Case: P12, M/18

DiseaseAssertion: VWD1

FamilyInfo: No family history

ParentalGenotype: NA

CaseHPOFreeText: The bleeding score was 4, aPTT was 37 seconds, FVIII:C was 46%, VWF:RCo was 42 IU/dL, and VWF:Ag was 27 IU/dL, with a VWF:RCo/VWF:Ag ratio of 1.6. The VWF multimer pattern was normal, RIPA was 10 ohms, and the platelet count was 250 × 10⁹/L.

CasePreviousTesting: NA

GenotypingMethod: Direct sequencing of all exons, flanking intronic sequences, and the promoter of VWF was performed.

Gene: VWF

Variant: no mutation detected

HGVS:

ClinVar:

CAID:

gnomAD:

Case: P6, F/7

DiseaseAssertion: VWD1

FamilyInfo: No family history

ParentalGenotype: NA

CaseHPOFreeText: The bleeding score was 5, aPTT was 29 seconds, FVIII:C was 71%, VWF:RCo was 19 IU/dL, and VWF:Ag was 19 IU/dL, with a VWF:RCo/VWF:Ag ratio of 1.0. The VWF multimer pattern was normal, RIPA was not tested, and the platelet count was 475 × 10⁹/L.

CasePreviousTesting: NA

GenotypingMethod: Direct sequencing of all exons, flanking intronic sequences, and the promoter of VWF was performed.

Gene: VWF

Variant: no mutation detected

HGVS:

ClinVar:

CAID:

gnomAD:

Case: 2M-1

DiseaseAssertion: VWD2M

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: AcuStar RCo/Ag = 0.60; AcuStar CB/Ag = 1.16; ELISA CB/Ag = 1.12

CaseHPOFreeText:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: not described

PreviouslyPublished:

Gene: VWF

Variant: p.Arg1315Gln

HGVS: n/a

ClinVarID: n/a

CAID: n/a

gnomAD: n/a

Case: 2M-2

DiseaseAssertion: VWD2M

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: AcuStar RCo/Ag = 0.01; AcuStar CB/Ag = 1.16; ELISA CB/Ag = 1.41

CaseHPOFreeText:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: not described

PreviouslyPublished: 1409710

Gene: VWF

Variant: c.3970G>A (p.Gly1324Ser)

HGVS: NM_000552.5(VWF):c.3970G>A (p.Gly1324Ser)

ClinVarID: 300; https://www.ncbi.nlm.nih.gov/clinvar/variation/300/?new_evidence=false

CAID:

gnomAD: MAF = 0.00003267 in South Asian population; https://gnomad.broadinstitute.org/variant/12-6128614-C-T

Case: 2A-5

DiseaseAssertion: VWD2A

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: AcuStar RCo/Ag = 0.36; AcuStar CB/Ag = 0.15; ELISA CB/Ag = 0.24

CaseHPOFreeText:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: not described

PreviouslyPublished: PMID: 1537829

Gene: VWF

Variant: c.4789C>T (p.Arg1597Trp)

HGVS: NM_000552.5(VWF):c.4789C>T (p.Arg1597Trp)

ClinVarID: 285; https://www.ncbi.nlm.nih.gov/clinvar/variation/285/?new_evidence=false

CAID:

gnomAD: absent

Case: 2B-8

DiseaseAssertion: VWD2B

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: AcuStar RCo/Ag = 0.99; AcuStar CB/Ag = 1.35; ELISA CB/Ag = 1.02

CaseHPOFreeText:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: not described

PreviouslyPublished: 16985174

Gene: VWF

Variant: c.3797C>T (p.Pro1266Leu)

HGVS: NM_000552.5(VWF):c.3797C>T (p.Pro1266Leu)

ClinVarID: 314; https://www.ncbi.nlm.nih.gov/clinvar/variation/314/?new_evidence=false

CAID:

gnomAD: MAF (European, Finnish) = 0.003667; 1 homozygote; https://gnomad.broadinstitute.org/variant/12-6128787-G-A

Case: 2A-7

DiseaseAssertion: VWD2A

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: AcuStar RCo/Ag = 0.27; AcuStar CB/Ag = 0.10; ELISA CB/Ag = 0.39

CaseHPOFreeText:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: not described

PreviouslyPublished: PMID:1673047

Gene: VWF

Variant: c.4883T>C (p.Ile1628Thr)

HGVS: NM_000552.5(VWF):c.4883T>C (p.Ile1628Thr)

ClinVarID: 284; https://www.ncbi.nlm.nih.gov/clinvar/variation/284/?new_evidence=false

CAID:

gnomAD: absent

Case: 2A-1

DiseaseAssertion: VWD2A

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: AcuStar RCo/Ag = 0.49; AcuStar CB/Ag = 0.29; ELISA CB/Ag = 0.33

CaseHPOFreeText:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: not described

PreviouslyPublished: PMID: 8435341

Gene: VWF

Variant: c.4541T>G (p.Phe1514Cys)

HGVS: NM_000552.5(VWF):c.4541T>G (p.Phe1514Cys)

ClinVarID: 304; https://www.ncbi.nlm.nih.gov/clinvar/variation/304/?new_evidence=false

CAID:

gnomAD: absent

PMID: 29098718

Gene: VWF

HGNC: 12726 (type 1)

Note: This article is about how VWF levels change as VWD patients age.

Case: IP-2

DiseaseAssertion: VWD3

FamilyInfo: The mother reported no history of bleeding episodes and the laboratory data were in the border line of the normal range.

ParentalGenotype(s): mother is heterozygous for the p.Gln2551AlafsX16 in the VWF gene

CasePresentingHPOs: HP:0000421

CaseHPOFreeRext: VWF:Ag <6%, VWF:RCo <6% and FVIII:C 2%. Clinically, repetitive severe epistaxis and subcutaneous hematomas were observed.

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: Direct sequencing of exons 2–52 including exon/intron boundaries of the VWF gene

GenotypingMethod: multiple ligation‐dependent probe amplification (MLPA; using kit P011 and P012; MRC Holland, Amsterdam, the Netherlands) according to the manufacturer’s instructions. The PCR products were run on an ABI PRISM 3130XL sequencer with the GeneScan 500 LIZ size standard and analyzed using GeneMapper Software 5.0 (Applied Biosystems, Darmstadt, Germany).

PreviouslyPublished: NA

Gene: VWF

Variant: p.Gln2551AlafsX16

HGVS:

ClinVarID:

CAID:

gnomAD:

MultipleGeneVariants:

GeneName: VWF

Variant: whole gene deletion

ClinVarID or CAID:

gnomAD:

Case: Patient 16 (Family D), male, 67yo

DiseaseAssertion: VWD2B

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0030132, HP:0030129, HP:0030130, HP:0011871, HP:0012147

(Absence of large von Willebrand factor multimers, impaired ristocetin cofactor assay activity, Impaired von Willebrand factor collagen binding activity, Impaired RIPA, Reduced quantity of VWF)

CaseHPOFreeText: blood group O, Platelet count x103/μl = 60, PFA 100 sec = >300, SPA % = 20, MADR mg/mL = 0.15, VWF:Ag U/dL = 34.3, VWF:CB U/dL = 10.5, VWF:CB ratio = 0.31, VWF:RCo U/dL = 14.0, VWF:RCo ratio = 0.41, Platelet VWF U/dL = 142.50, FVIII U/dL = 43.5, BAT F/M = 20

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: Sequencing of exon 28 of VWF

PreviouslyPublished: NA

Gene: VWF

Variant: c.3946G>A (p.Val1316Met)

HGVS: NM_000552.4(VWF):c.3946G>A (p.Val1316Met)

ClinVarID: 290; https://www.ncbi.nlm.nih.gov/clinvar/variation/290/

CAID: NA

gnomAD: absent

Case: Patient 9 (Family B), male, 71yo

DiseaseAssertion: VWD2B

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0030132, HP:0030129, HP:0030130, HP:0011871, HP:0012147

(Absence of large von Willebrand factor multimers, impaired ristocetin cofactor assay activity, Impaired von Willebrand factor collagen binding activity, Impaired RIPA, Reduced quantity of VWF)

CaseHPOFreeText: blood group O, Platelet count x103/μl = 56, PFA 100 sec = >300, SPA % = 22, MADR mg/mL = 0.3, VWF:Ag U/dL = 81.2, VWF:CB U/dL = 25.9, VWF:CB ratio = 0.32, VWF:RCo U/dL = 33.75, VWF:RCo ratio = 0.41, Platelet VWF U/dL = 146.2, FVIII U/dL = 52, BAT F/M = NA

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: Sequencing of exon 28 of VWF

PreviouslyPublished: NA

Gene: VWF

Variant: c.3922C>T (p.Arg1308Cys)

HGVS: NM_000552.4(VWF):c.3922C>T (p.Arg1308Cys)

ClinVarID: 289; https://www.ncbi.nlm.nih.gov/clinvar/variation/289/

CAID: NA

gnomAD: absent

Case: Patient 3 (Family B), male, 55yo

DiseaseAssertion: VWD2B

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0030129, HP:0030130, HP:0011871, HP:0012147

(impaired ristocetin cofactor assay activity, Impaired von Willebrand factor collagen binding activity, Impaired RIPA, Reduced quantity of VWF)

CaseHPOFreeText: blood group O, Platelet count x103/μl = 204, PFA 100 sec = >300, SPA % = 0, MADR mg/mL = 0.45, VWF:Ag U/dL = 23.4, VWF:CB U/dL = 21.1, VWF:CB ratio = 0.9, VWF:RCo U/dL = 17.2, VWF:RCo ratio = 0.74, Platelet VWF U/dL = 42.6, FVIII U/dL = 60.5, BAT F/M = 20

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: Sequencing of exon 28 of VWF

PreviouslyPublished: NA

Gene: VWF

Variant 1: c.3797C>T (p.Pro1266Leu)

HGVS: NM_000552.4(VWF):c.3797C>T (p.Pro1266Leu)

ClinVarID: 314; https://www.ncbi.nlm.nih.gov/clinvar/variation/314/

CAID: NA

gnomAD: MAF = 0.003667 (92/25086 alleles; 1 homozygote) in the European (Finnish) population; https://gnomad.broadinstitute.org/variant/12-6128787-G-A?dataset=gnomad_r2_1

Variant 2: c.7085G>T (p.Cys2362Phe)

HGVS: NM_000552.4(VWF):c.7085G>T (p.Cys2362Phe)

ClinVarID: 315; https://www.ncbi.nlm.nih.gov/clinvar/variation/315/

CAID: NA

gnomAD: absent

Case#: Subject number 34, female, 28 years (diagnosis), 39 years (baseline visit)

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0001324 (Muscle Weakness)

CaseHPOFreeText:

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

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 17, male, 14 years (baseline visit)

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0003236 (Elevated circulating creatine kinase concentration)

CaseHPOFreeText:

CaseNotHPOs: HP:0001324 (Muscle Weakness), 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 22, male, 47 years (diagnosis), 64 years (baseline visit), 57 years (ERT), 56 (age at 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 16, male, 22 years (baseline visit)

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0003236 (Elevated circulating creatine kinase concentration)

CaseHPOFreeText:

CaseNotHPOs: HP:0001324 (Muscle Weakness), 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 6, female, 36 years (diagnosis), 51 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: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

Case#: Subject number 28, male, 20 years (diagnosis), 43 years (baseline visit), 43 (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

Case#: Subject number 23, male, 2 years (diagnosis), 8 years (baseline visit)

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0003236 (Elevated circulating creatine kinase concentration)

CaseHPOFreeText:

CaseNotHPOs: HP:0002870 (obstructive sleep apnea), HP:0001324 (Muscle Weakness), 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

Case#: Subject number 33, female, 16 years (diagnosis), 20 years (baseline visit)

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0003236 (Elevated circulating creatine kinase concentration)

CaseHPOFreeText:

CaseNotHPOs: HP:0002098 (respiratory distress), HP:0002870 (obstructive sleep apnea), 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 20, female, 29 years (diagnosis), 40 years (baseline visit), 40 years (ERT), 39 (age at 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 26, male, 35 years (diagnosis), 51 years (baseline visit), 51 years (ERT), 49 (age at 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 15, female, 35 years (diagnosis), 51 years (baseline visit), 46 years (ERT), 46 (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 24, female, 42 years (diagnosis), 57 years (baseline visit), 55 years (ERT), 54 (age at 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 27, male, 35 years (diagnosis), 51 years (baseline visit)

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

Case#: Subject number 11, male, 23 years (diagnosis), 31 years (baseline visit), 24 years (ERT), 23 (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 12, female, 20 years (diagnosis), 46 years (baseline visit), 39 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

Case#: Subject number 29, female, 40 years (diagnosis), 54 years (baseline visit), 48 (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

Case#: Subject number 2, male, 20 months (onset), 24 months (first admission)

DiseaseAssertion: Pompe disease

FamilyInfo: Patients 2 and 3 are full siblings

CasePresentingHPOs: HP:0002355 (difficulty walking), HP:0002205 (recurrent respiratory infections), HP:0004887 (respiratory failure requiring assisted ventilation)

CaseHPOFreeText: on BiPAP, ambulatory (transport ventilator), juvenile-onset, assistive device (wheelchair)

CaseNotHPOs:

CaseNotHPOFreeText: no dysphagia at baseline, no tracheostomy

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

PMID: 31392189

Gene: GAA

Disease: Pompe disease

Inheritance: Autosomal recessive

Case#: Subject number 2, male, 48 years (report), 39 years (onset), 43 years (diagnosis)

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0002617 (aneurysm)

CaseHPOFreeText: on BiPap, ambulatory

CaseNotHPOs: HP:0000365, HP:0000360, HP:0000939, HP:0009830, HP:0100647, HP:0010788, HP:0000821, HP:0002650, HP:0001638 (hearing loss, tinnitus, osteoporosis, peripheral neuropathy, Graves disease, Testicular cancer, hypothyroidism, scoliosis, cardiomyopathy)

CaseNotHPOFreeText: No infusion reaction, no tracheostomy

CasePreviousTesting: “documented deficiency of acid alpha-glucosidase enzyme activity”; on enzyme replacement therapy

Case21: Patient GI, gender and age are not specified, all of these patients are Caucasian (either Italian or European)

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: All patients presented with a current or past history of bleeding and a bleeding time >15 min. Bleeding symptoms were evaluated by examining available hospital records. Mild bleeders were defined as those who bled only after trauma or surgery or had minor symptoms, such as epistaxis. Moderate/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 transfusions

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: See Table 1

PlateletAggregation: See Table 1

CasePreviousTesting: To identify point mutations responsible for GT, we have sequenced all coding regions of Ib and 3 genes and intron/exon boundaries.

Gene: ITGB3

Variant: c.728T>T (Unregistered) GT database has the same variant listed and it won't show up in CAR

LegacyVariant: ^

ClinVar: ^

CAiD: ^

gnomAD: ^

PMID: 40126091

**Gene: ** ITGA2B

GNC: 6138

Case1: Male, elderly (specific age not specified), from Argentina (specific ethnicity not specified)

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Mild bleeding disorder

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: Flow cytometry showed patient's platelet aIIbb3 content was 40–50% of the usual range

PlateletAggregation: Platelets failed to aggregate with all physiological agonists including thrombin

CasePreviousTesting: N/A

Gene: ITGB3

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

LegacyVariant: (p.Ser752Pro)

ClinVar: 13556

CAiD: CA123230

gnomAD: N/A

PreviouslyPublished: Caen, 1985; Chenet al, 1992 (PMID's not available at this time, go to these articles from this curated paper)

PMID: 39501528

Gene: ITGB3

GNC: 6156

Case23: Female, age not specified

DiseaseAssertion: Glanzmann thrombasthenia type 1

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

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: All Table 1 states is "missense mutation" not enough information provided

LegacyVariant: N/A

ClinVar: N/A

CAiD: N/A

gnomAD: N/A

Case#: Female, 30 (age of diagnosis)

Disease: Glazmann's Thrombasthenia Like Syndrome

CasePresentingHPOs: HP:0000225, HP:0000978, HP:0006298

Gingival bleeding, Bruising susceptibility, Prolonged bleeding after dental extraction

CaseNotHPOs: NA

FamilyInfo: Pedigree figure 1. Father and two daughters affected.

PlateletAgreggation: Family member studied: Decreased PLT aggregation and diminished ATP release with the agonists ADP, collagen, and AA, with normal ristocetin agglutination

GenotypingMethod: Genetic analysis of ITGA2B and ITGB3 genes was performed by next-generation sequencing (NGS). Sanger sequencing used to confirm variants.

ClinVar: Not Found

CAID: CA400034251

Variant: NM_000212.3:c.2236A>C (ITGB3)

GnomAD: Not Found

ExpressionEvidence: Level of expression on PLT surface determined by FCM: CD41a (GPIIb/IIIa) 38%, CD61 (GPIIIa) 41%, and CD42b (GPIb) 85%. Healthy control value range: CD41a (GPIIb/IIIa) (85-115%); CD61 (GPIIIa) (80-120%); CD42b (GPIb) (70-130%).

Case#: Female, 75 (age when studied in 1975)

Disease: Glazmann's Thrombasthenia Like Syndrome

CasePresentingHPOs: HP:0001873, HP:0006298

Thrombocytopenia, Prolonged bleeding after dental extraction

CaseNotHPOs: NA

FamilyInfo: Pedigree figure 1. Several affected family members.

PlateletAgreggation:Daughter studied: Decreased PLT aggregation and diminished ATP release with the agonists ADP, collagen, and AA, with normal ristocetin agglutination

GenotypingMethod: Genetic analysis of ITGA2B and ITGB3 genes was performed by next-generation sequencing (NGS). Sanger sequencing used to confirm variants.

From Daughter

ClinVar: Not Found

CAID: CA400034393

Variant: NM_000212.3:c.2278C>T (ITGB3)

GnomAD: Not Found

ExpressionEvidence: Level of expression on PLT surface determined by FCM: CD41a (GPIIb/IIIa) 52%, CD61 (GPIIIa) 77%, and CD42b (GPIb) 129%. Healthy control value range: CD41a (GPIIb/IIIa) (85-115%); CD61 (GPIIIa) (80-120%); CD42b (GPIb) (70-130%).

Case#: Female, 37 (age when studied)

Disease: Glazmann's Thrombasthenia Like Syndrome

CasePresentingHPOs: HP:0001873, HP:0000978, HP:0000225

Thrombocytopenia, bruising susceptibility, gingival bleeding

CaseNotHPOs: NA

FamilyInfo: Pedigree figure 1. Several affected family members, history of thrombocytopenia.

PlateletAgreggation:Sister studied: Decreased PLT aggregation and diminished ATP release with the agonists ADP, collagen, and AA, with normal ristocetin agglutination

GenotypingMethod: Genetic analysis of ITGA2B and ITGB3 genes was performed by next-generation sequencing (NGS). Sanger sequencing used to confirm variants.

ClinVar: Not Found

CAID: CA400034393

Variant: NM_000212.3:c.2278C>T (ITGB3)

GnomAD: Not Found

ExpressionEvidence: Level of expression on PLT surface determined by FCM: CD41a (GPIIb/IIIa) 73%, CD61 (GPIIIa) 74%, and CD42b (GPIb) 111%. Healthy control value range: CD41a (GPIIb/IIIa) (85-115%); CD61 (GPIIIa) (80-120%); CD42b (GPIb) (70-130%).

Case25: (Proband CabGT-25), Gender, age and ethnicity not specified

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: ITGB3

Variant: c.112513_112516del (Not showing up in the CAR) and they could not determine the second variant

LegacyVariant: N/A

ClinVar: N/A

CAiD: N/A

gnomAD N/A

PMID: 26453840

Gene: DBT

Disease: Maple syrup urine disease

MonDO: MONDO:0009563

InheritancePattern: AR

PMID: 15615815

Gene: ACADSB

Disease: 2-methylbutyrylglycinuria

MonDO: MONDO:0012392

InheritancePattern: AR

PMID: 14742428

Gene: BCKDHB

Disease: MSUD, type 1a

MonDO: MONDO:0023691

InheritancePattern: AR

PMID: 17883863

Gene: ACADSB

Disease: 2-methylbutyrylglycinuria

MonDO: MONDO:0012392

InheritancePattern: AR

GroupPresentingHPOs: HP:0000768, HP:0002857, HP:0008454, HP:0001382, HP:0007957, HP:0000687, HP:0004630, HP:0002869, HP:0008807, HP:0002673, HP:0003311, HP:0003414, HP:0002656,

GroupNotHPOs:

GroupPreviousTesting:

GroupMethod1: single gene seq of GALNS exons and flanking intronic seqs

GroupMethod2: GALNS enzyme assa from leukocytes as prev described - range was 0 - 8 nmol/17hr/mg protein with ref range being 40 - 170s

GroupGenotypingMethod: single gene seq

NumberMales: 34

NumberFemales: 34

CountryOrigin: India

Ethnicity:

Race:

AgeRange: 1 - 26

TotalNumber: 68

FamilyInfo: Family blood samples were obtained and the authors state a 3 generation pedigree was constructed for each family but that data was not provided in the study.

NoFamily:

VariantCount: 40

NonVariant:

OtherVariant:

NonPatientCell: EFO:0005214

GOterm: GO:0016192

GeneAlteration: Undifferentiated N2A cells (murine neuroblastoma cell line) were infected with shRNAs to downregulate endogenous Rab39b expression by 45%.

FunctionalEvidence: N2A cells 4d after treatment with shRNA showed a change in morphology. Clumps of actin and reduced and/or altered membrane protrusions were observed. Rescue with WT RAB39B was able to restore the normal actin and cytoskeletal morphology, indicating that Rab39b may alter intracellular vesicular trafficking steps essential for membrane remodeling.

FAVariants:

NonPatientCell: CL:0002608

GOterm: GO:0016192

GeneAlteration: Rab39b expression was knocked down in mouse primary hippocampal neurons using shRNA

FunctionalEvidence: Expression of Rab39b was reduced by 40% as determined by RT-PCR. Morphological analysis showed significant alteration and the number of growth cones was decreased at each neurite terminal. Authors also show that RAB39B was localized to growth cones and could be involved in intracellular trafficking related to membrane recycling of Golgi-derived vesicles. Therefore RAB39B gene alterations can lead to impaired trafficking and lead to accumulation in membrane content and disorganized growth of growth cones.

FAVariants:

PMID: 34504088

Gene: GALNS

Disease: Mucopolysaccharidosis IVA

MonDO: MONDO:0009659

InheritancePattern: AR

Notes:

RescueModel: Rescue WT CAG::GALNS in murine model by ovexpression in a Galns variant frequently found in human's affected with MPSIVA

GeneAlteration: transduction by AAV9 of CAG promoted WT murine optimized Galns coding sequence. Widespread tissue transduction was visualized with a CAG promoted GFP cassette delivered by AAV9, subsequently GFP production was widespread and found in all relevant tissue including osteoblast rich areas.

RescueVariant: AAV9-Galns with the coding sequence under the control of a CAG promoter element

RescuePhenotype: HP:0004325, MP:0001258, HP:0005736

RescueMethod: p.Arg386Cys (MPSIVA) mice were first transducted with CAG::GFP via AAV9 to verify efficiency of delivering the coding sequence to target tissue like bone. Then a CAG::Galns (optimized WT) was transducted in to MPSIVA mice (Galns -/-) via AAV9 by 4 weeks of age to avoid the high mortality in the Galns homozygote starting at 2 months.

RescueEvidence: Early transduction of Galns -/- mice recovered higher than WT enzyme activity and WT levels of keratan sulfate detected in liver tissue. Abnormalities in the growth plate in Galns -/- mice were absent in those treated with AAV9-Galns resulting from a return to WT levels of enzyme activity and keratan sulfate in all bone tissue sampled. GALNS activity recovered in lung and heart tissue with the elevated heart rate in MPSIVA mice returned to WT.

ModelVariant: p.Arg386Cys

PMID: 11574891

Gene: TERC

Disease: Dyskeratosis congenita

MonDO: MONDO:0007485

InheritancePattern: AD

Notes: variant(s): NR_001566.1:n.408C>G, NR_001566.1:n.107_108delinsAG

CaseID 18

Zygosity Het for c.-129+9G>A, Het for c.357+1G>C

Phenotypes Iris grade 5 (aniridia or partial aniridia), HP:0000639, HP:0001104, HP:0001083, HP:0000482, HP:0000609

Segretation listed as sporadic, both parents unaffected and lack c.357+1G>C, father is het for c.-129+9G>A

NonHumanModel: Niu_Mouse

GeneAlteration: Transcription activator like effector nuclease (TALEN) - mediated strategy was used to target exon 1 of RAB39B to generate the knockout mice in the C57BL/6J background. A mouse line with a "GT" deletion at nucleotide 106-107 that caused a frameshift and early truncation of RAB39B was obtained. Authors confirmed absence of RAB39B loss of fucntion.

ModelPhenotype: Learning and memory deficits

HumanPhenotype: HP:0001249

ModelEvidence: 2-mo hemizygous male knock-out (KO) mice showed behavioral alterations compared to WT mice. KO mice showed reduced anxiety, impaired recognition memory, impaired short-term working memory, impaired spatial memory, impaired social novelty recognition, compromised motor skill learning, but motor ability was not affected. Authors indicate that impaired learning and memory was associated with altered synaptic plasticity.

ModelVariant:

WhereInPaper:

The evidence is scored minimal points as the phenotype recapitulated aligns with the human ID phenotype; however, the model provides no evidence of Parkinson disease phenotype. (0.5)

PMID: 32670181

Gene: RAB39B

Disease: early-onset parkinsonism-intellectual disability syndrome

MonDO: MONDO:0010709

Notes: The report analyzed RAB39B variation in a cohort of 176 individuals with early-onset Parkinson disease by copy number variation analysis, 5' and 3' UTR analyses. However, variants identified were classified as likely benign or uncertain significance.

PMID: 24357492

Gene: RAB39B

Disease: early-onset parkinsonism-intellectual disability syndrome

MonDO: MONDO:0010709

InheritancePattern: X-linked

Notes: Functional evidence?

PMID 17392301

First connection between pulmonary fibrosis and TERT?

PMID: 28148688

Gene: EXTL3

Disease: Neuro-immuno-skeletal Dysplasia Syndrome

MonDO ID: n/a

OMIM: 617425

PMID 28321846

Gene: PAX6

Variant NM_001368894.2:c.-128-2del

Disease: Ocular dysgenesis

InheritancePattern: AD

Disease PAX6-related ocular dysgenesis MONDO:0800183

Proband 26.03 and apparently de novo

PMID: 12721840

Gene: GALNS

Disease: Mucopolysaccharidosis IVA

MonDO: MONDO:0009659

InheritancePattern: AR

PMID 19535918 Gene: UNC80

PMID: 26399558

Gene: RAB39B

Disease: early-onset parkinsonism-intellectual disability syndrome

MonDO: MONDO:0010709

InheritancePattern: X-linked

PMID: 28132690

Gene: EXTL3

Disease: Neuro-immuno-skeletal Dysplasia Syndrome

MonDO ID: n/a

OMIM: 617425

PMID: 28708303 Gene: UNC80

PMID: 36245961

Gene: GALNS

Disease: Mucopolysaccharidosis IVA/ Morquio A

MonDO: MONDO:0009659

InheritancePattern: AR

Notes:

PMID: 35729508

Gene: GALNS

Disease: Mucopolysaccharidosis Type IVA

MonDO: MONDO:0009659

InheritancePattern: AR

Notes: Case Study - 23 probands

PMID: 12090986

Gene: TERC

Disease: Dyskeratosis congenita & bone marrow failure/pulmonary fibrosis

MonDO: MONDO:0007485, MONDO:0013879

InheritancePattern: AD

Notes: variants: NR_001566.1:n.58G>A, NR_001566.1:n.72C>G, NR_001566.1:n.110_113del

PMID: 25217002

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: 28662711

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: 20034980

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: 23845641

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: 15383938

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: 32106822

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: 32671223

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: 31996412

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: 18475055

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: 22357542

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: 33067065

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: N/A

OVID: 611206512

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: 19415739

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: 16381215

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: 33028284

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: 15658149

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: 8365725

Gene: F9

HGNCL: 3551

PMID: 16643212

Gene: F9

HGNC: 3551

PMID: 19236374

Gene: F9

HGNC: 3551

PMID: 28722788

Gene: F9

HGNC: 3551

PMID: 27213901

Gene: F9

HGNC: 3551

PMID: 34187575

Gene: F9

HGNC: 3551

PMID: 12588353

Gene: F9

HGNC: 3551

PMID: 3009023

Gene: F9

HGNC: 3551

PMID: 22544209

Gene: F9

HGNC: 3551

PMID: 21118338

Gene: F9

HGNC: 3551

PMID: 31026269

Gene: F9

HGNC: 3551

PMID:

Gene: F9

HGNC: 3551

PMID: 24375831

Gene: F9

HGNC: 3551

PMID: 1615486

Gene: F9

HGNC: 3551

PMID: 10595634

Gene: F9

HGNC: 3551

PMID: 1897528

Gene: F9

HGNC: 3551

PMID: 30846504

Gene: F9

HGNC: 3551

PMID: 8772212

Gene: F9

HGNC: 3551

PMID: 30576981

Gene: F9

HGNC: 3551