidonic acid also demonstrated decreased platelet aggregation. In contrast, ristocetin-induced platelet aggregation was borderline for Patient 2

      CasePreviousTesting: Sequenced ITGA2B and ITGB3 genes from one patient of each family (Patient 2 and 3) and Patient 1 and 4 were screened for the identified mutation in the corresponding family.

      Gene: ITGA2B

      Variant: NM_000419.3:c.1878G>C (p.Gln626His)

      LegacyVariant: N/A

      ClinVar: 2903

      CAiD: CA115852

      gnomAD: N/A

    1. GT 28

      Case9: GT28, Male, India, age of onset is 5 years old

      DiseaseAssertion: Glanzmann thrombasthenia

      FamilyInfo: N/A

      ParentalGenotype: N/A

      CasePresentingHPOs: N/A

      CaseHPOFreeText: Patients were recruited as they presented consecutively from 1996 to 1998 for evaluation of a mucocutaneous bleeding disorder

      CaseNotHPOs: N/A

      CaseNotHPOsFreeText: N/A

      ProteinExpression: N/A

      PlateletAggregation: All patients examined had defective ADP, epinephrine, and collagen induced aggregation and normal ristocetin induced aggregation

      CasePreviousTesting: Mutations were detected by the method of single strand conformation polymorphism (SSCP) analysis, followed by nucleotide sequencing and confirmation by restriction fragment length polymorphism (RFLP) assays. The sequences of the primers employed and the reaction conditions for PCR amplification of the exons, adjacent intronic regions, and 50 and 30 untranslated regions of the aIIb and b3 gene

      Gene: ITGA2B

      Variant: NM_000419.3:c.1139G>T (p.Gly380Val)

      LegacyVariant: N/A

      ClinVar: N/A

      CAiD: CA399804402

      gnomAD: N/A

    2. GT12

      Case3: GT12, Male, India, age of onset is 13 years old

      DiseaseAssertion: Glanzmann thrombasthenia

      FamilyInfo: N/A

      ParentalGenotype: N/A

      CasePresentingHPOs: N/A

      CaseHPOFreeText: Patients were recruited as they presented consecutively from 1996 to 1998 for evaluation of a mucocutaneous bleeding disorder

      CaseNotHPOs: N/A

      CaseNotHPOsFreeText: N/A

      ProteinExpression: N/A

      PlateletAggregation: All patients examined had defective ADP, epinephrine, and collagen induced aggregation and normal ristocetin induced aggregation

      CasePreviousTesting: Mutations were detected by the method of single strand conformation polymorphism (SSCP) analysis, followed by nucleotide sequencing and confirmation by restriction fragment length polymorphism (RFLP) assays. The sequences of the primers employed and the reaction conditions for PCR amplification of the exons, adjacent intronic regions, and 50 and 30 untranslated regions of the aIIb and b3 gene

      Gene: ITGA2B

      Variant: NM_000419.3:c.2015del (p.Gly672AlafsTer22)

      LegacyVariant: N/A

      ClinVar: N/A

      CAiD: CA915940724

      gnomAD: N/A

    3. GT 43

      Case13: GT43, Female, India, age of onset is 18 years old

      DiseaseAssertion: Glanzmann thrombasthenia

      FamilyInfo: N/A

      ParentalGenotype: N/A

      CasePresentingHPOs: N/A

      CaseHPOFreeText: Patients were recruited as they presented consecutively from 1996 to 1998 for evaluation of a mucocutaneous bleeding disorder

      CaseNotHPOs: N/A

      CaseNotHPOsFreeText: N/A

      ProteinExpression: N/A

      PlateletAggregation: All patients examined had defective ADP, epinephrine, and collagen induced aggregation and normal ristocetin induced aggregation

      CasePreviousTesting: Mutations were detected by the method of single strand conformation polymorphism (SSCP) analysis, followed by nucleotide sequencing and confirmation by restriction fragment length polymorphism (RFLP) assays. The sequences of the primers employed and the reaction conditions for PCR amplification of the exons, adjacent intronic regions, and 50 and 30 untranslated regions of the aIIb and b3 gene

      Gene: ITGA2B

      Variant: NM_000419.3:c.1520C>G (p.Pro507Arg)

      LegacyVariant: N/A

      ClinVar: N/A

      CAiD: CA399802643

      gnomAD: N/A

    1. GT1

      Case1: (GT1), Gender, age and ethnicity not reported

      DiseaseAssertion: Glanzmann thrombasthenia

      FamilyInfo: 1 brother and 1 sister that are both heterozygous for g.951G>A and p.Leu343Pro

      ParentalGenotype: Father: heterozygous for g.951G>A and p.Leu343Pro and Mother: heterozygous for both just like dad

      CasePresentingHPOs: N/A

      CaseHPOFreeText: Inclusion criteria were patients with a history of mucocutaneous bleeding (Figure 1 shows a bar diagram of all the clinical manifestations in the patient cohort in this article)

      CaseNotHPOs: N/A

      ProteinExpression: Platelet receptor alphaIIbbeta3 protein was analyzed by flow cytometry followed by western blotting

      Platelet Aggregation: Inclusion criteria for probands was absent or reduced platelet aggregation with agonists such as ADP, adrenaline, arachidonic acid, and collagen (no mention of ristocetin here-- this article does not tell us the specific aggregation for each proband in the paper)

      CasePreviousTesting: For mutation analysis of ITGA2B and ITGB3 genes, DNA extraction from whole blood, PCR, heteroduplex PCR followed by CSGE and DNA sequencing were performed. All 30 exons of ITGA2B and 15 exons of ITGB3, as well as their promoters, were analyzed by CSGE following heteroduplex PCR.

      Gene: ITGA2B

      Variant: NC_000017.11:g.44393555C>T (g.951G>A promoter variant) and NM_000419.3:c.1028T>C (p.Leu343Pro)

      LegacyVariant: N/A

      ClinVar: N/A

      CAiD: CA913189168 (promoter variant) and CA399804619 (p.Leu343Pro)

      gnomAD N/A

    2. GT32

      Case22: (GT32) Gender, age and ethnicity are not specified

      DiseaseAssertion: Glanzmann thrombasthenia

      FamilyInfo: Sister is normal and does not harbor the mutation

      ParentalGenotype: Father is heterozygous for the mutation and the mother is normal and does not harbor the mutation

      CasePresentingHPOs: N/A

      CaseHPOFreeText: Inclusion criteria were patients with a history of mucocutaneous bleeding (Figure 1 shows a bar diagram of all the clinical manifestations in the patient cohort in this article)

      CaseNotHPOs: N/A

      ProteinExpression: Platelet receptor alphaIIbbeta3 protein was analyzed by flow cytometry followed by western blotting

      Platelet Aggregation: Inclusion criteria for probands was absent or reduced platelet aggregation with agonists such as ADP, adrenaline, arachidonic acid, and collagen (no mention of ristocetin here-- this article does not tell us the specific aggregation for each proband in the paper)

      CasePreviousTesting: For mutation analysis of ITGA2B and ITGB3 genes, DNA extraction from whole blood, PCR, heteroduplex PCR followed by CSGE and DNA sequencing were performed. All 30 exons of ITGA2B and 15 exons of ITGB3, as well as their promoters, were analyzed by CSGE following heteroduplex PCR.

      Gene:

      Variant: NM_000419.3:c.1919_1920del

      LegacyVariant: N/A

      ClinVar: N/A

      CAiD: CA915940685

      gnomAD N/A

    1. Case1: Male, 67, ethnicity not specified

      DiseaseAssertion: Glanzmann thrombasthenia

      FamilyInfo: N/A

      ParentalGenotype: N/A

      CasePresentingHPOs: HP:0000978 Bruising susceptibility (From previously published PMID: 9226191)

      CaseHPOFreeText: Moderate bleeding tendency

      CaseNotHPOs: N/A

      CaseNotHPOsFreeText: N/A

      ProteinExpression: N/A

      PlateletAggregation: Platelets failed to aggregate and bind to fibrinogen in response to ADP, collagen, and thrombin but were able to support a subnormal clot retraction and the amount of αIIbβ3 complexes was estimated to be about 50% of the normal value (From previously published PMID: 9226191)

      CasePreviousTesting: N/A

      Gene: ITGB3

      Variant: NM_000212.2:c.2332T>C (p.Ser778Pro) (See Table 1)

      LegacyVariant: p.Ser752Pro

      ClinVar: 13556

      CAiD: CA123230

      gnomAD: N/A

      PreviouslyPublished: PMID: 9226191

    1. The patient

      Case1: Gender, age, ethnicity not specified

      DiseaseAssertion: Glanzmann thrombasthenia

      FamilyInfo: N/A

      ParentalGenotype: N/A

      CasePresentingHPOs: N/A

      CaseHPOFreeText: Lifelong bleeding tendency with prolonged bleeding time

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      ProteinExpression:

      PlateletAggregation: Absence of in vitro platelet aggregation seen in thrombasthenia (all the information we are provided with)

      CasePreviousTesting: RT-PCR on total RNA extracted from the patient's platelets followed by direct sequencing of die PCR products using GPIIb and GPIIIa primers described elsewhere

      Gene: ITGB3

      Variant: (p.Arg240Trp)

      LegacyVariant: (p.Arg214Trp)

      ClinVar: 13555

      CAiD: CA123228

      gnomAD: MAF in the East Asian population is 0.00005437 https://gnomad.broadinstitute.org/variant/17-45363729-C-T

      PreviouslyPublished: PMID: 3818957 and Reference 10 in this article

    1. brother

      CaseExome-2:II-2: Male, Japan, Asian

      CaseExome-2:II-2PresentingHPOs: HP:0001873, HP:0040185, HP:0000421 (Thrombocytopenia, Macrothrombocytopenia, Epistaxis)

      HPOsFreeText: Platelet Count at 124 (x (10^9)/l), Platelet Size at 2.9 ± 0.9 (μm), No bleeding tendency

      CaseNotHPOs:

      NotHPOsFreeText:

      CaseAddInfo: Brother of proband, II-1

    2. proband

      CaseSanger-3:II-2: Female, Japan, Asian

      CasePresentingHPOs: HP:0001873, HP:0040185, HP:0000421 (Thrombocytopenia, Macrothrombocytopenia, Epistaxis)

      HPOsFreeText: Platelet Count at 80 (x (10^9)/l), Platelet Size at 3.0 ± 0.9 (μm), 59% (2.5 μm) aggregation ADP

      CaseNotHPOs:

      NotHPOsFreeText:

      CaseAddInfo: Proband of Family Sanger-3

    3. proband

      CaseExome-2:II-1: Male, Japan, Asian

      CaseExome-2:II-1PresentingHPOs: HP:0001873, HP:0040185 (Thrombocytopenia, Macrothrombocytopenia)

      HPOsFreeText: Platelet Count at 54 (x (10^9)/l), Platelet Size at 3.1 ± 1.1 (μm), No bleeding tendency, 4.5 min bleeding time, 34% (2 μm) aggregation ADP

      CaseNotHPOs:

      NotHPOsFreeText:

      CaseAddInfo: Proband for Family Exome-2

    4. father

      CaseSanger-1:I-1: Male, Japan, Asian

      CasePresentingHPOs: HP:0001873, HP:0040185 (Thrombocytopenia, Macrothrombocytopenia)

      HPOsFreeText: Platelet Count at 131 (x (10^9)/l), Platelet Size at 4.2 ± 1.3 (μm), No bleeding tendency, 1 min bleeding time, 49% (2 μm) aggregation ADP

      CaseNotHPOs:

      NotHPOsFreeText:

      CaseAddInfo: Father of proband, II-1

    5. proband

      CaseSanger-1:II-1: Female, Japan, Asian

      CasePresentingHPOs: HP:0001873, HP:0040185 (Thrombocytopenia, Macrothrombocytopenia)

      HPOsFreeText: Platelet Count at 120 (x (10^9)/l), Platelet Size at 3.9 ± 1.6 (μm), No bleeding tendency, 66% (2 μm) aggregation ADP

      CaseNotHPOs:

      NotHPOsFreeText:

      CaseAddInfo: Proband for Family Sanger-1

    6. proband

      CaseSanger-2:III-2: Female, Japan, Asian

      CasePresentingHPOs: HP:0001873, HP:0040185 (Thrombocytopenia, Macrothrombocytopenia)

      HPOsFreeText: Platelet Count at 77 (x (10^9)/l), Platelet Size at 3.7 ± 1.5 (μm), No bleeding tendency, 2 min bleeding time

      CaseNotHPOs:

      NotHPOsFreeText:

      CaseAddInfo: Proband of Family Sanger-2, Had a sister, mother, and grandfather who had the disorder but were not genetically tested to confirm the presence or absence of her variant

    1. 926T > C and 236G > A in the other case

      Case: Haagerup II:5

      CasePresentingHPOs:

      CasePresentingHPOsFreeText: not specified

      CaseNOTHPOs:

      CaseNOTHPOSFreeText: not specified

      CasePreviousTesting: same as group

      CaseGenotypingMethod: same as group

      Variants: c926T>C and c236G>A

      ClinVarID: or CAID: ClinVarID: 8426; ClinVarID: 8424

      gnomAD: 2/129174 European (non-Finnish) alleles at a frequency of 0.00001548 with no homozygotes; not present in gnomAD

      AddCaseInfo:

      PreviouslyPublished: no

      VariantEvidence: predicted but variant was proven to segregate with disease; no detectable protease activity when analyzed by western blotting (PMID: 10074491)

    1. 3.3.1. Severe patients There were 115 individual genotypes represented in the 380 patients with a severe phenotype and two reported alleles; 31 genotypes were recurrent and 84 genotypes unique (Table 3). The most common genotypes in severe patients were W402X/W402X (109/380; 28.7%), W402X/Q70X (61/380; 16.1%) and Q70X/Q70X (24/380; 6.3%). In total, these two nonsense variants defined the genotypes of 51% (194/380) of severe patients. Of severe patients, 67.6% (257/380) were either homozygous or compound heterozygous for two variants predicted to severely disrupt gene transcription or translation (eg, nonsense variants, frameshifts, consensus splice site disruption or initiator codon variants). No clinically diagnosed attenuated patients were homozygous or compound heterozygous for such variants. Of the remaining 123 severe patients, 76 comprised 19 recurrent genotypes (Table 3) with the remaining 47 patients (12.6%) having unique genotypes (listed in Table S1). Thirty‐seven of the 84 unique genotypes identified in severe patients were compound heterozygous with two severe variants (as defined above) and were comprised of 34 separate severe variants (listed in Table S1). There were nine missense recurrent variants and one intronic recurrent variant that were exclusively seen in severe patients (Table 5A).

      Case#: Severe MPS1 patients

      DiseaseAssertion: Severe MPS I

      FamilyInfo: n/a, "neither the laboratory method used to determine the sequence variants nor whether parental testing confirmed the inheritance or phase of the variants is captured by the Registry"

      CasePresentingHPOs:

      CaseHPOFreeText: "All patients enrolled in the Registry have confirmation of MPS I diagnosis by either mutation analysis or measurement of IDUA levels."

      CaseNotHPOs:

      CaseNotHPOFreeText:

      CasePreviousTesting: n/a

      GenotypingMethod: n/a

      PreviouslyPublished: possible since this is a multinational registry

      Variant: c.1403-1G>T/c.1728-1G>C

      ClinVar: 556064

      CAID: CA355965306

      SupplementalData: Table S1 has the genotypes listed

    2. 3.3.1. Severe patients There were 115 individual genotypes represented in the 380 patients with a severe phenotype and two reported alleles; 31 genotypes were recurrent and 84 genotypes unique (Table 3). The most common genotypes in severe patients were W402X/W402X (109/380; 28.7%), W402X/Q70X (61/380; 16.1%) and Q70X/Q70X (24/380; 6.3%). In total, these two nonsense variants defined the genotypes of 51% (194/380) of severe patients. Of severe patients, 67.6% (257/380) were either homozygous or compound heterozygous for two variants predicted to severely disrupt gene transcription or translation (eg, nonsense variants, frameshifts, consensus splice site disruption or initiator codon variants). No clinically diagnosed attenuated patients were homozygous or compound heterozygous for such variants. Of the remaining 123 severe patients, 76 comprised 19 recurrent genotypes (Table 3) with the remaining 47 patients (12.6%) having unique genotypes (listed in Table S1). Thirty‐seven of the 84 unique genotypes identified in severe patients were compound heterozygous with two severe variants (as defined above) and were comprised of 34 separate severe variants (listed in Table S1). There were nine missense recurrent variants and one intronic recurrent variant that were exclusively seen in severe patients (Table 5A).

      Case#: Severe MPS1 patients

      DiseaseAssertion: Severe MPS I

      FamilyInfo: n/a, "neither the laboratory method used to determine the sequence variants nor whether parental testing confirmed the inheritance or phase of the variants is captured by the Registry"

      CasePresentingHPOs:

      CaseHPOFreeText: "All patients enrolled in the Registry have confirmation of MPS I diagnosis by either mutation analysis or measurement of IDUA levels."

      CaseNotHPOs:

      CaseNotHPOFreeText:

      CasePreviousTesting: n/a

      GenotypingMethod: n/a

      PreviouslyPublished: possible since this is a multinational registry

      Variant: c.1728-1G>C/W402X

      ClinVar: 556064

      CAID: CA355965306

      SupplementalData: Table S1 has the genotypes listed

    3. 3.3.1. Severe patients There were 115 individual genotypes represented in the 380 patients with a severe phenotype and two reported alleles; 31 genotypes were recurrent and 84 genotypes unique (Table 3). The most common genotypes in severe patients were W402X/W402X (109/380; 28.7%), W402X/Q70X (61/380; 16.1%) and Q70X/Q70X (24/380; 6.3%). In total, these two nonsense variants defined the genotypes of 51% (194/380) of severe patients. Of severe patients, 67.6% (257/380) were either homozygous or compound heterozygous for two variants predicted to severely disrupt gene transcription or translation (eg, nonsense variants, frameshifts, consensus splice site disruption or initiator codon variants). No clinically diagnosed attenuated patients were homozygous or compound heterozygous for such variants. Of the remaining 123 severe patients, 76 comprised 19 recurrent genotypes (Table 3) with the remaining 47 patients (12.6%) having unique genotypes (listed in Table S1). Thirty‐seven of the 84 unique genotypes identified in severe patients were compound heterozygous with two severe variants (as defined above) and were comprised of 34 separate severe variants (listed in Table S1). There were nine missense recurrent variants and one intronic recurrent variant that were exclusively seen in severe patients (Table 5A).

      Case#: Severe MPS1 patients

      DiseaseAssertion: Severe MPS I

      FamilyInfo: n/a, "neither the laboratory method used to determine the sequence variants nor whether parental testing confirmed the inheritance or phase of the variants is captured by the Registry"

      CasePresentingHPOs:

      CaseHPOFreeText: "All patients enrolled in the Registry have confirmation of MPS I diagnosis by either mutation analysis or measurement of IDUA levels."

      CaseNotHPOs:

      CaseNotHPOFreeText:

      CasePreviousTesting: n/a

      GenotypingMethod: n/a

      PreviouslyPublished: possible since this is a multinational registry

      Variant: Q70X/Y343X

      ClinVar: 222997

      CAID: CA356984

      SupplementalData: Table S1 has the genotypes listed

    1. Two other IDUA mutations occurred in CpG dinucleotides (678 G→A and Y202X) and were found in the same patient, along with M133I. The analysis of parental DNA showed that the mutation M133I was linked to the Y202X mutation in the father whereas the other mutation (678 G→A) was maternally inherited. The 678 G→A mutation, a transition in the first base of intron 6, is also a splice site mutation that would cause the change of a glycine to an aspartic acid in position 196 of the protein. However, since skin fibroblasts from this patient were not available, it was not known whether mutant mRNA coding for the G197D α-l-iduronidase was produced. Therefore, this IDUA change was considered only as a splice mutation and was not expressed in CHO-K1 cells.

      Case#: Patient #19, Brazilian

      DiseaseAssertion: MPS1, severe(Hurler)

      FamilyInfo: n/a

      CasePresentingHPOs:

      CaseHPOFreeText: underwent bone marrow transplant

      CaseNotHPOs:

      CaseNotHPOFreeText:

      Genotyping Method: Patients were screened for 10 known mutations using PCR and restriction enzymes and all 14 exons of the IDUA gene were amplified and analyzed by single strand conformational polymorphism (SSCP) analysis. PCRs were performed and sequenced using the big dye terminator kit and an ABI 373 automated sequencer (Applied Biosystems). Mutations were confirmed by sequencing the reverse strand using the same method.

      PreviouslyPublished: n/a

      Variant: allele 1: M133I/ Y202X (father); allele 2: 678 G→A (mother)

      other changes: A8, A20, Q33H, L118

      ClinVar: CA355961907

    1. A dinucleotide deletion in exon 4 of the PlA2 allelic form of glycoprotein IIIa: implications for the correlation of serologic versus genotypic analysis of human platelet alloantigens

      Case1: Patient PDJ (found in GT database as well) 57 years old, ethnicity not specified

      DiseaseAssertion: Thrombocytopenia

      FamilyInfo: N/A

      ParentalGenotype: N/A

      CasePresentingHPOs: N/A

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOsFreeText: N/A

      ProteinExpression: Quantitative analysis of GPllb-llla surface expression showed only 20,000 GPllb-llla receptors/platelet, approximately half of the value obtained with control platelets

      PlateletAggregation: N/A

      CasePreviousTesting: DNA sequence analysis of the GPIIIa gene was performed

      Gene: ITGB3

      Variant: NM_000212.2:c.709_710del

      LegacyVariant: N/A

      ClinVar: N/A

      CAiD: CA8623029

      gnomAD: MAF in the European (non-Finnish) population is 0.00001796 https://gnomad.broadinstitute.org/variant/17-45363717-CAG-C

    1. Patient‐III6

      Case2: Female, Israeli-Arab, (age is either 3 or 8)

      DiseaseAssertion: Glanzmann thrombasthenia

      FamilyInfo: See Fig 1C for pedigree

      ParentalGenotype: See Fig 1C for pedigree

      CasePresentingHPOs: HP:0000421, HP:0031364, HP:0000967, HP:0002239

      (Severe epistaxis, ecchymosis, petechiae, GI bleeding)

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      ProteinExpression: No surface expression of αIIbβ3 was found in patients’ platelets (See Fig 3)

      PlateletAggregation: N/A

      CasePreviousTesting: DNA fragments containing exons and flanking intronic regions of the aIIb and B3 genes were amplified by PCR using primers

      Gene: ITGA2B

      Variant: NM_000419.3:c.97A>G (p.Asn2Asp)

      LegacyVariant: N/A

      ClinVar: N/A

      CAiD: CA399806951

      gnomAD: N/A

    1. The patient

      Case1: The proband of interest is designated as VGTΔ724 in this article

      DiseaseAssertion: Glanzmann thrombasthenia

      FamilyInfo: N/A

      ParentalGenotype: N/A

      CasePresentingHPOs: HP:0000978, HP:0000967

      (Bruising, petechiae)

      CaseHPOFreeText: Mucosal bleeding

      CaseNotHPOs: N/A

      CaseNotHPOsFreeText: N/A

      ProteinExpression: N/A

      PlateletAggregation: Platelets fail to aggregate in response to physiologic agonists or spread on fibrinogen

      CasePreviousTesting: N/A

      Gene: ITGB3

      Variant: NM_000212.2:c.2248C>T (p.Arg750Ter) and NM_000212.2:c.1791del (p.Asn597Lysfs*72)

      LegacyVariant: (p.Arg724Ter)

      ClinVar: 13564 (p.Arg750Ter)

      CAiD: CA123246 (p.Arg750Ter) and CA8623358 (Asn597Lysfs*72)

      gnomAD: MAF in the African population is 0.0006008 https://gnomad.broadinstitute.org/variant/17-45384950-C-T (p.Arg750Ter)

    1. A six-year-old boy

      Case1: Male, 6 years old

      DiseaseAssertion: Glanzmann thrombasthenia

      FamilyInfo: N/A

      ParentalGenotype: N/A

      CasePresentingHPOs: HP:0004406, HP:0000967

      (Recurring nosebleed, petechia)

      CaseHPOFreeText: Diffused peliosis

      CaseNotHPOs: N/A

      CaseNotHPOsFreeText: N/A

      ProteinExpression: aIIb and b3 were absent in the platelets of this patient analyzed by flow cytometry.

      PlateletAggregation: There was no concentration aggregation action in response to ADP and adrenaline, but patient platelets could aggregate when treated by ristocetin

      CasePreviousTesting: Genomic DNA was isolated from cells, and exon 4 of ITGA2B was amplified. PCR products were resolved via agarose gels, purified for sequencing.

      Gene: ITGA2B

      Variant: NM_000419.3:c.480C>G and NM_000419.3:c.574+5G>C

      LegacyVariant: N/A

      ClinVar: N/A

      CAiD: CA399805892 and CA913203563

      gnomAD: MAF in the East Asian population 0.00005507 http://gnomad.broadinstitute.org/variant/17-42463013-G-C

    1. GT11

      Case#: 15 year old, female

      Disease: Glazmann's Thrombasthenia

      CasePresentingHPOs: HP:0000967, HP:0000978, HP:0000225, HP:0006298, HP:0001892

      PlateletAgreggation: Defective response to ADP, Adrenaline, Collagen, Arachidonic acid. Normal response to Ristocetin.

      GenotypingMethod: Genomic DNA was extracted from peripheral blood leukocytes for mutational analysis of the αIIb and β3 genes by DNA sequencing

      Allele 1:

      ClinVar: 953046

      CAID: CA399802348

      Variant: NM_000419.5:c.1651C>T

      GnomAD: Highest in East Asian population at a rate of 0.00005045 (1/19820)

      Allele 2:

      ClinVar: 225393

      CAID: CA290947544

      Variant: NM_000419.5:c.2333A>C

      GnomAD: East Asian: 0.0001087 (2/18394)

      ExpressionEvidence:Flow Cytometry of platelet integrin: 7.7% B3 expression, .82% A2B expression

    1. Patient 3

      Case3: Male, 10 years old, Korean

      DiseaseAssertion: Glanzmann thrombasthenia

      FamilyInfo: N/A

      ParentalGenotype: Figure 1 shows haplotype analysis

      CasePresentingHPOs: HP:0001342

      (Cerebral hemorrhage)

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOsFreeText: N/A

      ProteinExpression: Flow cytometry analyses revealed decreased expression at 7.2%/5.0% of the normal amount of CD41/CD61

      PlateletAggregation: Platelet aggregation tests were performed to evaluate responses to ADP, collagen, epinephrine, and ristocetin agonists

      CasePreviousTesting: Polymerase chain reaction for all exons ofITGA2Band/orITGB3were performed using primers. Sequence analysis was performed with reference to M_000419.3 andNP_000410.2 forITGA2Band NM_000212.2 and NP_000203.2 for ITGB3.

      Gene: ITGA2B

      Variant: NM_000419.3:c.2333A>C (p.Gln778Pro) and NM_000419.3:c.975del

      LegacyVariant: N/A

      ClinVar: 225393

      CAiD: CA290947544 and CA915940385

      gnomAD: MAF in the East Asian population is 0.0001087 http://gnomad.broadinstitute.org/variant/17-42453691-T-G