Patient12: 53yo

CasePresentingHPOs: HP:0003325, HP:0002093, HP:0002315

HPOsFreeText: morning headache, GAA = 5%, BMI = 27.4, left ventricular artery dominant, subcortical white matter lacunes

CaseNotHPOs:

NotHPOsFreeText: No cardiovascular risk

CaseAddInfo: 11yr disease duration, variants in trans

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant: 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_000152.4(GAA):c.670C>T (p.Arg224Trp)

ClinVar: 189188, https://www.ncbi.nlm.nih.gov/clinvar/variation/189188/

gnomAD: 2.53e-05, http://exac.broadinstitute.org/variant/17-78079671-C-T

Patient15: 53yo

CasePresentingHPOs: HP:0002315, HP:0004887, HP:0000822, HP:0003141, HP:0002870, HP:0020038

HPOsFreeText: hyperCKema, morning headaches, GAA = 13%, BMI = 29.6, right ventricular artery dominant, Normal CT

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 5yr disease duration, homozygous variants in trans

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant: 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

Patient21: Male, 35 years report, 1y< years onset

CasePresentingHPOs: HP:0001324, HP:0002240 (Muscle weakness, Hepatomegaly)

CaseAddInfo: LOPD

Patient34: Male, 13 years report, 16 months onset

CasePresentingHPOs: HP:0002527, HP:0001640 (Falls, Cardiomegaly)

HPOsFreeText: N/A

CaseNotHPOs: HP:0002240 (Hepatomegaly)

NotHPOsFreeText: N/A

CaseAddInfo: LOPD

Patient11: Male, 10 years report, 4 years onset

CasePresentingHPOs: HP:0001324 (Muscle weakness)

HPOsFreeText: GAA activity 16.9% from leukocyte

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

NotHPOsFreeText: No wheelchair needed, Respiratory Assistance not needed

CaseAddInfo: LOPD

Patient38: Male, 20 years report, 2 year onset

CasePresentingHPOs: HP:0001324, HP:0002098, HP:0002527 (Muscle weakness, Respiratory distress, Falls)

HPOsFreeText: GAA activity 2.7% from leukocyte, Wheelchair needed, Respiratory Assistance needed

CaseNotHPOs: HP:0001640, HP:0002240 (Cardiomegaly, Hepatomegaly)

NotHPOsFreeText: N/A

CaseAddInfo: LOPD

Patient19: Female, 61yo

CasePresentingHPOs: HP:0000822

HPOsFreeText: LOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 2yr disease duration, ERT lasted 9mo

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_000152.4(GAA):c.925G>A (p.Gly309Arg)

ClinVar: 188797, https://www.ncbi.nlm.nih.gov/clinvar/variation/188797/

gnomAD: 0.00002860, http://gnomad.broadinstitute.org/variant/17-78081665-G-A

Patient3: Female, 2mo at diagnosis, 5mo at ERT

CasePresentingHPOs:

HPOsFreeText: classic IOPD, moderate response to ERT, Pompe muscle pathology score = 1.4(a), 3.4(b), Glycogen = 19.5(a), 48.6(b) Vv(PAS + /mf)%, larger empty vacuoles = 10.2(a), 40.1(b) Vv (LEV/mf)%, Autophagic vacuoles = 0,27; 0 %/mf

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: biopsy taken from  musculus vastus lateralis

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: c.1859 G > A this is the variant listed in the paper, but I believe this is a typo as both Clinvar and the allele registry have this position listed as 'C' rather than 'G'

NM_000152.3:c.1859C>A

CAID: CA401369666, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.3%3Ac.1859C%3EA

gnomAD: n/a

Variant2: NM_000152.4:c.2481+102_2646+31del (p.Gly828_Asn882del) (exon 18 del)

ClinVar: 4031, https://www.ncbi.nlm.nih.gov/clinvar/variation/4031/

gnomAD: n/a

Patient4: Male, 2mo at diagnosis, 2.5mo at ERT

CasePresentingHPOs:

HPOsFreeText: classic IOPD, poor response to ERT, Pompe muscle pathology score = 4.1, Glycogen = 40.3 Vv(PAS + /mf)%, larger empty vacuoles = 52.2 Vv (LEV/mf)%, Autophagic vacuoles = 0 %/mf

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: biopsy taken from  musculus vastus lateralis

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.2213G>A (p.Trp738Ter)

ClinVar: 370222, https://www.ncbi.nlm.nih.gov/clinvar/variation/370222/

gnomAD: n/a

Variant2: NM_000152.4:c.delExon18

ClinVar: 4031 https://www.ncbi.nlm.nih.gov/clinvar/variation/4031/

gnomAD: n/a

Patient1: Female, 3mo at diagnosis, 4mo at ERT

CasePresentingHPOs:

HPOsFreeText: classic IOPD, moderate response to ERT, Pompe muscle pathology score = 2.2 (a), 3.3(b), Glycogen = 59.4(a), 63.8(b) Vv(PAS + /mf)%, larger empty vacuoles = 6.2(a), 18.3(b) Vv (LEV/mf)%, autophagic vacuoles = 0,25; 0 %/mf

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: biopsy taken from  musculus vastus lateralis

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.3:c.104T>C

CAID: CA401360259, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA401360259

gnomAD: n/a

Variant2: c.266 C > A This is the variant listed in the paper, but I believe this is a typo as both Clinvar and the allele registry have this position listed as 'G' rather than 'C'

NM_000152.4(GAA):c.266G>A (p.Arg89His)

ClinVar: 283219, https://www.ncbi.nlm.nih.gov/clinvar/variation/283219/#summary-evidence

gnomAD: 7.795e-05, http://exac.broadinstitute.org/variant/17-78078651-G-A

CaseD: Female, 9 months onset, 12 months diagnosis

CasePresentingHPOs: HP:0001270, HP:0003324 (Motor delay, Generalized weakness)

HPOsFreeText: CRIM positive, Requires non-invasive ventilation during nighttime

CaseNotHPOs: HP:0100543, HP:0002540, HP:0001638 (Cognitive impairment, Inability to walk, Cardiomyopathy)

CaseAddInfo: Infantile-Onset Pompe Disease

Case2: Female, 44 years onset, 54 years diagnosis, 65 years report

CasePresentingHPOs: HP:0003325, HP:0003327, HP:0003236, HP:0002747 (Limb-girdle muscle weakness, Axial muscle weakness, Increased serum CK, Respiratory muscle weakness)

CaseAddInfo: Late-Onset Pompe Disease

Patient12: Female

CasePresentingHPOs: HP:0002194, HP:0001522

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

CaseNotHPOs: HP:0004887

NotHPOsFreeText:

CaseAddInfo: Symptom onset at 4mo, diagnosis at 6mo, ERT at 8mo, ERT lasted for 0.5mo, died at 8.5mo

CasePMIDs: 22252923, 27629047

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant: NM_000152.3:c.1657C>T

CAID: CA401368835, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.3%3Ac.1657C%3ET

gnomAD: n/a

Case8: Male, 54 years report

HPOsFreeText: 8 years of ERT completed, 6 Minute Walking Test at 300 meters, Forced Vital Capacity at 33%

GenotypingMethod: GAA Gene Sequencing

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.1888+1G>A

CAID: CA8815511 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.1888%2B1G%3EA

gnomAD: European (Non-Finnish) 9.843e-6, Overall 4.375e-6 http://gnomad.broadinstitute.org/variant/17-78086511-G-A

CaseAddInfo: Late Onset Pompe Disease

Case14: Female, 69 years report

HPOsFreeText: 9 years of ERT completed, 6 Minute Walking Test at 200 meters, Forced Vital Capacity at 51%

GenotypingMethod: GAA Gene Sequencing

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.118C>T (p.Arg40Ter)

ClinVar: 426593 https://www.ncbi.nlm.nih.gov/clinvar/variation/426593/

gnomAD: South Asian 6.561e-5, Overall 1.428e-5 http://gnomad.broadinstitute.org/variant/17-78078503-C-T

CaseAddInfo: Late Onset Pompe Disease

Case3: Female, 72 years report

HPOsFreeText: 4 years of ERT completed, 6 Minute Walking Test at 264 meters, Forced Vital Capacity at 56%

GenotypingMethod: GAA Gene Sequencing

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.2481+102_2646+31del (p.Gly828_Asn882del) (exon 18 del)

ClinVar: 4031 https://www.ncbi.nlm.nih.gov/clinvar/variation/4031/

gnomAD: Not in gnomAD

CaseAddInfo: Late Onset Pompe Disease

Case5: Male, 57 years report

HPOsFreeText: 2 years of ERT completed, 6 Minute Walking Test at 461 meters, Forced Vital Capacity at 49%

GenotypingMethod: GAA Gene Sequencing

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.546+1G>T

CAID: CA401361913 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.546%2B1G%3ET

gnomAD: Not in gnomAD

CaseAddInfo: Late Onset Pompe Disease

Case15: Female, 54 years report

HPOsFreeText: 8 years of ERT completed, 6 Minute Walking Test at 229 meters, Forced Vital Capacity at 39%

GenotypingMethod: GAA Gene Sequencing

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.1717A>C (p.Asn573His)

CAID: CA401369056 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.1717A%3EC

gnomAD: Not in gnomAD

CaseAddInfo: Late Onset Pompe Disease

Patient7: IOPD Group, 10days old

CasePresentingHPOs:

HPOsFreeText: LDH = 431 U/L, CK = 237 U/L, ALT = 23 U/L, AST = 58 U/L, Mann-Whitney Test = 2

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo:

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

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

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

gnomAD: 0.0001240, https://gnomad.broadinstitute.org/variant/17-78086721-C-A

Case#: Subject number 16, male, 59 years (report)

DiseaseAssertion: Pompe disease

FamilyInfo: No known family member with PD

CasePresentingHPOs: HP:0002153 (hyperkalemia), HP:0002098 (respiratory distress), HP:0001324 (muscle weakness)

CaseHPOFreeText:

CaseNotHPOs: HP:0001252 (Hypotonia), HP:0001638 (cardiomyopathy), HP:0003326 (Myalgia), HP:0002015 (dysphagia), HP:0003546 (Exercise intolerance), HP:0002094 (dyspnoea)

CaseNotHPOFreeText: no biopsy, not asymptomatic

CasePreviousTesting: "Enzymatic activity was detected by fluorometric techniques" "The GAA sequence was performed in all patients whose enzyme activity measured in DBS and lymphocytes was decreased."

glucosidase activity: GAA activity was 0.17 mol/Lh in dried blood spots (normal range >0.75).

Variant 1: NM_000152.5(GAA):c.-32-13T>C

Variant 1 ClinVarID: 4027

Variant 1 CAid: CA116606

Variant 2: NM_000152.5(GAA):c.-32-13T>C

Variant 2 ClinVarID: 4027

Variant 2 CAid: CA116606

Zygosity: homozygous

ParentalGenotype: N/A

PreviouslyPublished: N/A

CaseIP2-5: Male, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 0.13 umol/hr/L, Serum CK at 443 U/L

GenotypingMethod: GAA Gene Sequencing and PCR Amplification

Variant1: NM_000152.4:c.1396G>T (p.Val466Phe)

CAID: CA401366509 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.1396G%3ET

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

CaseAddInfo: Infantile Onset Pompe Disease

CaseOPOPD-51: Male, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 1.03 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.1822C>T (p.Arg608Ter)

CAID: CA8815488 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.1822C%3ET

gnomAD: East Asian 5.103e-5, Overall 1.806e-5 http://gnomad.broadinstitute.org/variant/17-78086444-C-T

CaseAddInfo: One Pompe Mutation allele and One Pseudodeficency Mutation allele

CaseOPTPD-4: Male, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 0.72 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.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

Variant3: 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

CaseAddInfo: One Pompe Mutation allele and Two Pseudodeficency Mutation alleles, Nomenclature indicates patient is homozygous for Variant 1 and Variants 2 and 3 are in cis with each other and only one copy of 1

CaseIP-3: Female, Taiwan, Birth diagnosis

HPOsFreeText: 4MU enzyme activity at 0.42, MS/MS ennzyme activity at 0.10

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.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

CaseAddInfo: Infantile Onset Pompe Disease, Nomenclature indicates Variant 1 and 2 are in cis and that the patient is homozygous for this allele

CaseOPOPD-48: Female, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 1.02 umol/hr/L

GenotypingMethod: GAA Gene Sequencing and PCR Amplification

Variant1: NM_000152.4:c.1508_1510del (p.Val503del)

CAID: CA627699576 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.1508_1510del

gnomAD: East Asian 5.438e-5, Overall 3.980e-6 http://gnomad.broadinstitute.org/variant/17-78084592-ATGG-A

Variant2: 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: One Pompe Mutation allele and One Pseudodeficency Mutation allele, 1 other has the same genotype

CaseOPOPD-53: Female, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 0.80 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.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

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

Patient23: Male, Southern China

CasePresentingHPOs:

HPOsFreeText: IOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo:

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.1411_1414delGAGA (p.Glu471Profs)

ClinVar: 188874, https://www.ncbi.nlm.nih.gov/clinvar/variation/188874/

gnomAD: 1.688e-05, http://exac.broadinstitute.org/variant/17-78083827-CGAGA-C

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

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

gnomAD: 2.105e-05, http://exac.broadinstitute.org/variant/17-78086806-CACA-C

Patient8: Male, Southern China

CasePresentingHPOs:

HPOsFreeText: IOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo:

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.1411_1414delGAGA (p.Glu471Profs)

ClinVar: 188874, https://www.ncbi.nlm.nih.gov/clinvar/variation/188874/

gnomAD: 1.688e-05, http://exac.broadinstitute.org/variant/17-78083827-CGAGA-C

Patient5: Male, northern China

CasePresentingHPOs:

HPOsFreeText: IOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: homozygous

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

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

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

gnomAD: 1.65e-05, http://exac.broadinstitute.org/variant/17-78092467-G-T

Case#: Patient 5, Female, 3.0 months old at diagnosis, African American

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0032988, HP:0001638

(Persistent head lag, Cardiomyopathy)

CaseHPOFreeText:

Previous to ERT patient was invasively ventilated, patient was unable to sit or roll over. NJ feeds started at age 3 months

Currently patient requires Oxygen and BiPAP at night. Stands with support and uses G tube for feeding.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: No GAA measurement

Variant: NM_000152.5(GAA):c.2560C>T (p.Arg854Ter)

ClinVar: 4034

CAID: CA340130

gnomAD: Highest population MAF= 0.001891 (African)

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: Subject number 1, female, 38 years (diagnosis), 50 years (baseline visit), 47 years (ERT)

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0001324 (Muscle Weakness)

CaseHPOFreeText:

CaseNotHPOs: HP:0003236 (Elevated circulating creatine kinase concentration), HP:0002098 (respiratory distress), HP:0002870 (obstructive sleep apnea)

CaseNotHPOFreeText: No mechanical ventilation at Baseline Visit, no mechanical ventilation at last visit

CasePreviousTesting: "reduced enzymatic activity on fibroblasts, blood leukocytes or skeletal muscle and/or the presence of two known mutations in the GAA gene"

PreviouslyPublished: N/A

Case#: Subject number 31, male, 49 years (diagnosis), 51 years (baseline visit)

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0003236 (Elevated circulating creatine kinase concentration), HP:0002870 (obstructive sleep apnea)

CaseHPOFreeText:

CaseNotHPOs: HP:0002098 (respiratory distress), HP:0001324 (Muscle Weakness)

CaseNotHPOFreeText: no mechanical ventilation at Baseline Visit, no mechanical ventilation at last visit

CasePreviousTesting: "reduced enzymatic activity on fibroblasts, blood leukocytes or skeletal muscle and/or the presence of two known mutations in the GAA gene"

PreviouslyPublished: N/A

Case#: Subject number 10, male, 13 years (diagnosis), 42 years (baseline visit), 39 years (ERT), 38 (ventilation)

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0001324 (Muscle Weakness), HP:0002098 (respiratory distress)

CaseHPOFreeText: mechanical ventilation at Baseline Visit, mechanical ventilation at last visit

CaseNotHPOs: HP:0003236 (Elevated circulating creatine kinase concentration), HP:0002870 (obstructive sleep apnea)

CaseNotHPOFreeText:

CasePreviousTesting: "reduced enzymatic activity on fibroblasts, blood leukocytes or skeletal muscle and/or the presence of two known mutations in the GAA gene"

PreviouslyPublished: N/A

Case#: Subject number 19, female, 24 years (diagnosis), 35 years (baseline visit), 29 years (ERT)

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0001324 (Muscle Weakness)

CaseHPOFreeText:

CaseNotHPOs: HP:0003236 (Elevated circulating creatine kinase concentration), HP:0002870 (obstructive sleep apnea), HP:0002098 (respiratory distress)

CaseNotHPOFreeText: no mechanical ventilation at Baseline Visit, no mechanical ventilation at last visit

CasePreviousTesting: "reduced enzymatic activity on fibroblasts, blood leukocytes or skeletal muscle and/or the presence of two known mutations in the GAA gene"

PreviouslyPublished: N/A

Patient19: Male, 54yo at diagnosis and ERT

CasePresentingHPOs:

HPOsFreeText: anti rh-GAA antibodies titre = 1:6400, enzyme (μmol/g/h) = 0.41 (3-20), NIV and mobility aid required before and after ERT

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 35yr 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_000152.4(GAA):c.2242dupG (p.Glu748Glyfs)

ClinVar: 370651, https://www.ncbi.nlm.nih.gov/clinvar/variation/370651/

gnomAD: 1.66e-05, http://exac.broadinstitute.org/variant/17-78090813-T-TG

Patient17: Male, Caucasian

CasePresentingHPOs: HP:0003678, HP:0002093, HP:0003325, HP:0003701, HP:0003388, HP:0002111, HP:0003458

HPOsFreeText: normal CK levels, back muscle weakness, variability in muscle fibre diameter and glycogen accumulation. Slightly reduced alpha-glucosidase activity. Treated with ERT.

CaseNotHPOs: HP:0003236

CaseAddInfo: onset as a young adult, Pompe confirmed via Sanger Sequencing and DBS results.

CasePreviousTesting: same as group, EMG, muscle biopsy

CaseGenotypingMethod: same as group

Variant1: NM_000152.3:c.1192delC

CAID: CA628018372, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA628018372

gnomAD: n/a

Variant2: NM_000152.3:c.2716G>A

CAID: CA401326980, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA401326980

gnomAD: n/a

Patient3: male, German

CasePresentingHPOs: HP:0003677, HP:0003236, HP:0003325, HP:0003327

HPOsFreeText: CK < 10x increase , CK = 1729 U/L, reduced alpha-glucosidase activity, treated with ERT

CaseNotHPOs: HP:0002093, HP:0003457

CaseAddInfo: onset after 30yo, previously diagnosed with Brugada Syndrome, but Pompe was confirmed via Sanger Sequencing. Asymptomatic brother also diagnosed with Pompe.

CasePreviousTesting: same as group, EMG

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.2331+2T>A

ClinVar: 371281, https://www.ncbi.nlm.nih.gov/clinvar/variation/371281/

gnomAD: n/a

Variant2: 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

Case#: P 6, Male, 2.8 months when started ERT (Died at 18.2 months old), ethnicity unknown

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0001639 , HP:0001252 , HP:0003701, HP:0002090

(Hypertrophic cardiomyopathy, Muscular hypotonia, Proximal muscle weakness, Pneumonia)

CaseHPOFreeText: Pneumonia with deterioration was a complication during ERT. Also patient suffered progressive hypertrophic cardiomyopathy.

AR IV

Required ventilation

Best motor status was being able to sit

CaseNotHPOs: N/A

CaseNotHPOFreeText: Patient did not required tube feeding

CasePreviousTesting: CRIM status was unknown

Antibody titer was 1:84,000

Variant: NM_000152.5(GAA):c.915G>A (p.Gly305=)

ClinVar: 188478

CAID: CA198779

gnomAD: N/A

ParentalGenotype: Bothe the maternal an paternal allele of the GAA gene carried the variant c.915G>A (p.Gly305=)

PreviouslyPublished: N/A

Case#: Subject number 7(L)

DiseaseAssertion: Late Onset Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: CK testing: 283 U/L (30-135 U/L is normal), Hex4: 2.6 mmol/mol Creatinine (≤3.0 mmol/mol Creatinine is normal)

glucosidase activity: GAA activity #1 was 1.05 micromole/L/h and GAA activity #2 (NBS) 0.19 in dried blood spots (>2.10 micromole/L/h is normal). 2.2 in confirmatory testing (>3.88 is normal).

Variant 1: NM_000152.5(GAA):c.-32-13T>G

Variant 1 ClinVarID: 4027

Variant 1 CAid: CA116606

Variant 2: NM_000152.5(GAA):c.546 G>A

Variant 2 ClinVarID: 280955

Variant 2 CAid: CA8814895

Zygosity: compound heterozygous

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: Subject number 23(L)

DiseaseAssertion: Late Onset Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: CK testing: 48 U/L (60-305 U/L is normal), AST: 73 U/L (22-71 U/L is normal), ALT: 28 U/L (7-50 U/L is normal), BNP 102.3 pg/mL (0.0–100.0 pg/mL is normal)

glucosidase activity: GAA activity #1 was 1.12 micromole/L/h and GAA activity #2 (NBS) 0.62 in dried blood spots (>2.10 micromole/L/h is normal). 2.5 in confirmatory testing (>3.88 is normal).

Variant 1: NM_000152.5(GAA):c.2238G>C

Variant 1 ClinVarID: 265160

Variant 1 CAid: CA8815665

Variant 2: NM_000152.5(GAA):c.2238G>C

Variant 2 ClinVarID: 265160

Variant 2 CAid: CA8815665

Variant 3: NM_000152.5(GAA):c.2065G>A

Variant 3 ClinVarID: 4030

Variant 3 CAid: CA116612

Zygosity: homozygous

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: Patient 8, Gender N/A, Onset at 1-2 months. Death at 13 months. Southeast Asian

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0002240, HP:0001252, HP:0002789, HP:0001698 (Hepatomegaly, Muscular hypotonia, Tachypnea, Pericardial effusion)

CaseHPOFreeText: Hepatomegaly is mild, Pericardial effusion is mild, BHV, SDD

CaseNotHPOs: N/A

CaseNotHPOFreeText: Normal PR Interval

CasePreviousTesting: GAA activity in leukocytes was 1.46% of normal control value.

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

Variant: NM_000152.5(GAA):c.877G>A (p.Gly293Arg)

ClinVar: 4036

CAID: CA116622

gnomAD: Highest population MAF = 0.00005704 (Latino)

ParentalGenotype: Both parents were carriers of the variant c.877G>A (p.Gly293Arg)

PreviouslyPublished: N/A

Case#: Patient 3, Gender N/A, 5-6 months old when diagnosed.13 months when died, Southeast Asian

DiseaseAssertion: Pompe disease

FamilyInfo:

CasePresentingHPOs: HP:0002094 HP:0001639. HP:0005165 (Hypertrophic Cardiomyopathy, Dyspnea, Shortened PR interval)

CaseHPOFreeText: Generalized Muscle weakness

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: GAA enzyme activity in leukocytes was 0% of the normal control value.

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

Variant1: NM_000152.5(GAA):c.1099T>C (p.Trp367Arg)

ClinVar:<br /> 555820

CAID: CA401364951

gnomAD: N/A

Variant2: NM_000152.5(GAA):c.1942G>A (p.Gly648Ser)

ClinVar: 188902

CAID: CA274102

gnomAD: Highest population MAF = 0.0003365 (South Asian)

ParentalGenotype: Father was carrier for Variant1 NM_000152.5(GAA):c.1099T>C (p.Trp367Arg)

Mother was carrier of Variant 2 NM_000152.5(GAA):c.1942G>A (p.Gly648Ser)

PreviouslyPublished: N/A

Case16: Female, 37 years onset, 49 years diagnosis, Italy

HPOsFreeText: See Group Phenotypes, ERT started at 50, GAA Activity at ~4 pmol/min/mg before ERT and ~11 after

GroupGenotypingMethod: PCR Amplification and GAA Gene Sequencing

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 http://gnomad.broadinstitute.org/variant/17-78078341-T-G

Variant2: NM_000152.4:c.1465G>A (p.Asp489Asn)

ClinVar: 92465 https://www.ncbi.nlm.nih.gov/clinvar/variation/92465/

gnomAD: European (Finnish) 4.621e-5, Overall 1.195e-5 http://gnomad.broadinstitute.org/variant/17-78084553-G-A

CaseAddInfo: Late Onset Pompe Disease

Patient20: Female

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

HPOsFreeText: CRIM positive, Anti-rh GGA antibodies maximum titer = 1:1.600, tracheostomy, partial heart normalization, moderate periventricular white matter abnormalities (hypomyelination)

CaseNotHPOs: HP:0002421, HP:0001371

NotHPOsFreeText: infusion associated reaction

CaseAddInfo: homozygous variant in trans, symtom onset and diagnosis at 4yo, ERT at 5yo

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant: NM_000152.4(GAA):c.1564C>G (p.Pro522Ala)

ClinVar: 371277, https://www.ncbi.nlm.nih.gov/clinvar/variation/371277/

gnomAD: n/a

Patient6: female

CasePresentingHPOs: HP:0001270

HPOsFreeText: CRIM positive, partial heat normalization

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

NotHPOsFreeText: infusion associated reaction

CaseAddInfo: variants in trans, symptom onset at 4yo, diagnosis at 6yo, ERT at 10yo. Died due to infusion reaction with ERT.

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.3(GAA):c.742delC

CAID: CA658795236, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.3%3Ac.742delC

gnomAD: n/a

Variant2: NM_000152.4(GAA):c.896T>C (p.Leu299Pro)

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

gnomAD: n/a

Patient26: Female

CasePresentingHPOs: HP:0004887, HP:0001270, HP:0001371

HPOsFreeText: CRIM positive, Anti-rh GGA antibodies maximum titer = ≤ 1:400, heart normalization

CaseNotHPOs: HP:0025156, HP:0002546, HP:0000365

NotHPOsFreeText: infusion associated reaction

CaseAddInfo: variants in trans, symptom onset at 3yo, diagnosis at 5yo, ERT at 8yo

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.1064T>C (p.Leu355Pro)

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

gnomAD: 0.000007972, http://gnomad.broadinstitute.org/variant/17-78082197-T-C

Patient14: male

CasePresentingHPOs: HP:0004887, HP:0040288, HP:0002546, HP:0000365

HPOsFreeText: CRIM negative, Anti-rh GGA antibodies maximum titer = 1:204.800, immunomodulation, infusion associated reaction, able to sit independently, partial heart normalization

CaseNotHPOs: HP:0001371

CaseAddInfo: homozygous variants in trans. Symptom onset, diagnosis and ERT at 4yo.

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

Subject III-9: Female

CasePresentingHPOs:

HPOsFreeText: DBS neutral/acid = 36.0

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: asymptomatic, asserted carrier status

CasePMIDs:

CasePreviousTesting: DBS

CaseGenotypingMethod: GAA Genotyping

Variant: NM_000152.4(GAA):c.2560C>T (p.Arg854Ter)

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

gnomAD: 0.0002090, http://gnomad.broadinstitute.org/variant/17-78092070-C-T

Case26

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 code not given

Variant1: NM_000152.4: [del Exons 15–20]

ClinVar: N/A

gnomAD: N/A

Variant2: NM_000152.4:c.2012T>G (p.Met671Arg)

ClinVar: 92469 https://www.ncbi.nlm.nih.gov/clinvar/variation/92469/

gnomAD: Not in gnomAD

CaseAddInfo: Infantile Onset Pompe Disease

Case41

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.2481+102_2646+31del (p.Gly828_Asn882del) (exon 18 del)

ClinVar: 4031 https://www.ncbi.nlm.nih.gov/clinvar/variation/4031/

gnomAD: Not in gnomAD

CaseAddInfo: Infantile Onset Pompe Disease, Patient is homozygous for this variant

Patient2: 8yo

CasePresentingHPOs: HP:0001638

HPOsFreeText: rhGAA dosage = 20QW, independent walker

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 29days old at ERT start

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_000152.3:c.2842_2843insT

CAID: CA913184740, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA913184740

gnomAD: n/a

Case#: Patient 1

DiseaseAssertion: Pompe Disease

FamilyInfo: None given

CasePresentingHPOs: None

CaseHPOFreeText: None

CaseNotHPOs: None

CaseNotHPOFreeText: None

CasePreviousTesting: Single gene sequencing with Ion Torrent Persional Genome Machine

Glucosidase activity: 0.0 nmol 5MU/hr/mL

Variant 1: NM_000152.5:c.2065G>A

Variant 1 ClinVarID: 4030

Variant 1 CAid: CA116612

Variant 2: NM_000152.5:c.1726G>A

Variant 2 ClinVarID: 92467

Variant 2 CAid: CA145760

Variant 2: NM_000152.5:c.596A>G

Variant 3 ClinVarID: 92486

Variant 3 CAid: CA145785

Variant 2: NM_000152.5:c.668G>A

Variant 4 ClinVarID: 92488

Variant 4 CAid: CA145791

ParentalGenotype: Not provided

Case#: Subject number 6, male, 4 months (onset), 4 months (first admission)

DiseaseAssertion: Pompe disease

FamilyInfo: "no family history of neuromuscular disorders"

CasePresentingHPOs: HP:0004887 (respiratory failure requiring assisted ventilation), HP:0001639 (hypertrophic cardiomyopathy), HP:0001522 (death in infancy), HP:0002090 (pneumonia)

CaseHPOFreeText: infantile-onset, dysphagia at baseline

CaseNotHPOs:

CaseNotHPOFreeText: no tracheostomy, not on BiPAP

CasePreviousTesting: “GAA activity in peripheral blood leukocytes lower than normal”; on enzyme replacement therapy

Case5: Female, 43 years report, Italy

CasePresentingHPOs: HP:0002355, HP:0003551, HP:0002098 (Difficulty walking, Difficulty climbing stairs, Respiratory distress)

HPOsFreeText: Height is 1.68 m, Weight is 80 kg, BMI is 28.3 kg/cm2, 7 years on ERT, Forced Vital Capacity at 64%, Nocturnal non-invasive ventilation

CaseAddInfo: Late Onset Pompe Disease

Case#: Patient 6, female, diagnosed 2016 (not given age of diagnosis), age 30 during study period

DiseaseAssertion: Pompe Disease

FamilyInfo: None given

CasePresentingHPOs: None given

CaseHPOFreeText: Requires wheelchair for long distance movement

CaseNotHPOs: None given

CaseNotHPOFreeText: None given

CasePreviousTesting: None given

Variant 1: NM_000152.5:c.-32-13T>G (unclear variant nomenclature)

Variant 1 ClinVarID: 4027

Variant 1 CAid: CA116606

Variant 2: NM_000152.5:c.525del (unclear variant nomenclature)

Variant 2 ClinVarID: 4033

Variant 2 CAid: CA220406

ParentalGenotype: Not provided

Case#: Patient 1, male, diagnosed 2000 (not given age), age 62 during study period

DiseaseAssertion: Pompe Disease

FamilyInfo: None given

CasePresentingHPOs: None given

CaseHPOFreeText: Requires B-pap at night

CaseNotHPOs: None given

CaseNotHPOFreeText: None given

CasePreviousTesting: None given

Variant 1: NM_000152.5:c.-32-13T>A

Variant 1 ClinVarID: N/A

Variant 1 CAid: CA913184742

Variant 2: NM_000152.5:c.1003G>A

Variant 2 ClinVarID: 972790

Variant 2 CAid: CA501005

ParentalGenotype: Not provided

Case5HPOsFreeText: 10 mg/kg GAA treatment, GAA activity at 0.6 pmol/punch/hr, GAA activity at 6% 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

Unknown variant, likely a typo

Variant2: NM_000152.4:c.193G>T

ClinVar:

gnomAD:

CaseAddInfo:

Case9HPOsFreeText: 20 mg/kg GAA treatment, GAA activity at 0.6 pmol/punch/hr, GAA activity at 5.5% 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"

Variant: 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

CaseAddInfo: Patient is homozygous for this variant

Patient7:

CasePresentingHPOs:

HPOsFreeText: classic IOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: homozygous

CasePMIDs:

CasePreviousTesting:

CaseGenotypingMethod: method not described

Variant: NM_000152.4(GAA):c.1124G>T (p.Arg375Leu)

ClinVar: 283230, https://www.ncbi.nlm.nih.gov/clinvar/variation/283230/

gnomAD: 0.000008050, https://gnomad.broadinstitute.org/variant/17-78082336-G-T

Case8: Male, 1.5 yr onset, 2 yr diagnosis, 13.3 yr report

HPOsFreeText: FVC z-score sitting -0.91 (90% pred), FVC z-score supine -1.76 (80% pred), 93% MRC Scale, 1595 CK U/l, 16 GAA activity (nmol/h/mg)^h from cultured fibroblasts

NotHPOsFreeText: No wheelchair used, No respiratory support

Case#: Patient 4, Gender unknown, age unknown, ethnicity unknown

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0001638, HP:0003756

(Cardiomyopathy, Skeletal myopathy)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Sequence analysis of the GAA gene was performed in a CLIA and CAP certified laboratory. Cross Reactive Immune reaction was indeterminate in peripheral blood mononuclear cells (PBMCs)

Cross Reactive Immune reaction was not available in Dried blood spots.

Variant: NM_000152.5(GAA):c.2560C>T (p.Arg854Ter)

ClinVar: 4034

CAID:CA340130

gnomAD: Highest population MAF= 0.001891 (African)

ParentalGenotype: N/A

CasePD/Pathogenic-3: 2 weeks diagnosis

HPOsFreeText: GAA activity 4.9 (nmol · h−1 · mg−1), Mean percentage of normal 6.9%

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.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

Variant4: 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

CaseAddInfo: Patient has one pseudodeficency allele and one pathogenic allele, Nomenclature claims Variant 1 and 2 are in cis, Nomenclature claims Variant 3 and 4 are in cis

Case#: Patient 2, Male, 71 year old, ethnicity unknown

DiseaseAssertion: Pompe disease

diagnosed at age 52 with SMA type III following an EMG reporting neurogenic changes and a muscle biopsy from a hamstring muscle that demonstrated denervation atrophy

FamilyInfo: N/A

CasePresentingHPOs: HP:0003701, HP:0003445

(Proximal muscle weakness, EMG:neuropathic changes

CaseHPOFreeText: Normal strength in the upper extremities with moderate weakness of hip flexion at 3/5, hip abduction 3–4/5, hip adduction 3–4/5, and hamstrings 4/5.

EMG showed myotonic discharges in the anterior tibialis, medial gastrocnemius, iliopsoas, tensor fasciae latae, and biceps brachii muscles.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

Staining for PAS and acid phosphatase was normal.

Serum CK was 208 U/L (normal range 70–185)

CasePreviousTesting: GAA activity was 1.3pmol/punch/h (normal 10–49 pmol/punch/h) and he was found to have 2 heterozygous mutations

Variant 1: NM_000152.5(GAA):c.-32-13T>G

ClinVar: 4027

CAID: CA116606

gnomAD: Highest population MAF= 0.005541 (Ashkenazi Jewish)

Variant 2: NM_000152.5(GAA):c.1841C>A (p.Thr614Lys)

ClinVar: 167113

CAID: CA234050

gnomAD: Highest population MAF= 0.00004784 (European nin-Finnish)

ParentalGenotype:N/A

PreviouslyPublished:N/A

Case1: Female, 22 years old, ethnicity not specified

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: See Fig 1

ParentalGenotype: The patient's parents revealed reduced concentrations of glycoprotein llb-Illa and were considered to be heterozygotes. See Fig 1

CasePresentingHPOs: HP:0000421, HP:0000225, HP:0000132, HP:0000978

(Severe epistaxis, gingival bleeding, menorrhagia, spontaneous bruising)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

ProteinExpression: Platelets had much reduced alphaIIb3 when estimated by crossed immunoelectrophoresis

PlateletAggregation: Platelet aggregation was absent with ADP, arachidonic acid, and collagen.

CasePreviousTesting: Sequenced all exons and splice sites 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: (p.Arg327His) and (p.Gly381Arg)

ClinVar: 2896 and 381748

CAiD: CA115839 and CA8603182

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

PreviouslyPublished: PMID: 3762006 proband is mentioned in this article

Case2: Patient M2, Female, French Gypsy, age is not specified

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: See Figure 2 for pedigree

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

Case37: Patient RS

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: N/A

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

(Epistaxis, gingival bleeding, 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.1260G>A and the other variant won't show up in CAR

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA8623200

gnomAD: MAF in the African population is 0.00004005 https://gnomad.broadinstitute.org/variant/17-45368454-G-A

PreviouslyPublished: Reference 60

Case23: Family I from GT database, gender and age not specified

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: N/A

Gene: ITGB3

Variant: NM_000212.2:c.262C>T (p.Arg88Ter)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA400020703

gnomAD: MAF in the Other population 0.0001385 https://gnomad.broadinstitute.org/variant/17-45360816-C-T

PreviouslyPublished: Reference number 28

Case1: Patient KW (this patient can be found in the GT database)

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs: HP:0000421, HP:0000225

(Epistaxis, gingival bleeding)

CaseHPOFreeText: Blood transfusions needed

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: Surface expression of GPIIb/GPIIIa not reported for this patient

PlateletAggregation: N/A

CasePreviousTesting: N/A

Gene: ITGA2B

Variant: 4.5-KB DEL, EX2-9

LegacyVariant: N/A

ClinVar: 2890

CAiD: N/A

gnomAD: N/A

PreviouslyPublished: PMID: 1702098

Case30: Patient CM

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: N/A

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

(Epistaxis, gingival bleeding, 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.718C>T (p.Arg240Trp)

LegacyVariant: N/A

ClinVar: 13555

CAiD: CA123228

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

PreviouslyPublished: Reference 48 and 49

Case32: Patient SH

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: 20% GPIIIa and GPIIb surface expression

PlateletAggregation: N/A

CasePreviousTesting: N/A

Gene: ITGB3

Variant: NM_000212.2:c.725G>A (p.Arg242Gln)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA291224896

gnomAD: N/A

PreviouslyPublished: Reference number 5 in this article

Supplementary Table S1:

Case40: GT47, 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.832del (p.Asp278IlefsTer101)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA915940374

gnomAD: N/A

Supplementary Table S1:

Case34: GT40, Canadian/Pakistani, 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.857T>A (p.Val286Asp)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA399805011

gnomAD: N/A

Supplementary Table S1:

Case28: GT33a, USA/Laos, gender and age not specified or reported

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.262C>T (p.Arg88Ter) and NM_000212.2:c.2113del (p.Ley705Cysfs*4)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA400020703 and CA8623443

gnomAD: MAF in the Other population is 0.0001385 for (p.Arg88Ter) https://gnomad.broadinstitute.org/variant/17-45360816-C-T and MAF in the East Asian population is 0.0001087 for (p.Ley705Cysfs*4) https://gnomad.broadinstitute.org/variant/17-45380183-TC-T

Supplementary Table S1:

Case6: GT7, 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: 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 https://gnomad.broadinstitute.org/variant/17-45360741-C-T

Supplementary Table S1:

Case55: GT65, 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.574+1G>A and NM_000419.3:c.1946+3G>T

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA399805691 and CA626121071

gnomAD: MAF in the African population is 0.000 https://gnomad.broadinstitute.org/variant/17-42456008-C-A

Supplementary Table S1:

Case60: GT70, French/Arab, gender and ethnicity 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: ITGB3

Variant: M_000212.2:c.613_614+2del

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA915940309

gnomAD: N/A

Supplementary Table S1:

Case9: French/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: 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 is 0.000008801 https://gnomad.broadinstitute.org/variant/17-42449775-C-T for (p.Arg1026Gln)

Case1: Female, 5 years old, Swiss (from Morocco)

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: Affected brother

ParentalGenotype: Mother and father are heterozygous for the variant of interest

CasePresentingHPOs: HP:0001250, HP:0001270, HP:0000967, HP:0001892

(Seizures, retarded motor development, petechia, hemorrhagic diathesis)

CaseHPOFreeText: Subepndymal hematomas, cortical tubera, hydrocephalus internus

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: Flow cytometry protein expression results can be seen in Figure 1

PlateletAggregation: Platelets failed to aggregate with ADP, collagen, or arachidonic acid; however, ristocetin induced platelet agglutination was normal

CasePreviousTesting: Amplified DNA fragments containing exon 11 of the GPIIIa gene were purified by PCR preps DNA purification resin and wizard.

Gene: ITGB3

Variant: NM_000212.2:c.1702T>C (p.Cys568Arg)

LegacyVariant: (p.Cys542Arg)

ClinVar: N/A

CAiD: CA400032350

gnomAD: N/A

Case24: (GT38) Gender, age and ethnicity not specified

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: N/A

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: NM_000419.3:c.2338del

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA915940686

gnomAD N/A

Case33: (GT23) Gender, age and ethnicity are not specified

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: Both brothers are heterozygous for this mutation and sister is normal

ParentalGenotype: Father is heterozygous for the NM_000419.3:c.800-2A>T mutation and mother does not harbor this mutation. Mother is heterozygous for the NM_000419.3:c.1210+4A>G mutation and father does not have this mutation.

CasePresentingHPOs:

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: NM_000419.3:c.800-2A>T and NM_000419.3:c.1210+4A>G

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA399805150 and CA915940692

gnomAD N/A

Case5: (GT34), Gender, age and ethnicity not reported

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: N/A

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)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA913189168

gnomAD N/A

Case10: (GT45) Gender, age and ethnicity not specified

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: N/A

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

LegacyVariant: N/A

ClinVar: 2896

CAiD: CA115839

gnomAD N/A

Case31: (GT41) Gender, age and ethnicity are not specified

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: N/A

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: ITGB3

Variant: NM_000212.2:c.887_901del

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA626379036

gnomAD MAF in the South Asian population is 0.00003266 https://gnomad.broadinstitute.org/variant/17-45364541-AATGACGGGCAGTGTC-A

Case7: (GT26) Gender, age and ethnicity not specified

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: N/A

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: NM_000419.3:c.641T>C (p.Leu214Pro)

LegacyVariant: N/A

ClinVar: 2901

CAiD: CA115848

gnomAD N/A

Case2: GT18, Gender, age, ethnicity not specified

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: 1 brother is heterozygous for the g.951G>A promoter variant and does not have the other Leu343Pro mutation and one brother is normal and does not have the NM_000419.3:c.2915dup mutation

ParentalGenotype: Father: homozygous for the g.951G>A promoter variant and the Leu343Pro Mother: is heterozyous for both those mutations and mother does not have NM_000419.3:c.2915dup while the father is heterozygous for NM_000419.3:c.2915dup

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) and NM_000419.3:c.2915dup

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA913189168 (promoter variant) and CA399804619 (p.Leu343Pro) and CA8602531

gnomAD MAF in the East Asian population is 0.0001088 https://gnomad.broadinstitute.org/variant/17-42452054-C-CG for the NM_000419.3:c.2915dup variant

Case12: (GT39) Gender, age and ethnicity not specified

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: N/A

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: ITGB3

Variant: NM_000212.2:c.92G>A (p.Cys31Tyr)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA400031593

gnomAD N/A

Case13: Patient TG, gender, age and 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.3060G>A

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA500261104

gnomAD: N/A

Case7: Patient ID G, Female, 1 year 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)

(Easy bruising, recurrent epistaxis, gingival bleeding)

CaseHPOFreeText: Ear bleeding

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

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

CaseNotHPOsFreeText: Hemorrage after dental, hemorrhage after trauma, 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

Case1: Patient ID A, Male, 6 years old, ethnicity not specified

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: N/A (Parents are consangenous)

CasePresentingHPOs: HP:0000978, HP:0002239

(Easy bruising, gastrointestinal bleeding)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0000967, HP:0000979, HP:0004406, HP:0000225, HP:0002239, HP:0000790, HP:0005261

(Petechiae, purpura, recurrent epistaxis, gingival bleeding, intracranial hemorrhage, hematuria, hemarthrosis)

CaseNotHPOsFreeText: Hemhorrage after dental, hemhorrage 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 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.435C>A (p.Asn145Lys) and NM_000419.3:c.531T>A (p.Cys177Ter)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA399805991 and CA290955739

gnomAD: N/A

PreviouslyPublished: PMID: 20020534

Case14: Patient ID N, Male, 7 years old, ethnicity not specified

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs: HP:0000967, HP:0000979, HP:0000978, HP:0004406, HP:0000225

(Petechiae, purpura, easy bruising, recurrent epistaxis, gingival bleeding)

CaseHPOFreeText: Hemorrhage after dental, hemorrhage after trauma

CaseNotHPOs: HP:0002239, HP:0002239, HP:0000790, HP:0005261, HP:0002248

(GI bleeding, intracranial hemorrhage, hematuria, hemarthrosis, hematemesis)

CaseNotHPOsFreeText: Ear bleeding

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.774T>A (p.Cys258Ter)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA400023704

gnomAD: N/A

Case5: Patient ID E, Female, 1 year old, ethnicity not specified

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs: HP:0000978, HP:0000225

(Easy bruising, gingival bleeding)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0000967, HP:0000979, HP:0004406, HP:0002239, HP:0002239, HP:0000790, HP:0005261, HP:0002248

(Petechiae, purpura, recurrent epistaxis, 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 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: c.1460insAGGT (p.Ser477Gfs*111)

LegacyVariant: N/A

ClinVar: N/A

CAiD: Unregistered Variant

gnomAD: N/A