PMID: 1680373

Gene: F9

HGNC: 3551

PMID: 31267011

Gene: F9

HGNC: 3551

PMID: 34626083

Gene: F9

HGNC: 3551

PMID: 26063760

Gene: F9

HGNC: 3551

PMID: 15086324

Gene: F9

HGNC: 3551

PMID: 8055323

Gene: F9

HGNC: 3551

PMID: 31552493

Gene: F8

No Evidence: No mention of variants or probands in this article.

PMID: 29517974

Gene: F9

HGNC: 3551

PMID: 19262239

Gene: F9

HGNC: 3551

PMID: 10094553

Gene: F9

HGNC: 3551

PMID: 31523064

Gene: F8

NoEvidence: This article does not mention Hemophilia A, or F8. No mention of blood disorders in general.

PMID: 2743975

Gene: F9

HGNC: 3551

PMID: 33691693

Gene: TOPORS

PMID: 19853238

Gene: BEST1

PMID: 19183411

Gene: TOPORS

PMID: 33576794

Gene: TOPORS

PMID: 17924349

Gene: TOPORS

PMID: 21624210

Gene: IDUA

Disease: MPS1

Inheritance: Autosomal recessive

Case#: Family D proband, female, 2 months and 5 days old (age of diagnosis), 14 months old (age of onset), 10 years old (age at report), Tunisia.

DiseaseAssertion: MPS1-H

FamilyInfo: No affected family members (See Fig. 1), parents were 1st degree relatives (first cousins) (See Table 1).

CasePresentingHPOs: HP:0002094, HP:0001605, HP:0001999, HP:0004322 (Dyspnea, laryngeal paralysis, abnormal facial shape, short stature)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: IDUA activity (0.1 nmol/h/mg) (usual values: 1-5).

CaseUrineGAGs: glycosaminoglycans (97 mg/g of creatinine) (usual values: 9-46), abnormal electrophoresis profile with dermatan sulfate and heparan sulfate.

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1743C>G (p.Y581X)

Variant1ClinVarID: 550883

Variant1CAID: N/A

Variant2: c.1743C>G (p.Y581X)

Variant2ClinVarID: 550883

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

PMID: 23786846

Gene: IDUA

Disease: MPS1

Inheritance: Autosomal recessive

Case#: 8, Female, 0.7 years (diagnosed), 1.3 years (report), 7.0 kg (weight), 70 cm (height), Iranian

DiseaseAssertion: Hurler-Scheie Syndrome

FamilyInfo: Parents are consanguineous

CasePresentingHPOs: HP:0100790 (Hernia)

CaseHPOFreeText: Chronic Rhinorrhea

CaseNotHPOs: HP:0001249, HP:0001999, HP:0000943, HP:0001387, HP:0000365, HP:0007957, HP:0000238 (Mental Retardation, Facial Dysmorphic Features, Multiple Dysostosis, Joint Stiffness, Deafness, Corneal Opacity, Hydrocephalus)

CaseNotHPOFreeText: HM/HSM, Cardiac Manifestations

CaseEnzymeAssay: IDUA activity 1.06 (μmol/spot.20h)

CaseUrineGAGs: Quantitative urinary GAG 6.7 (mg/gCr)

CaseERT: N/A

CaseBMT: N/A

GenotypingMethod: Sanger Sequencing

Variant1: p.G84R

Variant2: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: 3, Male, 0.2 years (diagnosed), 1.5 years (report), 7.5 kg (weight), 72 cm (height), Iranian

DiseaseAssertion: Hurler-Scheie Syndrome

FamilyInfo: Parents are consanguineous

CasePresentingHPOs: N/A

CaseHPOFreeText: Chronic Rhinorrhea

CaseNotHPOs: HP:0001249, HP:0001999, HP:0000943, HP:0001387, HP:0100790, HP:0000365, HP:0007957, HP:0000238 (Mental Retardation, Facial Dysmorphic Features, Multiple Dysostosis, Joint Stiffness, Hernia, Deafness, Corneal Opacity, Hydrocephalus)

CaseNotHPOFreeText: HM/HSM, Cardiac Manifestations

CaseEnzymeAssay: IDUA activity 0.76 (μmol/spot.20h)

CaseUrineGAGs: Quantitative urinary GAG 10.80 (mg/gCr)

CaseERT: N/A

CaseBMT: N/A

GenotypingMethod: Sanger Sequencing

Variant1: p.Y109H

Variant2: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: 15, Male, 0.7 years (diagnosed), 4.2 years (report), 10.1 kg (weight), 60 cm (height), Iranian

DiseaseAssertion: Hurler-Scheie Syndrome

FamilyInfo: Parents are not consanguineous

CasePresentingHPOs: HP:0001249, HP:0001999, HP:0100790 (Mental Retardation, Facial Dysmorphic Features, Hernia)

CaseHPOFreeText: HM/HSM

CaseNotHPOs: HP:0000943, HP:0001387, HP:0000365, HP:0007957, HP:0000238 (Multiple Dysostosis, Joint Stiffness, Deafness, Corneal Opacity, Hydrocephalus)

CaseNotHPOFreeText: Chronic Rhinorrhea, Cardiac Manifestations

CaseEnzymeAssay: IDUA activity 0.23 (μmol/spot.20h)

CaseUrineGAGs: Quantitative urinary GAG 7.42 (mg/gCr)

CaseERT: N/A

CaseBMT: N/A

GenotypingMethod: Sanger Sequencing

Variant1: p.G84R

Variant2: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: 20, Female, 1.3 years (diagnosed), 12.5 years (report), 23 kg (weight), 80 cm (height), Iranian

DiseaseAssertion: Scheie Syndrome

FamilyInfo: Parents are not consanguineous

CasePresentingHPOs: HP:0001999, HP:0100790 (Facial Dysmorphic Features, Hernia)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0001249, HP:0000943, HP:0001387, HP:0000365, HP:0007957, HP:0000238 (Mental Retardation, Multiple Dysostosis, Joint Stiffness, Deafness, Corneal Opacity, Hydrocephalus)

CaseNotHPOFreeText: HM/HSM, Chronic Rhinorrhea, Cardiac Manifestations

CaseEnzymeAssay: IDUA activity 2.3 (μmol/spot.20h)

CaseUrineGAGs: Quantitative urinary GAG 7.6 (mg/gCr)

CaseERT: N/A

CaseBMT: N/A

GenotypingMethod: Sanger Sequencing

Variant1: Not Provided

Variant2: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: 10, Male, 0.6 years (diagnosed), 7.8 years (report), 9.0 kg (weight), 74 cm (height), Iranian

DiseaseAssertion: Hurler-Scheie Syndrome

FamilyInfo: Parents are not consanguineous

CasePresentingHPOs: HP:0001249, HP:0001999, HP:0000943, HP:0001387, HP:0100790, HP:0000365, HP:0000238 (Mental Retardation, Facial Dysmorphic Features, Multiple Dysostosis, Joint Stiffness, Hernia, Deafness, Hydrocephalus)

CaseHPOFreeText: HM/HSM, Chronic Rhinorrhea

CaseNotHPOs: HP:0007957 (Corneal Capacity)

CaseNotHPOFreeText: Cardiac Manifestations

CaseEnzymeAssay: IDUA activity 2.08 (μmol/spot.20h)

CaseUrineGAGs: Quantitative urinary GAG 7.8 (mg/gCr)

CaseERT: N/A

CaseBMT: N/A

GenotypingMethod: Sanger Sequencing

Variant1: p.G84R

Variant2: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#:Patient Sample unique ID 3, Infant screened positive at birth (specimens with activity ≤15% of the DMA for enzyme activity and a CLIR screening algorithm result of indeterminate or MPS I)

DiseaseAssertion:Severe MPS1, Hurler Syndrome

FamilyInfo:None

CasePresentingHPOs: HP:0007957 (mild corneal clouding), HP:0011729 (decreased joint range of motion), HP:0008454 (lumbar kyphosis)

CaseHPOFreeText: A history of multiple failed hearing tests, chronic serous otitis media, and pressure equalizer tube placement

CaseNotHPOs:None

CaseNotHPOFreeText: None

CaseEnzymeAssay: IDUA activity 0.163 (2.3) umol/L/h (%DMA) through dried blood spot during newborn screening and 4.3 pmol/punch/h Confirmatory IDUA enzyme

CaseUrineGAGs: DS 128.4 g/mol creatinine and HS 466.6 g/mol creatinine

CaseERT:No

CaseBMT: The patient received a cord blood transplantation at 7 months of age.

Variant1:1 homozygous pathogenic: c.208C>T; p.Q70* (∗ IDUA enzyme activity reference range is < 8.0 pmol/punch/hour.)

Variant1ClinVarID: 11909

Variant1CAID: CA204563

Variant2:1 homozygous pathogenic: c.208C>T; p.Q70* (∗ IDUA enzyme activity reference range is < 8.0 pmol/punch/hour.)

Variant2ClinVarID: 11909

Variant2CAID: CA204563

AdditionalVariants:N/A

ParentalGenotype:N/A

PreviouslyPublished:N/A

Case#: NY-604 ID number, Table S1.1 of Supplementary Material. Additional health information not provided.

DiseaseAssertion: Severe MPS-I

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: 2315 fmol/punch

CaseERT: N/A

CaseBMT: N/A

Variant1: N/A

Variant1ClinVarID: N/A

Variant1CAID: N/A

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: NJ-501 ID number, Table S1.1 of Supplementary Material. Male, 1 year and 1 month (age at first symptoms), 1 year and 2 months old (age at diagnosis). Stored ambient 3 yr

DiseaseAssertion: Severe MPS-I

FamilyInfo: N/A

CasePresentingHPOs: Macrocephaly, kyphosis, coarse facial features, corneal clouding, hearing impairment, developmental delays, speech delays (HP:0000256, HP:0002808, HP:0000280, HP:0007957, HP:0000365, HP:0001263, HP:0000750)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: 1147 fmol/punch

CaseERT: N/A

CaseBMT: N/A

Variant1: N/A

Variant1ClinVarID: N/A

Variant1CAID: N/A

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: CA-129 ID number, Table S1.1 of Supplementary Material. Female, 5 months old (age at first symptoms), 8 months old (age at diagnosis). Stored frozen (-20ºC) 14.8 yr.

DiseaseAssertion: Severe MPS-I

FamilyInfo: N/A

CasePresentingHPOs: Congestion, macrocephaly, pain, musculoskeletal deformities, short stature, short neck, corneal clouding (HP:0001742, HP:0000256, HP:0012531, HP:0011843, HP:0004322, HP:0000470, HP:0007957)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: 1083 fmol/punch

CaseERT: N/A

CaseBMT: N/A

Variant1: N/A

Variant1ClinVarID: N/A

Variant1CAID: N/A

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: NY-607 ID number, Table S1.1 of Supplementary Material. Additional health information not provided.

DiseaseAssertion: Severe MPS-I

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: 2169 fmol/punch

CaseERT: N/A

CaseBMT: N/A

Variant1: N/A

Variant1ClinVarID: N/A

Variant1CAID: N/A

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

PMID: 20026495

Gene: IDUA

Disease: MPS1

Inheritance: Autosomal recessive

PMID: 21639919

Gene: IDUA

Disease: MPS1

Inheritance: Autosomal recessive

PMID: 37239976

Gene: IDUA

Disease: MPS1

Inheritance: Autosomal recessive

Case#: Variant not associated with a proband. Variant listed in supplementary materials in Supplementary Table 4

DiseaseAssertion: Mucopolysaccharidosis type I, MPS I

FamilyInfo: N/A

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: X654C

Variant1ClinVarID: Not sure how to look up in CAR

Variant1CAID: Not sure how to look up in CAR

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: Variant not associated with a proband. Variant listed in supplementary materials in Supplementary Table 4

DiseaseAssertion: Mucopolysaccharidosis type I, MPS I

FamilyInfo: N/A

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: R89Q

Variant1ClinVarID: 11922

Variant1CAID: CA256124

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: Variant not associated with a proband. Variant listed in supplementary materials in Supplementary Table 4

DiseaseAssertion: Mucopolysaccharidosis type I, MPS I

FamilyInfo: N/A

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: G84R

Variant1ClinVarID:

Variant1CAID: CA355946488

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: YS of sibship 3, female, 0.4 years old (age at diagnosis), 0.7 years old (age at ERT enrollment), 8.3 years (duration of ERT)

DiseaseAssertion: MPS1-HS

FamilyInfo: Affected female OS (OS of sibship 3)

CasePresentingHPOs: HP:0007957, HP:0000943, HP:0002828 (Corneal opacity, dysostosis, joint contractures)

CaseHPOFreeText: Cardiac disease, mild musculoskeletal symptoms, mild to moderate ocular disease.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: Yes - After 8 years of ERT had no restrictions in ADL, no cognitive delays, and only mild musculoskeletal symptoms and mild to moderate ocular disease and cardiac symptoms remained stable.

CaseBMT: N/A

Variant1: N/A

Variant1ClinVarID: N/A

Variant1CAID: N/A

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: OS1 of sibship 6 (see Table 1), male, 9 years old (age at diagnosis), 13 years old (age at ERT enrollment), 6 years (duration of ERT)

DiseaseAssertion: MPS1-HS

FamilyInfo: Two affected siblings (OS2 and YS of sibship 6)

CasePresentingHPOs: HP:0007957, HP:0000943, HP:0002828 (Corneal opacity, dysostosis, joint contractures)

CaseHPOFreeText: Cardiac disease, musculoskeletal symptoms

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: Yes - Pulmonary function was 45–50 % of normal at T2. No restrictions in ADL.

CaseBMT: N/A

Variant1: N/A

Variant1ClinVarID: N/A

Variant1CAID: N/A

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient No. 3 (Table 1), White race, female, 1.95 years old (age at time of gene therapy), 75 IQ score, 2.13 years since gene therapy (2 years since latest visit).

DiseaseAssertion: MPS-IH

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: Yes

Variant1: c.208C>T (p.Q70X)

Variant1ClinVarID: 11909

Variant1CAID: CA204563

Variant2: c.208C>T (p.Q70X)

Variant2ClinVarID: 11909

Variant2CAID: CA204563

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

PMID: 37347427

Gene: IDUA

Disease: MPS1

Inheritance: Autosomal recessive

PMID:23465405

Gene: IDUA

Disease: MPS1

Inheritance: Autosomal recessive

PMID: 8213840

Gene: IDUA

Disease: MPS1

Inheritance: Autosomal recessive

PMID: 22306676

Gene: IDUA

Disease: MPS1

Inheritance: Autosomal recessive

PMID: 31298590

Gene: IDUA

Disease: MPS1

Inheritance: Autosomal recessive

PMID: 21364962

Gene: IDUA

Disease: MPS1

Inheritance: Autosomal recessive

PMID: 31046699

Gene: IDUA

Disease: MPS1

Inheritance: Autosomal recessive

PMID: 22371174

Gene: IDUA

Disease: MPS1

Inheritance: Autosomal recessive

PMID: 22371174

Gene: IDUA

Disease: MPS1

Inheritance: Autosomal recessive

Case#: Functional assay variant with a clinical significance of clinically benign.

DiseaseAssertion: MPS-I

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.246C>G (p.H82Q)

Variant1ClinVarID: 92637

Variant1CAID: CA220506

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Functional assay variant with a clinical significance of benign.

DiseaseAssertion: MPS-I

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.99T>G (p.H33Q)

Variant1ClinVarID: 92651

Variant1CAID: CA145894

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

PMID: 33301762

Gene: IDUA

Disease: MPS1

Inheritance: Autosomal recessive

PMID: 26260077

Gene: IDUA

Disease: MPS1

Inheritance: Autosomal recessive

Case#: Patient 11, male, age of diagnosis is 11 months

DiseaseAssertion: Mucopolysaccharidosis type I, MPS-I, Maternal Mucopolysaccharidosis type I

FamilyInfo: No family information provided in this paper

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

CaseEnzymeAssay: No results of iduronidase enzyme assay mentioned in this paper

CaseUrineGAGs: No record/details of urine GAG levels in this paper

CaseERT: Don't know

CaseBMT: Don't know

Variant1: c.208 C>T (p.Gln70*)

Variant1ClinVarID: 11909

Variant1CAID: CA204563

Variant2: c.208 C>T (p.Gln70*)

Variant2ClinVarID: 11909

Variant2CAID: CA204563

AdditionalVariants: No additional variants mentioned in this paper

ParentalGenotype: Variant of proband is from his mother; "11-month-old boy with a homozygous nonsense variant, c.208C>T (p.Gln70*), in exon 2 of IDUA, resulting from UPD(4)mat of 18 Mb on chromosome 4 pter."

PreviouslyPublished: Author states that he found this patient from 30737479 (PMID).

Case#: Patient 16 (see Table 2), Gestational age unavailable

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 0.32 nmol x mg-1 × hr-1

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: (p.H425fs) - unknown what the protein change is due to the frameshift

Variant1ClinVarID: N/A

Variant1CAID: N/A

Variant2: (p.H425fs) - unknown what the protein change is due to the frameshift

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

PMID: 24368159

Gene: IDUA

Disease: MPS1

Inheritance: Autosomal recessive

Case#: 21, Male, 1 month (onset), 1 month (diagnosed), 12 months (report)

DiseaseAssertion: Hurler Syndrome

FamilyInfo: N/A

CasePresentingHPOs: HP:0002240, HP:0000280, HP:0000943, HP:0007957 (Hepatomegaly (mild at diagnosis and none at 12m), Coarse Facial Features, Dysostosis Multiplex, Corneal Clouding)

CaseHPOFreeText: (Mental Development (delayed since infancy), Mild LV hypertrophy, Inguinal bilat. and Umbilical Hernia)

CaseNotHPOs: HP:0001387, HP:0001744 (Joint Stiffness, Splenomegaly)

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

GenotypingMethod: Not Provided

Variant1: N/A

Variant1ClinVarID: N/A

Variant1CAID: N/A

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case: T1-2, female, 52yo

DiseaseAssertion: VWD1

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeText: Blood type: O+, bleeding score = 12, VWF:Ag (IU/mL) = 0.14; VWF:RCo (IU/mL) = 0.13; FVIII:C (IU/mL) = 0.46

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: qRT-PCR

PreviouslyPublished:

Gene: VWF

Variant: c.221-977_532+7059del

HGVS: NM_000552.5(VWF):c.221-977_532+7059del

ClinVarID: 156329; https://www.ncbi.nlm.nih.gov/clinvar/variation/156329/?oq=c.221-977_532+7059del&m=NM_000552.5(VWF):c.221-977_532%207059del

CAID: n/a

gnomAD: absent

Case: 2N, female, 33yo

DiseaseAssertion: VWD2N

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeText: Blood type: A, bleeding score = 8, VWF:Ag (IU/mL) = 0.97; VWF:RCo (IU/mL) = 1.20; FVIII:C (IU/mL) = 0.44

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: qRT-PCR

PreviouslyPublished:

Gene: VWF

Variant 1: c.2561G>A (p.Arg854Gln)

Variant 2: unknown

HGVS: NM_000552.5(VWF):c.2561G>A (p.Arg854Gln)

ClinVarID: 296; https://www.ncbi.nlm.nih.gov/clinvar/variation/296/?new_evidence=false

CAID:

gnomAD: MAF = 0.005692 in European (Finnish) population; 2 homozygotes

Case: P2, F/42

DiseaseAssertion: VWD3

FamilyInfo: No

ParentalGenotype: NA

CaseHPOFreeText: The bleeding score was 12, aPTT was 58 seconds, FVIII:C was 7%, VWF:RCo was 6 IU/dL, and VWF:Ag was not determined. The VWF:RCo/VWF:Ag ratio was not available. RIPA was nearly absent, VWF multimer analysis was 2, and platelet count was 231 × 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: Patient D

DiseaseAssertion: VWD2N

FamilyInfo: Family 3

ParentalGenotype(s):

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

CaseHPOFreeText: PTsec = 37.9, FVIII U/dL = 31.1, FVIII ratio = 0.33, VWF:Ag U/dL = 95.0, VWF:FVIIIB U/dL = 23.8, VWF:FVIIIB ratio = 0.25, VWF:CB U/dL = 101.6, VWF:RCo U/dL = 112.4, RIPA % = 73.4, PlatVWF:Ag U/dL = 87.2

CaseNOTHPOs:

CaseNOTHPOFreeText: n/a

CasePreviousTesting: n/a

GenotypingMethod: "Genetic analysis was performed on exons 17-20 of the VWF gene as previously described" (PMID: 12393698)

PreviouslyPublished: n/a

Gene: VWF

Variant: c.2561G>A (p.Arg854Gln); homozygous

HGVS: NM_000552.5(VWF):c.2561G>A (p.Arg854Gln)

ClinVarID: 296; https://www.ncbi.nlm.nih.gov/clinvar/variation/296/?new_evidence=false

CAID: n/a

gnomAD: MAF (European, Finnish) = 0.005692; https://gnomad.broadinstitute.org/variant/12-6143978-C-T

Case: Patient C

DiseaseAssertion: VWD2N

FamilyInfo: Family 2

ParentalGenotype(s):

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

CaseHPOFreeText: PTsec = 38.0, FVIII U/dL = 37.6, FVIII ratio = 0.26, VWF:Ag U/dL = 146.2, VWF:FVIIIB U/dL = 34.0, VWF:FVIIIB ratio = 0.20, VWF:CB U/dL = 157.5, VWF:RCo U/dL = 137.4, RIPA % = 87.9, PlatVWF:Ag U/dL = 102.7

CaseNOTHPOs:

CaseNOTHPOFreeText: n/a

CasePreviousTesting: n/a

GenotypingMethod: "Genetic analysis was performed on exons 17-20 of the VWF gene as previously described" (PMID: 12393698)

PreviouslyPublished: n/a

Gene: VWF

Variant: c.2561G>A (p.Arg854Gln); homozygous

HGVS: NM_000552.5(VWF):c.2561G>A (p.Arg854Gln)

ClinVarID: 296; https://www.ncbi.nlm.nih.gov/clinvar/variation/296/?new_evidence=false

CAID: n/a

gnomAD: MAF (European, Finnish) = 0.005692; https://gnomad.broadinstitute.org/variant/12-6143978-C-T

Case: Patient 5 (Family B), male, 26yo

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 = 176, PFA 100 sec = >300, SPA % = 8, MADR mg/mL = 0.6, VWF:Ag U/dL = 17.6, VWF:CB U/dL = 9.2, VWF:CB ratio = 0.52, VWF:RCo U/dL = 10.4, VWF:RCo ratio = 0.59, Platelet VWF U/dL = 76.6, FVIII U/dL = 38.8, BAT F/M = 8

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 19 (Family F), male, 44yo

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 = 116, PFA 100 sec = >300, SPA % = 15.7, MADR mg/mL = 0.3, VWF:Ag U/dL = 44.7, VWF:CB U/dL = 11.8, VWF:CB ratio = 0.48, VWF:RCo U/dL = 11.4, VWF:RCo ratio = 0.71, Platelet VWF U/dL = 130, FVIII U/dL = 27.7, BAT F/M = 10

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: Sequencing of exon 28 of VWF

PreviouslyPublished: NA

Gene: VWF

Variant: c.3916C>T (p.Arg1306Trp)

HGVS: NM_000552.4(VWF):c.3916C>T (p.Arg1306Trp)

ClinVarID: 288; https://www.ncbi.nlm.nih.gov/clinvar/variation/288/

CAID: NA

gnomAD: absent

Case: Patient 21 (Family H), male, 40yo

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 A, Platelet count x103/μl = 158, PFA 100 sec = >300, SPA % = NA, MADR mg/mL = 0.45, VWF:Ag U/dL = 32.5, VWF:CB U/dL = 14.7, VWF:CB ratio = 0.45, VWF:RCo U/dL = 18.7, VWF:RCo ratio = 0.59, Platelet VWF U/dL = 130, FVIII U/dL = 39.0, BAT F/M = NA

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: Sequencing of exon 28 of VWF

PreviouslyPublished: NA

Gene: VWF

Variant: c.3916C>T (p.Arg1306Trp)

HGVS: NM_000552.4(VWF):c.3916C>T (p.Arg1306Trp)

ClinVarID: 288; https://www.ncbi.nlm.nih.gov/clinvar/variation/288/

CAID: NA

gnomAD: absent

Case: Patient 13 (Family C), male, 37yo

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 = 132, PFA 100 sec = >300, SPA % = 0, MADR mg/mL = 0.6, VWF:Ag U/dL = 51.9, VWF:CB U/dL = 10.6, VWF:CB ratio = 0.20, VWF:RCo U/dL = 25.2, VWF:RCo ratio = 0.48, Platelet VWF U/dL = 133.4, FVIII U/dL = 34.5, BAT F/M = 17

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 15 (Family C), female, 14yo

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 = 126, PFA 100 sec = >300, SPA % = 0, MADR mg/mL = 0.45, VWF:Ag U/dL = 35.0, VWF:CB U/dL = 4.0, VWF:CB ratio = 0.11, VWF:RCo U/dL = 12.7, VWF:RCo ratio = 0.38, Platelet VWF U/dL = 141, FVIII U/dL = 46.0, BAT F/M = 6

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: P41, Chinese, female, 13yo

DiseaseAssertion: VWD3

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type A blood, bleeding score = 18; VWF:Ag (%) = 1.6, VWF:RCo (%) = 1.5, FVIII:C (%) = 2.8, VWF:CB (%) = 1.7, VWFpp (%) = 1.3, VWF:RCo/VWF:Ag = 0.9, VWF:CB/VWF:Ag = 1.1, VWFpp/VWF:Ag = 0.8, FVIII:C/VWF:Ag = 1.8

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.2547-13T>A - Unregistered Variant

HGVS: NA

ClinVarID: NA

CAID: NA

gnomAD: NA

Case: P35, Chinese, female, 60yo

DiseaseAssertion: VWD3

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type O blood, bleeding score = 20; VWF:Ag (%) = 1.5, VWF:RCo (%) = 1.3, FVIII:C (%) = 3.1, VWF:CB (%) = 1.1, VWFpp (%) = 1.3, VWF:RCo/VWF:Ag = 0.9, VWF:CB/VWF:Ag = 0.7, VWFpp/VWF:Ag = 0.9, FVIII:C/VWF:Ag = 2.1

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.5870delA - unregistered variant

HGVS: NA

ClinVarID: NA

CAID: NA

gnomAD: NA

Case: Patient IV-3 (son of III-3; first cousin of proband's mother IV-4) DiseaseAssertion: Type 2A VWD, based on low plasma VWF:Ag and activity and lack of plasma HMW VWF multimers. FamilyInfo: Son of III-3 (proband's granduncle); first cousin of IV-4 (proband's mother); part of 5-affected-member pedigree (Fig. 1). ParentalGenotype(s): Father (III-3) heterozygous for the variant, affected. Mother's genotype not reported. CasePresentingHPOs: HP:0012147 (Reduced quantity of VWF; VWF:Ag 19.5 U/dL), HP:0030129 (Impaired VWF:RCo; VWF:Rco 7.6 U/dL), HP:0030132 (Absence of large VWF multimers — plasma), HP:0003645 (Prolonged partial thromboplastin time; APTT 45.2 sec) CaseHPOFreeText: Described only generically as having "abnormal bleedings" / "similar clinical symptoms" — no itemized bleeding symptoms given specifically for this individual. FVIII:C 29.0 U/dL (nv 50-150). RIPA not tested (N/A). TT 18.6 sec and PT 13.4 sec both within normal range. CaseNOTHPOs: NA CaseNOTHPOFreeText: Platelet-associated VWF multimers normal (HMW multimers present) per the group finding covering this patient. CasePreviousTesting: Targeted confirmation of the familial VWF variant; not genome-wide. GenotypingMethod: Sanger sequencing/allele-specific analysis, same platform as proband. PreviouslyPublished: NA Gene: VWF Variant: Same novel heterozygous in-frame 6-bp deletion, exon 28, ΔD1529V1530 (VWF A2 domain) HGVS: c.4585_4590del (p.Asp1529_Val1530del) ClinVarID: NA CAID: NA gnomAD: NA

PMID: 29165738

Gene: VWF

HGNC: 12726 (type 1)

Note: Insufficient Evidence due to lack of variant information. This paper designates variants as only "missense, deletion, etc" and lacks specific neucleotide changes. All probands with identifiable variants in this paper were from other PMIDs, which were confirmed to be previously curated or added to the list to be curated.

Case: 2A-3

DiseaseAssertion: VWD2A

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: AcuStar RCo/Ag = 0.33; AcuStar CB/Ag = 0.08; ELISA CB/Ag = 0.25

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: VWD type 2M patients

DiseaseAssertion: VWD 2M

FamilyInfo: Patients with 2M genetics variant in A3 or A1 domain of VWF

ParentalGenotypes(s):

CasePresentingHPOs:

CaseHPOFreeText: bleeding score= 5, VWF:Ag ratio = 0.32,VWF collagen(VWF:CB/VWF:AG)=0.80. A3 domain VWF:ACT(0.45,1.03) and VWF:CB(0.45,0.63)

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

Gene: VWF

Variant:

HGVS:

ClinVar:

CAID:

gnomAD:

Case#: 01025, Age 54, Male, Blood type AB- (Table S3)

Disease Assertion: VWD 1

FamilyInfo: Not listed

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding score 5, VWF:Ag: 27, VWF:RCo: 36, FVIII:C: 45, VWF:CB: 25

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

Protein Expression: N/A

CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations

Gene: VWF

Variant: Not determined

ClinVar: N/A

CAID: N/A

gnomAD: N/A

Case: Patient III-1, Male, 43 years (as of Dec 2010 follow-up) DiseaseAssertion: VWD type 2A, phenotype IIC ("VWD2AIIC-Miami"). Bleeding score 9 (elevated; nv <4). FamilyInfo: Son of II-3; part of 4-member, 2-generation pedigree, dominant transmission. ParentalGenotype(s): Mother (II-3) heterozygous for the variant, affected. Father's genotype not tested/not reported. CasePresentingHPOs: HP:0000421 (Epistaxis), HP:0001934 (Persistent bleeding after trauma — bleeding from minor wounds), HP:0004846 (Prolonged bleeding after surgery — post-surgical bleeding, bleeding at tooth extraction), HP:0030130 (Impaired VWF collagen binding activity; VWF:CB/Ag ratio 0.14, nv ≥0.8), HP:0030129 (Impaired VWF:RCo; VWF:RCo/Ag ratio 0.18, nv ≥0.8), HP:0030132 (Absence of large VWF multimers) CaseHPOFreeText: VWF:Ag markedly ELEVATED at 2.72× normal (nv 0.5-1.6) — highest of the four patients. Absolute VWF:RCo 0.40 and VWF:CB 0.37 (both below the ≥0.5 absolute threshold, so reduced in both absolute and ratio terms, unlike II-3). VWF:GPIbα binding 0.55 absolute / 0.20 ratio. FVIII:C 0.99 (normal, nv ≥0.6) with reduced FVIII-binding ratio (F8Br 0.49, nv ≥0.6). VWF propeptide:Ag ratio (ppr) 0.32, markedly reduced (nv 0.8-2.2). PFA-100 closure times markedly prolonged (both >300 sec). Hematoma and oral cavity bleeding also reported. No menorrhagia (not applicable, male). CaseNOTHPOs: NA CaseNOTHPOFreeText: NA CasePreviousTesting: Same family-wide testing history as Patient II-3 (extensive prior negative Sanger sequencing, causative variant found only via MLPA); not genome-wide. GenotypingMethod: Same as Patient II-3 — MLPA plus confirmatory RT-PCR/sequencing. PreviouslyPublished: PMID 8324222 (Ledford et al. 1993) — same family as originally reported. Gene: VWF Variant: Heterozygous complex in-frame duplication of VWF exons 9-10 (same variant as Patient II-3). HGVS: NM_000552.3:c.998_1156dup (p.Glu333_Pro385dup) ClinVarID: NA CAID: NA gnomAD: NA

Case: Patient III-5, Female, 37 years (as of Dec 2010 follow-up) DiseaseAssertion: VWD type 2A, phenotype IIC ("VWD2AIIC-Miami"). Bleeding score not done (nd). FamilyInfo: Daughter of II-3; part of 4-member, 2-generation pedigree, dominant transmission. ParentalGenotype(s): Mother (II-3) heterozygous for the variant, affected. Father's genotype not tested/not reported. CasePresentingHPOs: HP:0030130 (Impaired VWF collagen binding activity; VWF:CB/Ag ratio 0.14, nv ≥0.8), HP:0030129 (Impaired VWF:RCo; VWF:RCo/Ag ratio 0.15, nv ≥0.8), HP:0030132 (Absence of large VWF multimers) CaseHPOFreeText: Specific bleeding symptoms not individually itemized in the text for this patient (her bleeding score was not done, and the itemized symptom list in the Results section explicitly covers only the three patients with bleeding scores recorded). Text states only that "all studied patients" including this one have "a significant bleeding tendency with typical mucocutaneous bleeding symptoms." VWF:Ag ELEVATED at 2.01× normal (nv 0.5-1.6). Absolute VWF:RCo 0.30 and VWF:CB 0.29 (both below the ≥0.5 absolute threshold). VWF:GPIbα binding 0.39 absolute / 0.19 ratio. FVIII:C 0.85 (normal, nv ≥0.6) with reduced FVIII-binding ratio (F8Br 0.44, nv ≥0.6). VWF propeptide:Ag ratio (ppr) 0.61, reduced (nv 0.8-2.2). PFA-100 closure times prolonged (Epinephrine >267 sec, ADP >278 sec). CaseNOTHPOs: NA CaseNOTHPOFreeText: NA CasePreviousTesting: Same family-wide testing history as Patient II-3; not genome-wide. GenotypingMethod: Same as Patient II-3 — MLPA plus confirmatory RT-PCR/sequencing. PreviouslyPublished: PMID 8324222 (Ledford et al. 1993) — same family as originally reported. Gene: VWF Variant: Heterozygous complex in-frame duplication of VWF exons 9-10 (same variant as Patient II-3). HGVS: NM_000552.3:c.998_1156dup (p.Glu333_Pro385dup) ClinVarID: NA CAID: NA gnomAD: NA

Case: Patient III-3, Female, 41 years (as of Dec 2010 follow-up) DiseaseAssertion: VWD type 2A, phenotype IIC ("VWD2AIIC-Miami"). Bleeding score 14 (elevated; nv <4). FamilyInfo: Daughter of II-3; part of 4-member, 2-generation pedigree, dominant transmission. ParentalGenotype(s): Mother (II-3) heterozygous for the variant, affected. Father's genotype not tested/not reported. CasePresentingHPOs: HP:0000421 (Epistaxis), HP:0000132 (Menorrhagia), HP:0001934 (Persistent bleeding after trauma — bleeding from minor wounds), HP:0004846 (Prolonged bleeding after surgery — bleeding at tooth extraction), HP:0030130 (Impaired VWF collagen binding activity; VWF:CB/Ag ratio 0.12, nv ≥0.8), HP:0030129 (Impaired VWF:RCo; VWF:RCo/Ag ratio 0.15, nv ≥0.8), HP:0030132 (Absence of large VWF multimers) CaseHPOFreeText: VWF:Ag ELEVATED at 1.78× normal (nv 0.5-1.6) — least elevated of the four, though still above range. Absolute VWF:RCo 0.27 and VWF:CB 0.22 (both below the ≥0.5 absolute threshold). VWF:GPIbα binding 0.35 absolute / 0.20 ratio. FVIII:C 0.75 (normal, nv ≥0.6) with reduced FVIII-binding ratio (F8Br 0.50, nv ≥0.6). VWF propeptide:Ag ratio (ppr) 0.57, reduced (nv 0.8-2.2). PFA-100 closure times markedly prolonged (Epinephrine >300 sec, ADP >284 sec). No explicit mention of post-surgery bleeding for this patient specifically (unlike II-3 and III-1). CaseNOTHPOs: NA CaseNOTHPOFreeText: NA CasePreviousTesting: Same family-wide testing history as Patient II-3; not genome-wide. GenotypingMethod: Same as Patient II-3 — MLPA plus confirmatory RT-PCR/sequencing. PreviouslyPublished: PMID 8324222 (Ledford et al. 1993) — same family as originally reported. Gene: VWF Variant: Heterozygous complex in-frame duplication of VWF exons 9-10 (same variant as Patient II-3. HGVS: NM_000552.3:c.998_1156dup (p.Glu333_Pro385dup) ClinVarID: NA CAID: NA gnomAD: NA

Case: Patient II-3, Female, 67 years (as of Dec 2010 follow-up) DiseaseAssertion: VWD type 2A, phenotype IIC ("VWD2AIIC-Miami") — a historically named variant of type 2A characterized by paradoxically elevated VWF:Ag with reduced function; dominantly inherited in this family (unlike classic/most VWD2AIIC, which is recessive). Bleeding score 21 (very high; nv <4). FamilyInfo: Mother of III-1, III-3, and III-5 (all three affected); 4-member, 2-generation pedigree, dominant transmission. ParentalGenotype(s): NA — her own parents not part of this study. CasePresentingHPOs: HP:0000421 (Epistaxis), HP:0000132 (Menorrhagia), HP:0001934 (Persistent bleeding after trauma — bleeding from minor wounds), HP:0004846 (Prolonged bleeding after surgery — post-surgical bleeding, bleeding at tooth extraction), HP:0030130 (Impaired VWF collagen binding activity; VWF:CB/Ag ratio 0.18, nv ≥0.8), HP:0030129 (Impaired VWF:RCo; VWF:RCo/Ag ratio 0.22, nv ≥0.8), HP:0030132 (Absence of large VWF multimers) CaseHPOFreeText: VWF:Ag markedly ELEVATED at 2.50× normal (nv 0.5-1.6). Absolute VWF:RCo 0.54 and VWF:CB 0.46 (both near/within the lower end of normal in absolute terms, nv ≥0.5, but severely reduced relative to the elevated antigen). VWF:GPIbα binding 0.74 absolute / 0.30 ratio. FVIII:C 1.08 (normal, nv ≥0.6) with reduced FVIII-binding ratio (F8Br 0.61, at threshold, nv ≥0.6). VWF propeptide:Ag ratio (ppr) 0.71, reduced (nv 0.8-2.2) — indicates decreased clearance of mature VWF relative to propeptide. PFA-100 closure times markedly prolonged (Epinephrine and ADP both >300 sec, nv ≤165/≤118). Hematoma (bruising) and oral cavity bleeding also reported. Post-partum bleeding ultimately requiring hysterectomy. Historical DDAVP test performed in this patient specifically showed findings consistent with delayed VWF clearance. Oral contraceptive/desmopressin use not specified. CaseNOTHPOs: NA CaseNOTHPOFreeText: NA CasePreviousTesting: Extensive prior negative testing — partial sequencing in the original 1993 study plus subsequent complete Sanger sequencing of all VWF coding exons by multiple independent groups over ~20 years found no candidate mutation. The causative variant was only found via MLPA (multiplex ligation-dependent probe amplification), which detects copy-number changes that exon sequencing alone misses. Not genome-wide; VWF-targeted. GenotypingMethod: MLPA identified signal gain at exons 9-10 in all 4 family members; confirmed by duplication-junction-specific RT-PCR (sense primer in exon 10, antisense in exon 9) and by RT-PCR/sequencing across exons 8-11. Full genomic characterization (PCR primer walking, RepeatMasker, MFold in silico DNA-folding analysis) defined a complex rearrangement: a 5,047 bp duplication (intron 8 through part of intron 10, including exons 9 and 10) plus two deletions (1,348 bp and 2,301 bp) within intron 10, apparently mediated by inverted Alu repeat elements (proposed mechanism: replication slippage for the duplication, a stable Alu3/Alu4 inverted-repeat DNA secondary structure for the deletion). PreviouslyPublished: PMID 8324222 (Ledford MR, Rabinowitz I, Sadler JE, Kent JW, Civantos F. "New variant of von Willebrand disease type II with markedly increased levels of von Willebrand factor antigen and dominant mode of inheritance: von Willebrand disease type IIC Miami." Blood. 1993;82:169-75) — this is the original report of this same family. Gene: VWF Variant: Heterozygous complex in-frame duplication of VWF exons 9-10 (net transcript-level effect), D1 domain (VWF propeptide region). Recombinant expression studies (not patient-specific, applies to the variant generally): "homozygous" mutant VWF secreted only as dimers (no higher-order multimers); co-expression with WT VWF reproduced the patients' plasma multimer pattern exactly; mutant retained in unusually large intracellular granules colocalizing with PDI in the ER; ADAMTS13 proteolysis was not resistant, but an aberrant extra proteolytic band appeared in both patient plasma and recombinant mutant; infusion of recombinant mutant VWF into VWF-/- mice showed significantly prolonged half-life vs. WT (mean residence time 3.15h vs 1.90h, p=0.015), supporting decreased clearance as the mechanism for the paradoxically elevated VWF:Ag. HGVS: NM_000552.3:c.998_1156dup (p.Glu333_Pro385dup) ClinVarID: NA CAID: NA gnomAD: NA

Case: Proband (II-1), male, 56yo, Italian

DiseaseAssertion: VWD1 and Hemophilia A

FamilyInfo: Pedigree in Fig. 1 - Father had VWD1 and Mother had Hemophilia A - parents have normal or higher VWF levels, and normal FVIII/VWF:Ag ratios, as well as a normal bleeding score; 2 daughters carry F8 variant

ParentalGenotype(s): Paternal = NM_000552.4(VWF):c.4751A>G (p.Tyr1584Cys); Maternal = NM_000132.3(F8):c.2167G>A (p.Ala723Thr)

CasePresentingHPOs: HP:0012147, HP:0030129, HP:0030130, HP:0001892, HP:0000421, HP:0000978, HP:0004846, HP:0000225, HP:0005261, HP:0040242

(Reduced quantity of VWF, Impaired ristocetin cofactor assay activity, Impaired von Willebrand factor collagen binding activity, abnormal bleeding, epistaxis, Bruising susceptibility, Prolonged bleeding after surgery, bleeding gums, joint hemorrhage, muscle hemorrhage)

CaseHPOFreeText: blood group = 0, aPTT = 0.56sec, FVIII = 9.8 IU/dL, VWF:Ag = 43.2 IU/dL, VWF:CB = 35.6 IU/dL, VWF:Rco = 42.1 IU/dL, VWF:FVIIIB = 41.3 IU/dL, Platelet VWF:Ag = 58.2 IU/dL, bleeding score = 27

CaseNOTHPOs: HP:0011871

(Impaired RIPA)

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: PCR and direct sequencing of VWF and FVIII

PreviouslyPublished: NA

Gene: VWF

Variant: c.4751A>G (p.Tyr1584Cys)

HGVS: NM_000552.4(VWF):c.4751A>G (p.Tyr1584Cys)

ClinVarID: 310; https://www.ncbi.nlm.nih.gov/clinvar/variation/310/

CAID: NA

gnomAD: MAF = 0.004024 (519/128972 alleles, 4 homozygotes) in European (non-Finnish) population

MultipleGeneVariants:

Gene: F8

Variant: c.2167G>A (p.Ala723Thr)

HGVS: NM_000132.3(F8):c.2167G>A (p.Ala723Thr)

ClinVarID: 10246; https://www.ncbi.nlm.nih.gov/clinvar/variation/10246/

CAid: NA

gnomAD: MAF = 0.00005257 (1/19022 alleles, 1 hemizygote) in South Asian population

PMID: 30036281<br /> Gene: VWF<br /> Disease: von Willebrand disease<br /> MonDO: 0015631<br /> HGNCID:

PMID: 35888124 Gene: MYBPC3 HCNC ID: 7551

PMID: 41033995 Gene: ACTC1 HGNC: 143

Case#: Subject number 32, male, 39 years (diagnosis), 43 years (baseline visit)

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0001324 (Muscle Weakness)

CaseHPOFreeText:

CaseNotHPOs: HP:0002098 (respiratory distress), HP:0003236 (Elevated circulating creatine kinase concentration), 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 14, male, 41 years (diagnosis), 51 years (baseline visit), 45 years (ERT), 50 (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 9, female, 29 years (diagnosis), 55 years (baseline visit), 48 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

PMID: 33732206

Gene: GAA

Disease: Pompe disease

Inheritance: Autosomal recessive

Case#: Subject number 35, female, 35 years (diagnosis), 35 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 3, female, 47 months (onset), 49 months (first admission)

DiseaseAssertion: Pompe disease

FamilyInfo: Patients 2 and 3 are full siblings

CasePresentingHPOs: HP:0012378 (fatigue), HP:0009046 (difficulty running), HP:0001609 (hoarse voice), HP:0000508 (ptosis), HP:0004887 (respiratory failure requiring assisted ventilation)

CaseHPOFreeText: ambulatory (transport ventilator), juvenile-onset

CaseNotHPOs:

CaseNotHPOFreeText: no tracheostomy, no dysphagia at baseline, not on BiPAP

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

Case#: Subject number 1, female, 15 months (onset), 32 months (first admission)

DiseaseAssertion: Pompe disease

FamilyInfo: "no family history of neuromuscular disorders"

CasePresentingHPOs: HP:0002355 (difficulty walking), HP:0002205 (recurrent respiratory infections), HP:0002747 (respiratory insufficiency due to muscle weakness), HP:0004887 (respiratory failure requiring assisted ventilation)

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

CaseNotHPOs:

CaseNotHPOFreeText: no dysphagia at baseline

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

Case#: Case 2, Boy, Death at 7 months old, Hispanic

DiseaseAssertion: Pompe disease

FamilyInfo: Parents were carriers of the variant in Patient 2 (Figure 2.C)

CasePresentingHPOs: HP:0002205, HP:0001945, HP:0000980, HP:0001290, HP:0000158, HP:0002791, HP:0002240, HP:0200128

(Recurrent respiratory infections, Fever, Pallor, Generalized hypotonia, Macroglossia, Hypoventilation, Hepatomegaly, Biventricular hypertrophy )

CaseHPOFreeText: Systolic and diastolic dysfunction.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Ejection fraction was 40%

Serum Creatine Kinase levels were 650 IU/L

GAA enzyme activity on dried blood spots was 0.6 pmol/L, below normal levels (normal range: 10.0- 49 pmol/L).

Variant: c.1987delC

ClinVar: N/A

CAID: N/A

gnomAD: N/A

ParentalGenotype: Both parents are carriers of the variant c.1987delC

PreviouslyPublished: N/A

Case#: Subject number 1, female, 70 years (report), 67 years (onset), 70 years (diagnosis)

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0000158 (macroglossia), HP:0002015 (dysphagia), HP:0001260 (dysarthria), HP:0003701 (proximal muscle weakness), HP:0000224 (hypogeusia), HP:0002515 (waddling gait), HP:0030234 (highly elevated creatine kinase), HP:0025435 (Increased lactate dehydrogenase level), HP:0012544 (Elevated aldolase level)

CaseHPOFreeText: adult-onset Pompe disease

CaseNotHPOs: HP:0002317 (gait instability), HP:0031249 (parageusia), HP:0032043 (odynophagia), HP:0000458 (anosmia), HP:0000651 (diploplia), HP:0002607 (bowel incontinence)

CaseNotHPOFreeText:

CasePreviousTesting: (MRI) scan of the brain, "electromyogram revealed a myotonic myopathy with electrophysiological features supportive of inflammation, fiber splitting, vacuolization, and/or myonecrosis," liver function test was within normal limits, pulmonary function test showed mild-to-moderate restriction and reduced total lung capacity, acid alpha-glucosidase activity in blood was evaluated, and it was revealed to be 0.0 (normal: >0.5 nmol/h/mL)

PMID: 31467850

Gene: GAA

Disease: Pompe disease

Inheritance: Autosomal recessive

PMID: 7529063

Gene: ITGA2B

HGNC: 6138

PMID:

Gene: ITGB3

HGNC: 6156