Case#: Patient 18, born in 2012 (paper published in 2017), 7 months (age at first treatment)

DiseaseAssertion: MPSI-H

FamilyInfo: N/A

CasePresentingHPOs: Corneal clouding (HP:0007957)

CaseHPOFreeText: N/A

CaseNotHPOs: Retinopathy, cataract (HP:0000488, HP:0000518)

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 79.39 ng/mol (42.66 weight matched enzyme reference assay)

CaseUrineGAGs: 0.51 DS/CS

CaseERT: Yes

CaseBMT: Yes, Uncle

Variant1: c.1045G>T (p.D349Y)

Variant1ClinVarID: 638075

Variant1CAID: CA355963146

Variant2: c.1045G>T (p.D349Y)

Variant2ClinVarID: 638075

Variant2CAID: CA355963146

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 20, born in 2003 (paper published in 2017), 20 months (age at first treatment)

DiseaseAssertion: MPSI-H

FamilyInfo: N/A

CasePresentingHPOs: Corneal clouding (HP:0007957)

CaseHPOFreeText: N/A

CaseNotHPOs: Retinopathy, cataract (HP:0000488, HP:0000518)

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 57.2 ng/mol (26 weight matched enzyme reference assay)

CaseUrineGAGs: 0.63 DS/CS

CaseERT: No

CaseBMT: Yes, Cord

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

Variant1ClinVarID: 11909

Variant1CAID: CA204563

Variant2: c.1898C>A (p.S633X)

Variant2ClinVarID: 1068474

Variant2CAID: CA355966009

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

PMID: 21394825

Gene: IDUA

Disease: MPS1

Inheritance: Autosomal recessive

Case#: Patient 13, Italy

DiseaseAssertion: MPS1-H/S

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.265C>T (p.R89W)

Variant1ClinVarID: 580286

Variant1CAID: CA2801156

Variant2: c.1487C>G (p.P496R)

Variant2ClinVarID: 496861

Variant2CAID: CA2802275

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 19, Italy

DiseaseAssertion: MPS1-H

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.1727+1G>A

Variant1ClinVarID: 638077

Variant1CAID: CA355965296

Variant2: c.1487C>G (p.P496R)

Variant2ClinVarID: 496861

Variant2CAID: CA2802275

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 33, Italy

DiseaseAssertion: MPS1-H

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.208C>T (p.Q70X)

Variant1ClinVarID: 11909

Variant1CAID: CA204563

Variant2: c.1487C>G (p.P496R)

Variant2ClinVarID: 496861

Variant2CAID: CA2802275

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 46, Poland

DiseaseAssertion: MPS1-S

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.208C>T (p.Q70X)

Variant1ClinVarID: 11909

Variant1CAID: CA204563

Variant2: c.227A>G (p.Y76C)

Variant2ClinVarID: 552686

Variant2CAID: CA2801140

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: MPS 1 patient

DiseaseAssertion: N/A

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.208C>T (p.Q70X)

Variant1ClinVarID: 11909

Variant1CAID: CA204563

Variant2: c.501C>G (p.Y167X)

Variant2ClinVarID: 92644

Variant2CAID: CA220511

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: 12, Female, 0.9 years (diagnosed), 10.1 years (report), 26 kg (weight), 108 cm (height), Iranian

DiseaseAssertion: Hurler-Scheie Syndrome

FamilyInfo: Parents are consanguineous

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

CaseHPOFreeText: HM/HSM

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

CaseNotHPOFreeText: Chronic Rhinorrhea, Cardiac Manifestations

CaseEnzymeAssay: IDUA activity 1.01 (μmol/spot.20h)

CaseUrineGAGs: Quantitative urinary GAG 7.4 (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#: 2, Male, 0.9 years (diagnosed), 4.2 years (report), 11 kg (weight), 65 cm (height), Iranian

DiseaseAssertion: Hurler-Scheie Syndrome

FamilyInfo: Parents are consanguineous

CasePresentingHPOs: HP:0000943, HP:0001387 (Multiple Dysostosis, Joint Stiffness)

CaseHPOFreeText: HM/HSM,

CaseNotHPOs: HP:0001249, HP:0001999, HP:0100790, HP:0000365, HP:0007957, HP:0000238 (Mental Retardation, Facial Dysmorphic Features, Hernia, Deafness, Corneal Opacity, Hydrocephalus)

CaseNotHPOFreeText: NM/HSM, Chronic Rhinorrhea, Cardiac Manifestations

CaseEnzymeAssay: IDUA activity 7.06 (μmol/spot.20h)

CaseUrineGAGs: Quantitative urinary GAG 14.22 (mg/gCr)

CaseERT: N/A

CaseBMT: N/A

GenotypingMethod: Sanger Sequencing

Variant1: p.S157P

Variant2: 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: L346R

Variant1ClinVarID: 11927

Variant1CAID: CA256128

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: F188L

Variant1ClinVarID:

Variant1CAID: CA355961777

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: W306L

Variant1ClinVarID: 2203497

Variant1CAID: CA355962596

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: P533R

Variant1ClinVarID: 11910

Variant1CAID: CA256112

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: Patient 32, 3 years old (age at report), male, Indian

DiseaseAssertion: MPS1-H

FamilyInfo: Sibling of Patient 31

CasePresentingHPOs: Coarse facial features, hepatosplenomegaly, joint contractures, corneal clouding, recurrent infections, dysostosis multiplex, hernia (HP:0000280, HP:0001433, HP:0002828, HP:0007957, HP:0002719, HP:0000943, HP:0100790)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 2.5% (Range of residual enzyme activity: 0.0%-4.8%)

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1373T>C (p.Leu458Pro)

Variant1ClinVarID: N/A

Variant1CAID: CA355964255

Variant2: c.1373T>C (p.Leu458Pro)

Variant2ClinVarID: N/A

Variant2CAID: CA355964255

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 20, 2 years old (age at report), male, Indian

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: Coarse facial features, hepatosplenomegaly, intellectual disability (HP:0000280, HP:0001433, HP:0001249)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 4.0% (Range of residual enzyme activity: 0.0%-4.8%)

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.793-1G>A

Variant1ClinVarID: 557472

Variant1CAID: CA2802097

Variant2: c.793-1G>A

Variant2ClinVarID: 557472

Variant2CAID: CA2802097

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 9, 11 years old (age at report), female, Indian

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: Coarse facial features, hepatosplenomegaly, joint contractures, corneal clouding, recurrent infections, dysostosis multiplex, hernia (HP:0000280, HP:0001433, HP:0002828, HP:0007957, HP:0002719, HP:0000943, HP:0100790)

CaseHPOFreeText: Cardiac disease

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 4.5% (Range of residual enzyme activity: 0.0%-4.8%)

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.523_534del (p.Trp175_Glu178del)

Variant1ClinVarID: 2734635

Variant1CAID: CA645372297

Variant2: c.523_534del (p.Trp175_Glu178del)

Variant2ClinVarID: 2734635

Variant2CAID: CA645372297

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 24, 1 years old (age at report), female, Indian

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: Coarse facial features, joint contractures, corneal clouding, dysostosis multiplex, intellectual disability (HP:0000280, HP:0002828, HP:0007957, HP:0000943, HP:0001249)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 2.7% (Range of residual enzyme activity: 0.0%-4.8%)

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1096_1099del (p.Thr366Argfs*73)

Variant1ClinVarID: 1065522

Variant1CAID: CA2499217017

Variant2: c.1096_1099del (p.Thr366Argfs*73)

Variant2ClinVarID: 1065522

Variant2CAID: CA2499217017

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: PKMPS1P11, 8 years old (age at presentation), female, Pakastani. Poor performance in school due to difficulty in writing.

DiseaseAssertion: MPS-I

FamilyInfo: Born to parents in a consanguineous marriage

CasePresentingHPOs: Coarse facial features, joint stiffness, stunted and mild thoracic kyphosis (HP:0000256, HP:0001387, HP:0002808)

CaseHPOFreeText: Widening of the wrist

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1469T>C (p.L490P)

Variant1ClinVarID: 11919

Variant1CAID: CA220503

Variant2: c.1469T>C (p.L490P)

Variant2ClinVarID: 11919

Variant2CAID: CA220503

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 2, female, 6 years (age at presentation)

DiseaseAssertion: MPS1-H/S

FamilyInfo: Consanguinity in the family present for this patient.

CasePresentingHPOs: Corneal clouding, dysostosis multiplex, hepatomegaly, joint contractures, splenomegaly (HP:0007957, HP:0000943, HP:0002240, HP:0100790, HP:0001744)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.223G>C (p.A75P)

Variant1ClinVarID: N/A

Variant1CAID: CA355946364

Variant2: c.223G>C (p.A75P)

Variant2ClinVarID: N/A

Variant2CAID: CA355946364

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 27, female, 1 year 6 months (age at presentation).

DiseaseAssertion: MPS1-H/S

FamilyInfo: Consanguinity in the family present for this patient.

CasePresentingHPOs: Corneal clouding, coarse facial features, dysostosis multiplex, hepatomegaly, inguinal hernia, joint stiffness, sleep disturbances, splenomegaly, umbilical hernia (HP:0007957, HP:0000256, HP:0000943, HP:0002240, HP:0000023, HP:0001387, HP:0002360, HP:0001744, HP:0001537)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1855C>T (p.R619X)

Variant1ClinVarID: 280976

Variant1CAID: CA2802455

Variant2: c.1855C>T (p.R619X)

Variant2ClinVarID: 280976

Variant2CAID: CA2802455

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: OS of sibship 9, female, 7 years old (age at diagnosis), 14 years old (age at ERT enrollment), 7 years (duration of ERT)

DiseaseAssertion: MPS1-HS

FamilyInfo: Affected YS (YS of sibship 9)

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

CaseHPOFreeText: Cardiac disease, ocular, respiratory, and musculoskeletal involvement.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: Yes - At T2, ocular and cardiac symptoms progressed from mild to moderate/severe. In addition, pulmonary function worsened, and contractures and lower extremity weakness progressed. Had stabilization of dysostosis multiplex and no progression of motor function delays.

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#: Case information was not provided

DiseaseAssertion: MPS I-H/S

FamilyInfo: Proband of family B

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.1469T>C (p.L490P)

Variant1ClinVarID: 11919

Variant1CAID: CA220503

Variant2: c.1469T>C (p.L490P), Confirmed homozygous in Figure 1

Variant2ClinVarID: 11919

Variant2CAID: CA220503

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Family 17, Cyprus

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: The paper states that "Hurler form is characterized by skeletal abnormalities, hepatosplenomegaly and severe mental retardation" but is not specific to this patient.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: The α-L-iduronidase enzyme activities in leucocytes from all patients in the study was measured using the artificial substrate 4-methylumbelliferyl α-L iduronide (Sigma). Values ranged from 0 to 2.47 nmol/h/mg protein (reference range: 28–92 nmol/h/mg protein) and did not correlate to the clinical phenotype.

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.659delG; c.747delG in the paper (old nomenclature)

Variant1ClinVarID: N/A

Variant1CAID: CA2802045

Variant2: c.659delG; c.747delG in the paper (old nomenclature)

Variant2ClinVarID: N/A

Variant2CAID: CA2802045

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Family 20, UK

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: The paper states that "Hurler form is characterized by skeletal abnormalities, hepatosplenomegaly and severe mental retardation" but is not specific to this patient.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: The α-L-iduronidase enzyme activities in leucocytes from all patients in the study was measured using the artificial substrate 4-methylumbelliferyl α-L iduronide (Sigma). Values ranged from 0 to 2.47 nmol/h/mg protein (reference range: 28–92 nmol/h/mg protein) and did not correlate to the clinical phenotype.

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1205G>A (p.W402X)

Variant1ClinVarID: 11908

Variant1CAID: CA220498

Variant2: c.65delC; c.153delC in the paper (old nomenclature)

Variant2ClinVarID: 929238

Variant2CAID: CA437911597

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 23, male, Han origin, 3.5 years old (age at diagnosis)

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: Global Developmental Delay, Macrocephaly, Joint stiffness, Mongolian macula, Hepatosplenomegaly, Hernia, Airway obstruction (HP:0001263, HP:0000256, HP:0001387, HP:0011369, HP:0001433, HP:0100790, HP:0006536)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: Cardiac disease

CaseEnzymeAssay: IDUA activity 3.5 nmol/h/mg protein. The normal range in Chinese controls was found to be 27.2–52 nmol/h/mg protein.

CaseUrineGAGs: Diagnosis was confirmed biochemically by the demonstration of an increased excretion of urinary dermatan sulfate and heparan sulfate.

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1-2C>G

Variant1ClinVarID: N/A

Variant1CAID: CA2586973510

Variant2: c.1189+5G>T

Variant2ClinVarID: N/A

Variant2CAID: CA2586965966

AdditionalVariants: N/A

ParentalGenotype: The transmission of sequence variations found in each patient was inferred by sequencing the corresponding exons of the patient's parents - confirmed in trans by parental testing.

PreviouslyPublished N/A

Case#: Patient 2, Han origin, male, 1 year and 3 months old (age at diagnosis)

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: Global Developmental Delay, Macrocephaly, Joint stiffness, Mongolian macula, Hepatosplenomegaly, Hernia (HP:0001263, HP:0000256, HP:0001387, HP:0011369, HP:0001433, HP:0100790)

CaseHPOFreeText: Cardiac disease

CaseNotHPOs: Airway obstruction (HP:0006536)

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: IDUA activity 1.2 nmol/h/mg protein. The normal range in Chinese controls was found to be 27.2–52 nmol/h/mg protein.

CaseUrineGAGs: Diagnosis was confirmed biochemically by the demonstration of an increased excretion of urinary dermatan sulfate and heparan sulfate.

CaseERT: N/A

CaseBMT: N/A

Variant1: c.159C>A (p.C53X)

Variant1ClinVarID: 1458768

Variant1CAID: CA355945972

Variant2: c.546G>C (p.E182D)

Variant2ClinVarID: 4069690

Variant2CAID: CA355961740

AdditionalVariants: N/A

ParentalGenotype: The transmission of sequence variations found in each patient was inferred by sequencing the corresponding exons of the patient's parents - confirmed in trans by parental testing.

PreviouslyPublished N/A

Case#: Patient 29, male, Han origin, 11 years old (age at diagnosis)

DiseaseAssertion: MPS1-S

FamilyInfo: N/A

CasePresentingHPOs: Macrocephaly, Joint stiffness, Hepatosplenomegaly, Hernia, Airway obstruction (HP:0000256, HP:0001387, HP:0001433, HP:0100790, HP:0006536)

CaseHPOFreeText: Cardiac disease

CaseNotHPOs: Global Developmental Delay, Mongolian macula (HP:0001263, HP:0011369)

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: IDUA activity 1.2 nmol/h/mg protein. The normal range in Chinese controls was found to be 27.2–52 nmol/h/mg protein.

CaseUrineGAGs: Diagnosis was confirmed biochemically by the demonstration of an increased excretion of urinary dermatan sulfate and heparan sulfate.

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1037T>G (p.L346R)

Variant1ClinVarID: 11927

Variant1CAID: CA256128

Variant2: c.1898C>T (p.S633L)

Variant2ClinVarID: 556406

Variant2CAID: CA355966010

AdditionalVariants: N/A

ParentalGenotype: The transmission of sequence variations found in each patient was inferred by sequencing the corresponding exons of the patient's parents - confirmed in trans by parental testing.

PreviouslyPublished N/A

Case#: Patient 35, female, Han origin, 3 years old (age at diagnosis)

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: Global Developmental Delay, Macrocephaly, Joint stiffness, Hepatosplenomegaly, Hernia, Airway obstruction (HP:0001263, HP:0000256, HP:0001387, HP:0001433, HP:0100790, HP:0006536)

CaseHPOFreeText: N/A

CaseNotHPOs: Mongolian macula (HP:0011369)

CaseNotHPOFreeText: Cardiac disease

CaseEnzymeAssay: IDUA activity 1.2 nmol/h/mg protein. The normal range in Chinese controls was found to be 27.2–52 nmol/h/mg protein.

CaseUrineGAGs: Diagnosis was confirmed biochemically by the demonstration of an increased excretion of urinary dermatan sulfate and heparan sulfate.

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1227dupG (paper says c.1225dupC but according to the variant sequence this should be c.1227dupG - a known variant)

Variant1ClinVarID: 929237

Variant1CAID: CA1139658406

Variant2: c.1244_1271del27 - Allele registry states that the range is off by 1, noting a deletion of 28 being found instead of 27.

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: The transmission of sequence variations found in each patient was inferred by sequencing the corresponding exons of the patient's parents - confirmed in trans by parental testing.

PreviouslyPublished N/A

Case#: male, 23 year olds (age at report), progressive impairment in ability to perform in school.

DiseaseAssertion: MPS I-H/S

FamilyInfo: N/A

CasePresentingHPOs: Mental deterioration (HP:0001268)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: Yes - the patient had been treated with intravenous rhIDU for 13 years before IT rhIDU and had not undergone HSCT. The patient was also enrolled concurrently in an IRB approved non‐interventional longitudinal study of brain structure and function in MPS at the University of Minnesota. He showed stable or improved neurocognitive outcomes after 24 months of IT rhIDU. The patient showed the greatest improvement in his ability to encode verbal stimuli, moving from significantly impaired to the average level. This was accompanied by a significant improvement in adaptive behavior and an improvement to an above average level, in his ability to remember verbal material in a context. Nonverbal memory, both encoding and recall increased although those scores remained below the average range. A baseline of average IQ and attention performance also somewhat improved.

CaseBMT: No

Variant1: c.979G>C (p.A327P)

Variant1ClinVarID: 167190

Variant1CAID: CA234128

Variant2: c.793G>C (p.G265R)

Variant2ClinVarID: 638074

Variant2CAID: CA2802098

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 2 was biochemically diagnosed with MPS I because they showed an increase in urinary GAGs and a reduction in IDUA activity in leukocytes. Patient 2 was diagnosed at 1 year.

DiseaseAssertion: MPSI-H/S

FamilyInfo: N/A

CasePresentingHPOs: Coarse facies, corneal clouding, skeletal abnormalities, cardiac abnormalities, and hepatosplenomegaly (HP:0000256, HP:0007957, HP:0002360, HP:0001627, HP:0001433)

CaseHPOFreeText: N/A

CaseNotHPOs: Intellectual disability, growth delay, hernias (HP:0001249, HP:0001510, HP:0100790)

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: IDUA activity of 2.8 nmol/mg/protein/hr. No reference range provided.

CaseUrineGAGs: 733.8 CPC unit/g creatinine. No reference range provided.

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1163C>A (p.T388K)

Variant1ClinVarID: 198696

Variant1CAID: CA247499

Variant2: c.1163C>A (p.T388K)

Variant2ClinVarID: 198696

Variant2CAID: CA247499

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: 8 year-old Chinese Han boy. At age 3 years physical disabilities began appearing.

DiseaseAssertion: Mucopolysaccharidosis type I, MPS-I

FamilyInfo: Proband is the third child of healthy non-consanguineous parents. Paper states there is "no family history of related genetic diseases." Figure 1 has a pedigree of proband's family.

CasePresentingHPOs: HP:0000280 (coarse facial features), HP:0000256 (macrocephaly), HP:0007957 (corneal clouding), HP:0000158 (macroglossia), HP:0004322 (short stature), HP:0000470 (short neck), HP:0001537 (umbilical hernia), HP:0034392 (joint contracture), HP:0011369 (large Mongolian spot on the back skin), HP:0040079 (irregular teeth), HP:0002240 (hepatomegaly), HP:0034337 (claw hand deformity),

CaseHPOFreeText: Dorsal kyphosis; extreme myopia found via optical examination (visual acuity reached 0.4 in right eye and 0.5 in left eye); thickening of heart valves, mild tricuspid, and aortic valve regurgitation found via Color Doppler ultrasonography; normal intelligence indicated with Wechsler Preschool and Primary Scale of Intelligence scale; cone-shaped phalanges; bilateral coxa vara; small epiphyses on the distal femur and proximal-distal tibiofibula; thin bone cortex; short femoral shaft; multiple diffuse abnormal signals in the bilateral frontal-parietal lobes and left part of the corpus callosum; proband was born at a 3.35 kg weight and 51 cm height

CaseNotHPOs:

CaseNotHPOFreeText: No prominent abnormalities found in blood thyroid hormone levels

CaseEnzymeAssay: "alpha-L-iduronidase activity was significantly decreased in the patient leukocytes (0.65 nmol/h/mg protein)"

CaseUrineGAGs: No urine GAG levels reported for this proband

CaseERT: Don't know

CaseBMT: Don't know

Variant1: c.159‐9T>A

Variant1ClinVarID:

Variant1CAID: CA3044589050

Variant2: c.159‐9T>A

Variant2ClinVarID:

Variant2CAID: CA3044589050

AdditionalVariants: No other pathogenic variants were found/were associated with clinical features

ParentalGenotype: Proband's father is heterozygous for c.159‐9T>A IDUA mutation. DNA from mother and sister of proband showed wild-type allele. Paper states that proband's MPS-I is "caused by UPD(4)pat leading to homozygosity for one pathogenic splicing variant. . ."

PreviouslyPublished: No mention of previous publication

Case#: Subject 4, male in his 10s (age at enrollment), died in his sleep within the first 48 hours of the initial dose during pilot study.

DiseaseAssertion: MPS1-HS

FamilyInfo: N/A

CasePresentingHPOs: HP:0002176, HP:0001638 (Spinal cord compression, cardiomyopathy)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: Yes - Enzyme replacement therapy with laronidase

CaseBMT: N/A

Variant1: c.1208G>A (p.W402X)

Variant1ClinVarID: 11908

Variant1CAID: CA220498

Variant2: c.713T>A (p.L238Q)

Variant2ClinVarID: 265418

Variant2CAID: CA2802065

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: 15, Female, Infancy (onset), 10 months (diagnosed), 12 years (report)

DiseaseAssertion: Hurler-Scheie Syndrome

FamilyInfo: Not Provided

CasePresentingHPOs: HP:0004322, HP:0000256, HP:0001387, HP:0002240, HP:0001744, HP:0000023, HP:0000158, HP:0000280, HP:0000943, HP:0007957 (Short Stature, Macrocephaly, Joint Stiffness, Hepatomegaly (moderate), Splenomegaly (moderate), Inguinal Hernia, Large Tongue, Coarse Facial Features, Dysostosis Multiplex, Corneal Clouding)

CaseHPOFreeText: (Mental Development (Delayed), Systolic murmur 3-4/6, After ERT: decreased illness (obstructive bronchitis), decreased organomegaly, increased mobility)

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: Decreased excretion of GAGs in the urine

CaseERT: Had an ERT

CaseBMT: N/A

GenotypingMethod: Not Provided

Variant1: p.Q70X

Variant1ClinVarID: 11909

Variant1CAID: CA204563

Variant2: p.R628X

Variant2ClinVarID: 550421

Variant2CAID: CA2802462

AdditionalVariants: p.A8, p.A20, p.Q33H, p.L118

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: 3, Female, 6 months (onset), 13 months (diagnosed), 14 months (report)

DiseaseAssertion: Hurler Syndrome

FamilyInfo: Not Provided

CasePresentingHPOs: HP:0002240, HP:0001744, HP:0000280, HP:0000943, HP:0007957 (Hepatomegaly (moderate), Splenomegaly (mild), Coarse Facial Features, Dysostosis Multiplex, Corneal Clouding)

CaseHPOFreeText: Mental Development (Developmental quotient 92 in 13m), Hyperechogenic mitral valve (with insufficiency of 1st-2nd grade)

CaseNotHPOs: HP:0004322, HP:0000256, HP:0001387 (Short Stature, Macrocephaly, Joint Stiffness)

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: Hematopoietic Stem Cell Transplantation (performed in March 2008)

GenotypingMethod: Not Provided

Variant1: p.W402X

Variant1ClinVarID: 11908

Variant1CAID: CA220498

Variant2: p.W402X

Variant2ClinVarID: 11908

Variant2CAID: CA220498

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: 10, Male, 2 months (onset), 2 months (diagnosed), 2 months (report), deceased (due to severe graft versus host disease)

DiseaseAssertion: Hurler Syndrome

FamilyInfo: Not Provided

CasePresentingHPOs: HP:0002240, HP:0001744, HP:0001537, HP:0000158, HP:0000280, HP:0000943, HP:0007957 (Hepatomegaly (moderate), Splenomegaly (moderate), Umbilical Hernia, Large Tongue, Coarse Facial Features, Dysostosis Multiplex, Corneal Clouding)

CaseHPOFreeText: Mental Development (Delayed since early infancy)

CaseNotHPOs: HP:0000256 (Macrocephaly)

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: Hematopoietic Stem Cell Transplantation at 5m

GenotypingMethod: Not Provided

Variant1: p.Q70X

Variant1ClinVarID: 11909

Variant1CAID: CA204563

Variant2: p.Q70X

Variant2ClinVarID: 11909

Variant2CAID: CA204563

AdditionalVariants: p.Q33H/Q33H, p.L118/L118

ParentalGenotype: N/A

PreviouslyPublished N/A

PMID: 31298590

Gene: IDUA

Disease: MPS1

Inheritance: Autosomal recessive

Case#: Patient 4, 11 years old, Iranian

DiseaseAssertion: MPS1-H (Severe)

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: IDUA activity not detected

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1029C>A (p.Y343X)

Variant1ClinVarID: 222997

Variant1CAID: CA356984

Variant2: c.1029C>A (p.Y343X)

Variant2ClinVarID: 222997

Variant2CAID: CA356984

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 8, male, 5 months (age at HSCT), 0.9 months (age at ERT)

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Veno-occlusive disease (VOD), adenovirus infection

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 0.06 (at diagnosis), 20.1 (after HSCT) Units not provided.

CaseUrineGAGs: N/A

CaseERT: Yes - 124 days duration

CaseBMT: Yes - Through a sibling with stem cells sourcing from the BM (bone marrow).

Variant1: c.1882C>T (p.R628X)

Variant1ClinVarID: 550421

Variant1CAID: CA2802462

Variant2: c.1882C>T (p.R628X)

Variant2ClinVarID: 550421

Variant2CAID: CA2802462

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 9, female, 7.9 months (age at diagnosis), 12.0 months (age at HSCT), 9.5 - 12.7 months (age at ERT), 4 MRI + neuropsychological observations over the course of 7 years.

DiseaseAssertion: MPS-1H

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 24.8 nmol/h/mg (Normal values: 11-43 nmol/h/mg)

CaseUrineGAGs: N/A

CaseERT: Yes

CaseBMT: Yes, transplanted with an unrelated cord blood unit.

Variant1: c.1487C>G (p.P496R)

Variant1ClinVarID: 496861

Variant1CAID: CA2802275

Variant2: c.1487C>G (p.P496R)

Variant2ClinVarID: 496861

Variant2CAID: CA2802275

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

1 individual from "other regions" was reported to have this variant in a cohort of 291 people with MPS1.

CAID: CA355961907

Genotype: NM_000203.3 c.606C>A p.(Tyr202Ter)

HPOFreeText: Phenotype: unknown

GenotypingMethod: bidirectional Sanger sequencing of the IDUA gene. IDUA exons and adjacent intron regions were amplified by PCR reactions and then sequenced

SupplementalInfo: Supplemental table S1

Mentioned that this variant has been seen in a previous publication: Matte (2003), but it doesn't sound like it's the same individual

Case#: No additional case information provided

DiseaseAssertion: MPSI-H/S

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 0.4 umol/g hr, reference range 10–50 umol/g hr.

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1871A>T (p.D624V)

Variant1ClinVarID: N/A

Variant1CAID: CA355965955

Variant2: c.17_24dupCCCGCGCC (p.A9PfsTer102)

Variant2ClinVarID: N/A

Variant2CAID: CA645372294

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: No additional case information provided

DiseaseAssertion: MPSI-H

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 0.09 umol/g hr, reference range 10–50 umol/g hr.

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1278_1284dupCCCCCAG (p.G429PfsTer82)

Variant1ClinVarID: N/A

Variant1CAID: CA645372299

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

Variant2ClinVarID: 11909

Variant2CAID: CA204563

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Pt 5, age is 11 months (proband can be found in Table 1)

DiseaseAssertion: Hurler syndrome, mucopolysaccharidosis type IH, MPS IH, MPS type I

FamilyInfo: No family information provided

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

CaseEnzymeAssay: In methods it is stated that an IDUA activity assay was conducted on cartilaginous pellets generated from patient-derived bone marrow stromal cells at 5 weeks. However, results of the IDUA activity assays are not stated.

CaseUrineGAGs: "Significantly higher levels of GAGs in MPS IH compared with HD pellets at.1 week of chondrogenic differentiation, thus indicating that GAG accumulation in MPS IH can be seen during cell condensation and early differentiation stages." Total GAG content for each sample in ug GAG/ug DNA shown in Figure 4 graphs.

CaseERT: Don't know

CaseBMT: Don't know

Variant1: p.W402X

Variant1ClinVarID:

Variant1CAID: PA3051368272

Variant2: p.W402X

Variant2ClinVarID:

Variant2CAID: PA3051368272

AdditionalVariants: No additional variants mentioned

ParentalGenotype: No parental information provided

PreviouslyPublished: No mention of being previously published

Case#: Patient 10, 10 years old, Iranian

DiseaseAssertion: MPS1-S (Attenuated)

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 0.45 µmol/g.h (Normal ranges: 10-50 µmol/g.h)

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.152G>A (p.G51D)

Variant1ClinVarID: 193061

Variant1CAID: CA274902

Variant2: Unknown

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Infant 2

DiseaseAssertion: N/A

FamilyInfo: Has an older sibling with the same genotype

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 0.3 nmol/h/mg; normal range, ≥1.0 nmol/h/mg

CaseUrineGAGs: 18.07 mg/mmol creatinine; normal ranges, 0-53 mg/mmol creatinine

CaseERT: N/A

CaseBMT: N/A

Variant1: c.721T>C (p.C241R)

Variant1ClinVarID: 3720559

Variant1CAID: CA355962132

Variant2: c.1163C>T (p.T388M)

Variant2ClinVarID: 558615

Variant2CAID: CA355963455

AdditionalVariants: N/A

ParentalGenotype: c.721T>C (paternal); c.1163C>T (maternal)

PreviouslyPublished N/A

Case#: Patient 12 (see Table 2), 40 weeks (Gestational age)

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Upper respiratory tract involvement

CaseNotHPOs: Inguinal hernia (HP:0000023)

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.653T>C (p.L218P)

Variant1ClinVarID: 222995

Variant1CAID: CA:356986

Variant2: c.653T>C (p.L218P)

Variant2ClinVarID: 222995

Variant2CAID: CA:356986

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient D2, Druze religious group, located in lower Galilee.

DiseaseAssertion: MPS1-H

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.928C>T (p.Q310X)

Variant1ClinVarID: 11915

Variant1CAID: N/A

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: No individual patient information available. 11/59 patients studied (18.7%) had this variant. This variant originates from two regions of Iran. 5 patients came from the city of Rasht in the Gilan province, making it a focal point for this variant. 6 patients came from five different provinces in the southwestern regions of Iran.

DiseaseAssertion: MPS1

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.1A>C

Variant1ClinVarID: 550458

Variant1CAID: CA355945204

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished This variant has previously been reported in studies conducted by Atceken et al. (2016) and Bertola et al. (2011), in patients from Turkey and Spain respectively. However, there has been no report suggestive of a founder effect for this variant.

Case#: Patient 3 (see Table 2), male, 16.5 years old (age at report), 7.6 years (duration of treatment), 6 surgeries

DiseaseAssertion: MPS1-HS

FamilyInfo: N/A

CasePresentingHPOs: HP:0000238, HP:0002176, HP:0002360 (Hydrocephalus, spinal cord compression, sleep abnormality)

CaseHPOFreeText: Psychiatric problems

CaseNotHPOs: N/A

CaseNotHPOFreeText: Shunt placement

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: Yes

CaseBMT: N/A

Variant1: c.712T>A (p.L238Q) CDNA and protein change do not match. Known variant p.L238Q has a CDNA change of c.713T>A.

Variant1ClinVarID: 265418

Variant1CAID: CA2802065

Variant2: c.1205G>A (p.W402X)

Variant2ClinVarID: 11908

Variant2CAID: CA220498

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

PMID: 25102484

Gene: IDUA

Disease: MPS1

Inheritance: Autosomal recessive

Case#: Patient V, origin of proband is United Kingdom

DiseaseAssertion: Hurler syndrome (H)

FamilyInfo: No family information is provided

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

CaseEnzymeAssay: IDUA enzyme activity for this proband is N/A. The reference range is also N/A.

CaseUrineGAGs: Information not stated in this paper

CaseERT: Don't know

CaseBMT: Don't know

Variant1: c.1598C>G, p.P533R

Variant1ClinVarID: 11910

Variant1CAID: CA256112

Variant2: c.(157 + 1_158‐1)_(1727 + 1_1728‐1)dup

Variant2ClinVarID: Not sure how to look up in CAR

Variant2CAID: Not sure how to look up in CAR

AdditionalVariants: No additional variants mentioned

ParentalGenotype: No parental genotype information provided

PreviouslyPublished: I do not believe this proband was previously published. The paper states that variant "c.1598C>G have been found in patients previously." It does not link the variant to a specific paper but instead references a list of papers. Here are the PMIDs of those paper: 7951228, 1301196, 1301941, and 7550232

Case#: Patient 2, female, 2 years (age of onset), 5 years (age at report)

DiseaseAssertion: MPS1

FamilyInfo: Born from a consanguineous marriage (second cousin parents), she had a twin sister that died a few weeks after birth. Her mother experienced intrauterine fetal death (IUFD) during her first pregnancy and after the second pregnancy infant died of congenital heart defects (CHD).

CasePresentingHPOs: Claw hand deformity, deafness, coarse facial features, dolichocephaly, neurodevelopmental delay, developmental regression (HP:0034337, HP:0000365, HP:0000256, HP:0000268, HP:0012758, HP:0002376)

CaseHPOFreeText: Began pronouncing words at 9 months, sitting at 10 months, and started walking at the age of 2. Her developmental conditions lapsed after the age of 2.

CaseNotHPOs: Intellectual disability (HP:0001249)

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: GAG electrophoresis revealed increased amounts of DS and CS

CaseERT: She currently is taking Aldorazyme medication

CaseBMT: N/A

Variant1: c.612_615dupCTGC

Variant1ClinVarID: 226413

Variant1CAID: CA10576338

Variant2: c.612_615dupCTGC

Variant2ClinVarID: 226413

Variant2CAID: CA1057633

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: No additional case information provided

DiseaseAssertion: MPSI-H

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: Abnormal

CaseUrineGAGs: Abnormal

CaseERT: N/A

CaseBMT: N/A

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

Variant1ClinVarID: 11909

Variant1CAID: CA204563

Variant2: c.1269C>A (p.S423R)

Variant2ClinVarID: 856833

Variant2CAID: CA91169964

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: 02059, Age 38, Male, Blood type A+ (Table S3)

Disease Assertion: VWD 1

FamilyInfo: Patient is a member of family # 02059. There is one other member of the family (patient 02060). 02060 has the same exonic variant (c.3614G>A), but has a different intronic variant ( c.7438-169G>A).

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding score 12, VWF:Ag: 5.4, VWF:RCo: 6.1, FVIII:C:11, VWF:CB: 4.5

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: NM_000552.4:c.3614G>A (p.Arg1205His) and

ClinVar: 308 ClinVar

CAID: CA114160 CAID1

gnomAD:

Case#: 02001, Age 63, Female, Blood Type A+ (Table S3)

Disease Assertion: VWD 1

FamilyInfo:( Family 0201) 8 family members were included in the study. All of them had type VWD type 1. All had the same variant besides patient 02019.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding Score 14, VWF:Ag: 9.7, VWF:RCo: 2.6, FVIII:C: 19, VWF:CB: 6

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: NM_000552.4:c.3614G>A (p.Arg1205His)

ClinVar: 308 ClinVar

CAID: CA114160

CAID

gnomAD: N/A

Case#: 02069, Age 45, Female, Blood Type O+ (Table S3)

Disease Assertion: VWD 1

FamilyInfo: The patients was 1 of 3 members of family #0226.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding Score 5, VWF:Ag: 30, VWF:RCo:27, FVIII:C: 81, VWF:CB: 40

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: NM_000552.4:c.3467C>T (p.Thr1156Met) and NM_000552.3:c.-3151T>G

ClinVar: 100264 ClinVar

CAID: CA228414 CAID

gnomAD: N/A

Case#: 27030, Age 23, Male, Blood Type O+ (Table S3)

Disease Assertion: VWD 1

FamilyInfo: The patient is one of 6 members in Family #2703. All members have the same variant.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: VWF:Ag:26, VWF:RCo:28.6, FVIII:C:81, VWF:CB: 30

CaseNotHPOs: N/A

CaseNotHPOFreeText: Bleeding Score 2

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: NM_000552.4:c.1533+15G>A (p.=)

ClinVar: 100182 ClinVar

CAID: CA228275 CAID

gnomAD: MAF of 0.002649 ( 93/ 35104 alleles) in the Latino Population. gnomAD

Case#: 01037, Age 16, Male, Blood Type O- (Table S3)

Disease Assertion: VWD 1

FamilyInfo: Not listed

Parental Genotype: Not listed

CasePresentingHPOs:

CaseHPOFreeText: Bleeding type 14, VWF:Ag: 22, VWF:RCO: 32, FVIII:C: 28, VWF:CB: 22

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: NM_000552.4:c.3426T>C (p.Cys1142=) and NM_000552.4:c.3485_3486inv (p.Pro1162Leu)

ClinVar: 256668 and 619934

ClinVar1 ClinVar2

CAID: CA6402757 and CA658683073

CAID1 CAID2

gnomAD: MAF of 0.2228 (2240/10052 alleles) in the African population (CA6402757).

gnomAD1

Case#: 03015, Age 37, Female, Blood Type O+ (Table S3)

Disease Assertion: VWD 1

FamilyInfo: Patient is the only member of family #0399.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding score 0, VWF:Ag: 17, VWF:RCo: 17.7, FVIII:C 15, VWF:CB 16

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#: 10013, Age 23, Female, Blood Type O+ (Table S3)

Disease Assertion: VWD1

FamilyInfo: The patient is the only member of Family#1011.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding Score 3, VWF:Ag:7.2, VWF:RCo:5.6, FVIII:C:19, VWF:CB:6.5

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: NM_000552.4:c.5198T>C (p.Leu1733Pro)

ClinVar: N/A

CAID: CA383496267 CAID

gnomAD: N/A

Case#: 02047, Age 71, Male, Blood Type: O+ (Table S3)

Disease Assertion:VWD 1

FamilyInfo: Family# 0218; 3 Family members were included in the study. All 3 members had VWD type 1. All 3 have the same variant as patient 02047.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding Score 9, VWF:Ag: 9.3, VWF:RCo:6.4, FVIII:C: 30, VWF:CB: 6.1

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: NM_000552.4:c.5471C>A (p.Pro1824His)

ClinVar: 100430 ClinVar

CAID:CA228725

CAID

gnomAD: N/A

Case#: 32010, Age 21, Male, Blood Type not determined (Table S3)

Disease Assertion: VWD 1

FamilyInfo: The patient is one of two members of Family#3210. The second member is a carrier of the variant c.3931C>T.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding Score 12, VWF:Ag:7.2, VWF:RCo: 5.7, FVIII:C: 21, VWF:CB: 6.8

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: NM_000552.4:c.3931C>T (p.Gln1311Ter) and NM_000552.4:c.55G>A (p.Gly19Arg)

ClinVar: 100307 and 100432 ClinVar1 ClinVar

CAID: CA228496 and CA228729 CAID1 CAID2

gnomAD: MAF of 0.0003921 (12/ 30604 alleles) in the South Asian population (CA228496). gnomAD

MAF of 0.0008819 (27/ 30616 alleles) in the South Asian population.

gnomAD

Case#: 06002, Age 39, Female,Blood Type O+ (Table S3)

Disease Assertion: VWD1

FamilyInfo: Two total members in Family #0602. Patient 06003 has the c.2685G>C variant and a seperate intronic variant.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding score 8, VWF:Ag: 25, VWF:RCo: 19.1, FVIII:C:88, VWF:CB:24

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: NM_000552.4:c.2685G>C (p.Gln895His) and NM_000552.4:c.4751A>G (p.Tyr1584Cys)

ClinVar: 310

ClinVar

CAID: CA383519910 and CA114162

CAID1 CAID2

gnomAD: MAF of 0.004024 (519/128972 alleles) in the European (non-Finnish) population.

gnomAD

Case#: 06009, Age 60, Female, Blood Type O+ (Table S3)

Disease Assertion: VWD1

FamilyInfo: The patient is the only member of family#0607.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding Score 2, VWF:Ag:23, VWF:RCo: 25, FVIII:C 83, VWF:CB: 23

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: NM_000552.4:c.2435del (p.Pro812fs)

ClinVar: 303 ClinVar

CAID: CA114153 CAID

gnomAD: MAF of 0.0003601(9/ 24994 alleles) in the European (Finnish) population.

gnomAD

Case#: 13006, Age 66, Male, Blood Type A-

Disease Assertion: VWD 1

FamilyInfo: The patient is the only member of Family# 1304.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding Score 8, VWF:Ag:10, VWF:RCo: 6, FVIII:C:16, VWF:CB:6.1

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: NM_000552.4:c.3614G>A (p.Arg1205His)

ClinVar: 308 ClinVar

CAID: CA114160 CAID

gnomAD: N/A

Case#: 13014, Age20, Male, Blood type O+ (TableS3)

Disease Assertion: VWD 1

FamilyInfo: The patient is the only member of Family#1311.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding Score 6, VWF:Ag:24, VWF:RCo: 22.5, FVIII:C:40, VWF:CB: 20

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

ClinVar: 310 ClinVar

CAID: CA114162 CAID

gnomAD: MAF of 0.004024 (519/ 128972 alleles) in the European (non-Finnish) population

Case#: 03044, Age 27, Female (Table S3)

Disease Assertion: VWD 1

FamilyInfo: Patient was the only member of family #03230

Parental Genotype: not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding Score 3, VWF:Ag: 22, VWF:RCo:18, FVIIIC:29, VWF:CB: 17

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: c.6699_6702dup (p.Cys2235ArgfsTer8)

ClinVar:

CAID:

gnomAD:

Case#: 27012, Age 24, Female, Blood Type O+ (Table S3)

Disease Assertion: VWD 1

FamilyInfo: The patient is the only member of Family #2707.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: VWF:Ag: 33, VWF:RCo: 29, FVIII:C: 91, VWF:CB: 32

CaseNotHPOs: N/A

CaseNotHPOFreeText: Bleeding score 0

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: NM_000552.4:c.3467C>T (p.Thr1156Met) and c.-3151T>G

ClinVar: 100264 ClinVar

CAID: CA228414 CAID

gnomAD:

Case#: 22011, Age 67, Male, Blood Type A- (Table S3)

Disease Assertion: VWD 1

FamilyInfo: The patient is the only member of Family#2207.

Parental Genotype: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding score 7, VWF:Ag: 18, VWF:RCo:16, FVIII:C:46, VWF:CBNM_0:14

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: NM_000552.4:c.6799-47G>A (p.=), NM_000552.4:c.7464C>T (p.Gly2488=), NM_000552.4:c.998-46C>T (p.=)

ClinVar: 619755 ClinVar1

CAID: CA6401901, CA232284628, CA6403602 CAID1 CAID2 CAID3

gnomAD: MAF of 0.0005876 (17/ 28930 alleles) in the South Asian population (CA6401901). gnomAD1

MAF of 0.000008799 (1/ 113644 alleles) in the European (non-Finnish) population (CA232284628). gnomAD2

MAF of 0.00007581 (8/105528 alleles) in the European (non-Finnish) population (CA6403602) gnomAD3

Case: Patient 33, Family K (Table 1.), F/49, Afro-Caribbean

DiseaseAssertion: VWD2A (IIE)

FamilyInfo: Patient 18 (F/53, Afro-Caribbean), Patient 29 (F/33, Afro-Caribbean), Patient 32 (F/17, Afro-Caribbean) also from Family K. (Table 1.)

ParentalGenotype(s): NA

CasePresentingHPOs:

CaseHPOFreeRext: BAT =17, FVIII:C (IU/dL) = 3, VWF:Ag (IU/dL) = 3, VWF:Act (IU/dL) = 7

CaseNOTHPOs:

CaseNOTHPOFreeText: Blood type A+

CasePreviousTesting:

GenotypingMethod: All samples were analyzed by captured-based high throughput sequencing which was performed with a custom-design of the VWF gene provided by Twist BioScience (San Francisco, USA). It comprised all 52 exons, intronic flanking regions, promoter and 3’UTR region of the VWF gene. Libraries were prepared by using the Twist NGS target enrichment solution (Twist BioScience) according to the manufacturer protocol. Samples were analyzed on a NovaSeq 6000 sequencer (Illumina) with a median read depth of 2500X by using the 300-cycle S1 NovaSeq 6000seq reagent kit with 150-bp paired-end reads. The raw data were analyzed with Mutect21 and Vardict2 tools. The inhouse NGSreport software (CHU Lille) was used for data visualization, sequences check and conservation of variants with high quality metrics. In some cases, patients genomic DNA was screened for sequence variations (large deletions, insertions and duplications) by Multiplex Ligation-dependent Probe Amplification (MCR Holland).

PreviouslyPublished: NA

Gene: VWF

Variant: c.1661del, p.(Lys554Serfs*23)

HGVS: NM_000552.5:c.1661del (p.Lys554Serfs*23)

ClinVarID:

CAID: CA2617232671

gnomAD: MAF is 0.00001332 (1/75048 alleles) in African/African/American population https://gnomad.broadinstitute.org/variant/chr12-6057916-CT-C?dataset=gnomad_r4

Variant: c.2365A > G, p.(Thr789Ala)

HGVS: NM_000552.5:c.2365A>G (p.Thr789Ala)

ClinVarID: 256659

CAID: CA6403090

gnomAD: MAF of 0.5793 (43409/74928 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6044368-T-C?dataset=gnomad_r4

Variant: c.2385T > C, p.(Tyr795 =)

HGVS: NM_000552.5:c.2385T>C (p.Tyr795=)

ClinVarID: 256660

CAID: CA6403087

gnomAD: MAF of 0.5788 (43385/74952 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6044348-A-G?dataset=gnomad_r4

Variant: c.2880G > A, p.(Arg960 =)

HGVS: NM_000552.5:c.2880G>A (p.Arg960=)

ClinVarID: 195657

CAID: CA201877

gnomAD: MAF of 0.3169 (23737/74896 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6029429-C-T?dataset=gnomad_r4

Variant: c.3505T > A, p.(Cys1169Ser)

HGVS: NM_000552.5:c.3505T>A (p.Cys1169Ser)

ClinVarID:

CAID: CA383511219

gnomAD:

Variant: c.4138A > G, p.(Ile1380Val)

HGVS: NM_000552.5:c.4138A>G (p.Ile1380Val)

ClinVarID: 310063

CAID: CA6402595

gnomAD: MAF of 0.1184 (8878/74958 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6019280-T-C?dataset=gnomad_r4

Variant: c.4304A > G, p.(Asn1435Ser)

HGVS: NM_000552.5:c.4304A>G (p.Asn1435Ser)

ClinVarID: 310062

CAID: CA6402552

gnomAD: MAF of 0.1124 (8427/74964 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6019114-T-C?dataset=gnomad_r4

Variant: c.4414G > C p.(Asp1472His)

HGVS: NM_000552.5:c.4414G>C (p.Asp1472His)

ClinVarID: 256679

CAID: CA6402534

gnomAD: MAF of 0.5076 (38011/74882 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6019004-C-G?dataset=gnomad_r4

Variant: c.6554G > A, p.(Arg2185Gln)

HGVS: NM_000552.5:c.6554G>A (p.Arg2185Gln)

ClinVarID: 100443

CAID: CA228748

gnomAD: MAF of 0.1927 (14427/74878 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-5993906-C-T?dataset=gnomad_r4

Case: Patient 29, Family K (Table 1.), F/33, Afro-Caribbean

DiseaseAssertion: VWD2A (IIE)

FamilyInfo: Patient 18 (F/53, Afro-Caribbean), Patient 32 (F/17, Afro-Caribbean), Patient 33 (F/49, Afro-Caribbean) also from Family K. (Table 1.)

ParentalGenotype(s): NA

CasePresentingHPOs:

CaseHPOFreeRext: BAT =13, FVIII:C (IU/dL) = 75, VWF:Ag (IU/dL) = 25, VWF:Act (IU/dL) = 18

CaseNOTHPOs:

CaseNOTHPOFreeText: Blood type O+

CasePreviousTesting:

GenotypingMethod: All samples were analyzed by captured-based high throughput sequencing which was performed with a custom-design of the VWF gene provided by Twist BioScience (San Francisco, USA). It comprised all 52 exons, intronic flanking regions, promoter and 3’UTR region of the VWF gene. Libraries were prepared by using the Twist NGS target enrichment solution (Twist BioScience) according to the manufacturer protocol. Samples were analyzed on a NovaSeq 6000 sequencer (Illumina) with a median read depth of 2500X by using the 300-cycle S1 NovaSeq 6000seq reagent kit with 150-bp paired-end reads. The raw data were analyzed with Mutect21 and Vardict2 tools. The inhouse NGSreport software (CHU Lille) was used for data visualization, sequences check and conservation of variants with high quality metrics. In some cases, patients genomic DNA was screened for sequence variations (large deletions, insertions and duplications) by Multiplex Ligation-dependent Probe Amplification (MCR Holland).

PreviouslyPublished: NA

Gene: VWF

Variant: c.3505T > A, p.(Cys1169Ser)

HGVS: NM_000552.5:c.3505T>A (p.Cys1169Ser)

ClinVarID:

CAID: CA383511219

gnomAD:

Variant: c.4138A > G, p.(Ile1380Val)

HGVS: NM_000552.5:c.4138A>G (p.Ile1380Val)

ClinVarID: 310063

CAID: CA6402595

gnomAD: MAF of 0.1184 (8878/74958 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6019280-T-C?dataset=gnomad_r4

Variant: c.4304A > G, p.(Asn1435Ser)

HGVS: NM_000552.5:c.4304A>G (p.Asn1435Ser)

ClinVarID: 310062

CAID: CA6402552

gnomAD: MAF of 0.1124 (8427/74964 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6019114-T-C?dataset=gnomad_r4

Variant: c.4414G > C p.(Asp1472His)

HGVS: NM_000552.5:c.4414G>C (p.Asp1472His)

ClinVarID: 256679

CAID: CA6402534

gnomAD: MAF of 0.5076 (38011/74882 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6019004-C-G?dataset=gnomad_r4

Case: Patient 31, Family O (Table 1.), F/73, Afro-Caribbean

DiseaseAssertion: VWD2A (IIE)

FamilyInfo: Patient 30 (M/42, Afro-Caribbean) also from Family O. (Table 1.)

ParentalGenotype(s): NA

CasePresentingHPOs:

CaseHPOFreeRext: BAT = 2, FVIII:C (IU/dL) = 31, VWF:Ag (IU/dL) = 20, VWF:Act (IU/dL) = 22

CaseNOTHPOs:

CaseNOTHPOFreeText: Blood group O+

CasePreviousTesting:

GenotypingMethod: All samples were analyzed by captured-based high throughput sequencing which was performed with a custom-design of the VWF gene provided by Twist BioScience (San Francisco, USA). It comprised all 52 exons, intronic flanking regions, promoter and 3’UTR region of the VWF gene. Libraries were prepared by using the Twist NGS target enrichment solution (Twist BioScience) according to the manufacturer protocol. Samples were analyzed on a NovaSeq 6000 sequencer (Illumina) with a median read depth of 2500X by using the 300-cycle S1 NovaSeq 6000seq reagent kit with 150-bp paired-end reads. The raw data were analyzed with Mutect21 and Vardict2 tools. The inhouse NGSreport software (CHU Lille) was used for data visualization, sequences check and conservation of variants with high quality metrics. In some cases, patients genomic DNA was screened for sequence variations (large deletions, insertions and duplications) by Multiplex Ligation-dependent Probe Amplification (MCR Holland).

PreviouslyPublished: NA

Gene: VWF

Variant: c.1530G > A, p.(Val510 =) p.

HGVS: NM_000552.5:c.1530G>A (p.Val510=)

ClinVarID:

CAID: CA6403368

gnomAD: MAF of 0.00002198 (2/91004 alleles) in South Asian population https://gnomad.broadinstitute.org/variant/chr12-6062957-C-T?dataset=gnomad_r4

Variant: c.1892C > T, p.(Ala631Val)

HGVS: NM_000552.5:c.1892C>T (p.Ala631Val)

ClinVarID: 422844

CAID: CA6403245

gnomAD: MAF of 0.001908 (137/71810 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6056910-G-A?dataset=gnomad_r4

Variant: c.2220G > A, p.(Met740Ile)

HGVS: NM_000552.5:c.2220G>A (p.Met740Ile)

ClinVarID: 100206

CAID: CA201316

gnomAD: MAF of 0.1816 (13626/75022 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6046784-C-T?dataset=gnomad_r4

Variant: c.2451T > A, p.(His817Gln)

HGVS: NM_000552.5:c.2451T>A (p.His817Gln)

ClinVarID: 100224

CAID: CA228345

gnomAD: MAF of 0.1150 (8626/75016 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6036483-A-T?dataset=gnomad_r4

Variant: c.3445T > C, p.(Cys1149Arg)

HGVS: NM_000552.5:c.3445T>C (p.Cys1149Arg)

ClinVarID: 309

CAID: CA228410

gnomAD: MAF of 0.000003160 (1/316464 alleles) in European (non-Finnish) population https://gnomad.broadinstitute.org/variant/chr12-6022833-A-G?dataset=gnomad_r4

Variant: c.4414G > C p.(Asp1472His)

HGVS: NM_000552.5:c.4414G>C (p.Asp1472His)

ClinVarID: 256679

CAID: CA6402534

gnomAD: MAF of 0.5076 (38011/74882 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6019004-C-G?dataset=gnomad_r4

Variant: c.6554G > A, p.(Arg2185Gln)

HGVS: NM_000552.5:c.6554G>A (p.Arg2185Gln)

ClinVarID: 100443

CAID: CA228748

gnomAD: MAF of 0.1927 (14427/74878 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-5993906-C-T?dataset=gnomad_r4

Case: Patient 49, Family W (Table 1.), F/57, Afro-Caribbean

DiseaseAssertion: VWD2M

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs:

CaseHPOFreeRext: BAT = NA, FVIII:C (IU/dL) = 57, VWF:Ag (IU/dL) = 50, VWF:Act (IU/dL) = 29

CaseNOTHPOs:

CaseNOTHPOFreeText: Blood group A+

CasePreviousTesting:

GenotypingMethod: All samples were analyzed by captured-based high throughput sequencing which was performed with a custom-design of the VWF gene provided by Twist BioScience (San Francisco, USA). It comprised all 52 exons, intronic flanking regions, promoter and 3’UTR region of the VWF gene. Libraries were prepared by using the Twist NGS target enrichment solution (Twist BioScience) according to the manufacturer protocol. Samples were analyzed on a NovaSeq 6000 sequencer (Illumina) with a median read depth of 2500X by using the 300-cycle S1 NovaSeq 6000seq reagent kit with 150-bp paired-end reads. The raw data were analyzed with Mutect21 and Vardict2 tools. The inhouse NGSreport software (CHU Lille) was used for data visualization, sequences check and conservation of variants with high quality metrics. In some cases, patients genomic DNA was screened for sequence variations (large deletions, insertions and duplications) by Multiplex Ligation-dependent Probe Amplification (MCR Holland).

PreviouslyPublished: NA

Gene: VWF

Variant: c.4315G > A, p.(Val1439Met)

HGVS: NM_000552.5:c.4315G>A (p.Val1439Met)

ClinVarID: 1334625

CAID: CA6402550

gnomAD: MAF of 0.005146 (386/75012 alleles) in African American population https://gnomad.broadinstitute.org/variant/chr12-6019103-C-T?dataset=gnomad_r4

Variant: c.4414G > C p.(Asp1472His)

HGVS: NM_000552.5:c.4414G>C (p.Asp1472His)

ClinVarID: 256679

CAID: CA6402534

gnomAD: MAF of 0.5076 (38011/74882 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6019004-C-G?dataset=gnomad_r4

Case: Patient 18, Family K (Table 1.), F/53, Afro-Caribbean

DiseaseAssertion: VWD2A (IIE)

FamilyInfo: Patient 29 (F/33, Afro-Caribbean), Patient 32 (F/17, Afro-Caribbean), Patient 33 (F/49, Afro-Caribbean) also from Family K. (Table 1.)

ParentalGenotype(s): NA

CasePresentingHPOs:

CaseHPOFreeRext: BAT =27, FVIII:C (IU/dL) = 19, VWF:Ag (IU/dL) = 16, VWF:Act (IU/dL) = 4

CaseNOTHPOs:

CaseNOTHPOFreeText: Blood type A+

CasePreviousTesting:

GenotypingMethod: All samples were analyzed by captured-based high throughput sequencing which was performed with a custom-design of the VWF gene provided by Twist BioScience (San Francisco, USA). It comprised all 52 exons, intronic flanking regions, promoter and 3’UTR region of the VWF gene. Libraries were prepared by using the Twist NGS target enrichment solution (Twist BioScience) according to the manufacturer protocol. Samples were analyzed on a NovaSeq 6000 sequencer (Illumina) with a median read depth of 2500X by using the 300-cycle S1 NovaSeq 6000seq reagent kit with 150-bp paired-end reads. The raw data were analyzed with Mutect21 and Vardict2 tools. The inhouse NGSreport software (CHU Lille) was used for data visualization, sequences check and conservation of variants with high quality metrics. In some cases, patients genomic DNA was screened for sequence variations (large deletions, insertions and duplications) by Multiplex Ligation-dependent Probe Amplification (MCR Holland).

PreviouslyPublished: NA

Gene: VWF

Variant: c.1661del, p.(Lys554Serfs*23)

HGVS: NM_000552.5:c.1661del (p.Lys554Serfs*23)

ClinVarID:

CAID: CA2617232671

gnomAD: MAF is 0.00001332 (1/75048 alleles) in African/African/American population https://gnomad.broadinstitute.org/variant/chr12-6057916-CT-C?dataset=gnomad_r4

Variant: c.2365A > G, p.(Thr789Ala)

HGVS: NM_000552.5:c.2365A>G (p.Thr789Ala)

ClinVarID: 256659

CAID: CA6403090

gnomAD: MAF of 0.5793 (43409/74928 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6044368-T-C?dataset=gnomad_r4

Variant: c.2385T > C, p.(Tyr795 =)

HGVS: NM_000552.5:c.2385T>C (p.Tyr795=)

ClinVarID: 256660

CAID: CA6403087

gnomAD: MAF of 0.5788 (43385/74952 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6044348-A-G?dataset=gnomad_r4

Variant: c.2880G > A, p.(Arg960 =)

HGVS: NM_000552.5:c.2880G>A (p.Arg960=)

ClinVarID: 195657

CAID: CA201877

gnomAD: MAF of 0.3169 (23737/74896 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6029429-C-T?dataset=gnomad_r4

Variant: c.3505T > A, p.(Cys1169Ser)

HGVS: NM_000552.5:c.3505T>A (p.Cys1169Ser)

ClinVarID:

CAID: CA383511219

gnomAD:

Variant: c.4414G > C p.(Asp1472His)

HGVS: NM_000552.5:c.4414G>C (p.Asp1472His)

ClinVarID: 256679

CAID: CA6402534

gnomAD: MAF of 0.5076 (38011/74882 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6019004-C-G?dataset=gnomad_r4

Variant: c.6554G > A, p.(Arg2185Gln)

HGVS: NM_000552.5:c.6554G>A (p.Arg2185Gln)

ClinVarID: 100443

CAID: CA228748

gnomAD: MAF of 0.1927 (14427/74878 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-5993906-C-T?dataset=gnomad_r4

Case: Patient 23, Family I (Table 1.), F/86, Afro-Caribbean

DiseaseAssertion: VWD2A (IIE)

FamilyInfo: Patient 13 (F/65, Afro-Caribbean), Patient 21 (F/97, Afro-Caribbean), Patient 22 (F/67, Afro-Caribbean), Patient 24 (F/92, Afro-Caribbean), Patient 25 (F/62, Afro-Carribean) also from Family I. (Table 1.)

ParentalGenotype(s): NA

CasePresentingHPOs:

CaseHPOFreeRext: BAT =16, FVIII:C (IU/dL) = 24, VWF:Ag (IU/dL) = 15, VWF:Act (IU/dL) = 14

CaseNOTHPOs:

CaseNOTHPOFreeText: Blood group O+

CasePreviousTesting:

GenotypingMethod: All samples were analyzed by captured-based high throughput sequencing which was performed with a custom-design of the VWF gene provided by Twist BioScience (San Francisco, USA). It comprised all 52 exons, intronic flanking regions, promoter and 3’UTR region of the VWF gene. Libraries were prepared by using the Twist NGS target enrichment solution (Twist BioScience) according to the manufacturer protocol. Samples were analyzed on a NovaSeq 6000 sequencer (Illumina) with a median read depth of 2500X by using the 300-cycle S1 NovaSeq 6000seq reagent kit with 150-bp paired-end reads. The raw data were analyzed with Mutect21 and Vardict2 tools. The inhouse NGSreport software (CHU Lille) was used for data visualization, sequences check and conservation of variants with high quality metrics. In some cases, patients genomic DNA was screened for sequence variations (large deletions, insertions and duplications) by Multiplex Ligation-dependent Probe Amplification (MCR Holland).

PreviouslyPublished: NA

Gene: VWF

Variant: c.1530G > A, p.(Val510 =) p.

HGVS: NM_000552.5:c.1530G>A (p.Val510=)

ClinVarID:

CAID: CA6403368

gnomAD: MAF of 0.00002198 (2/91004 alleles) in South Asian population https://gnomad.broadinstitute.org/variant/chr12-6062957-C-T?dataset=gnomad_r4

Variant: c.1892C > T, p.(Ala631Val)

HGVS: NM_000552.5:c.1892C>T (p.Ala631Val)

ClinVarID: 422844

CAID: CA6403245

gnomAD: MAF of 0.001908 (137/71810 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6056910-G-A?dataset=gnomad_r4

Variant: c.2220G > A, p.(Met740Ile)

HGVS: NM_000552.5:c.2220G>A (p.Met740Ile)

ClinVarID: 100206

CAID: CA201316

gnomAD: MAF of 0.1816 (13626/75022 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6046784-C-T?dataset=gnomad_r4

Variant: c.2451T > A, p.(His817Gln)

HGVS: NM_000552.5:c.2451T>A (p.His817Gln)

ClinVarID: 100224

CAID: CA228345

gnomAD: MAF of 0.1150 (8626/75016 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6036483-A-T?dataset=gnomad_r4

Variant: c.3258C > T, p.(Tyr1086 =)

HGVS: NM_000552.5:c.3258C>T (p.Tyr1086=)

ClinVarID: 256664

CAID: CA6402788

gnomAD: MAF of 0.1284 (9131/71128 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6023752-G-A?dataset=gnomad_r4

Variant: c.3445T > C, p.(Cys1149Arg)

HGVS: NM_000552.5:c.3445T>C (p.Cys1149Arg)

ClinVarID: 309

CAID: CA228410

gnomAD: MAF of 0.000003160 (1/316464 alleles) in European (non-Finnish) population https://gnomad.broadinstitute.org/variant/chr12-6022833-A-G?dataset=gnomad_r4

Variant: c.4414G > C p.(Asp1472His)

HGVS: NM_000552.5:c.4414G>C (p.Asp1472His)

ClinVarID: 256679

CAID: CA6402534

gnomAD: MAF of 0.5076 (38011/74882 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6019004-C-G?dataset=gnomad_r4

Variant: c.6554G > A, p.(Arg2185Gln)

HGVS: NM_000552.5:c.6554G>A (p.Arg2185Gln)

ClinVarID: 100443

CAID: CA228748

gnomAD: MAF of 0.1927 (14427/74878 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-5993906-C-T?dataset=gnomad_r4

Case: Patient 41, Family S (Table 1.), M/63, Afro-Caribbean

DiseaseAssertion: Indeterminant

FamilyInfo: Patient 39 (F/76, Afro-Caribbean), Patient 40 (F/38, Afro-Caribbean)and Patient 52 (F/48, Afro Caribbean) also from Family S. (Table 1.)

ParentalGenotype(s): NA

CasePresentingHPOs:

CaseHPOFreeRext: BAT = 0, FVIII:C (IU/dL) = 100, VWF:Ag (IU/dL) = 92, VWF:Act (IU/dL) = 36

CaseNOTHPOs:

CaseNOTHPOFreeText: Blood group O+

CasePreviousTesting:

GenotypingMethod: All samples were analyzed by captured-based high throughput sequencing which was performed with a custom-design of the VWF gene provided by Twist BioScience (San Francisco, USA). It comprised all 52 exons, intronic flanking regions, promoter and 3’UTR region of the VWF gene. Libraries were prepared by using the Twist NGS target enrichment solution (Twist BioScience) according to the manufacturer protocol. Samples were analyzed on a NovaSeq 6000 sequencer (Illumina) with a median read depth of 2500X by using the 300-cycle S1 NovaSeq 6000seq reagent kit with 150-bp paired-end reads. The raw data were analyzed with Mutect21 and Vardict2 tools. The inhouse NGSreport software (CHU Lille) was used for data visualization, sequences check and conservation of variants with high quality metrics. In some cases, patients genomic DNA was screened for sequence variations (large deletions, insertions and duplications) by Multiplex Ligation-dependent Probe Amplification (MCR Holland).

PreviouslyPublished: NA

Gene: VWF

Variant: c.4138A > G, p.(Ile1380Val)

HGVS: NM_000552.5:c.4138A>G (p.Ile1380Val)

ClinVarID: 310063

CAID: CA6402595

gnomAD: MAF of 0.1184 (8878/74958 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6019280-T-C?dataset=gnomad_r4

Variant: c.4304A > G, p.(Asn1435Ser)

HGVS: NM_000552.5:c.4304A>G (p.Asn1435Ser)

ClinVarID: 310062

CAID: CA6402552

gnomAD: MAF of 0.1124 (8427/74964 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6019114-T-C?dataset=gnomad_r4

Variant: c.4414G > C p.(Asp1472His)

HGVS: NM_000552.5:c.4414G>C (p.Asp1472His)

ClinVarID: 256679

CAID: CA6402534

gnomAD: MAF of 0.5076 (38011/74882 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6019004-C-G?dataset=gnomad_r4

Variant: c.4628C > G p.(Ser1543Cys)

HGVS: NM_000552.5:c.4628C>G (p.Ser1543Cys)

ClinVarID: 4533008

CAID: CA383500651

gnomAD:

Case: Patient 28, Family F (Table 1.), F/55, Afro-Caribbean

DiseaseAssertion: VWD2A (IIE)

FamilyInfo: Patient 8 (M/86, Afro-Caribbean) and Patient 9 (F/76, Afro-Caribbean) also from Family F. (Table 1.)

ParentalGenotype(s): NA

CasePresentingHPOs:

CaseHPOFreeRext: BAT = 6, FVIII:C (IU/dL) = 112, VWF:Ag (IU/dL) = 10, VWF:Act (IU/dL) = 14

CaseNOTHPOs:

CaseNOTHPOFreeText: Blood group A+

CasePreviousTesting:

GenotypingMethod: All samples were analyzed by captured-based high throughput sequencing which was performed with a custom-design of the VWF gene provided by Twist BioScience (San Francisco, USA). It comprised all 52 exons, intronic flanking regions, promoter and 3’UTR region of the VWF gene. Libraries were prepared by using the Twist NGS target enrichment solution (Twist BioScience) according to the manufacturer protocol. Samples were analyzed on a NovaSeq 6000 sequencer (Illumina) with a median read depth of 2500X by using the 300-cycle S1 NovaSeq 6000seq reagent kit with 150-bp paired-end reads. The raw data were analyzed with Mutect21 and Vardict2 tools. The inhouse NGSreport software (CHU Lille) was used for data visualization, sequences check and conservation of variants with high quality metrics. In some cases, patients genomic DNA was screened for sequence variations (large deletions, insertions and duplications) by Multiplex Ligation-dependent Probe Amplification (MCR Holland).

PreviouslyPublished: NA

Gene: VWF

Variant: c.1530G > A, p.(Val510 =) p.

HGVS: NM_000552.5:c.1530G>A (p.Val510=)

ClinVarID:

CAID: CA6403368

gnomAD: MAF of 0.00002198 (2/91004 alleles) in South Asian population https://gnomad.broadinstitute.org/variant/chr12-6062957-C-T?dataset=gnomad_r4

Variant: c.1892C > T, p.(Ala631Val)

HGVS: NM_000552.5:c.1892C>T (p.Ala631Val)

ClinVarID: 422844

CAID: CA6403245

gnomAD: MAF of 0.001908 (137/71810 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6056910-G-A?dataset=gnomad_r4

Variant: c.2220G > A, p.(Met740Ile)

HGVS: NM_000552.5:c.2220G>A (p.Met740Ile)

ClinVarID: 100206

CAID: CA201316

gnomAD: MAF of 0.1816 (13626/75022 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6046784-C-T?dataset=gnomad_r4

Variant: c.2451T > A, p.(His817Gln)

HGVS: NM_000552.5:c.2451T>A (p.His817Gln)

ClinVarID: 100224

CAID: CA228345

gnomAD: MAF of 0.1150 (8626/75016 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6036483-A-T?dataset=gnomad_r4

Variant: c.3426T > C, p.(Cys1142 =)

HGVS: NM_000552.5:c.3426T>C (p.Cys1142=)

ClinVarID: 256668

CAID: CA6402757

gnomAD: MAF of 0.2077 (7935/38206 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6022852-A-G?dataset=gnomad_r4

Variant: c.3445T > C, p.(Cys1149Arg)

HGVS: NM_000552.5:c.3445T>C (p.Cys1149Arg)

ClinVarID: 309

CAID: CA228410

gnomAD: MAF of 0.000003160 (1/316464 alleles) in European (non-Finnish) population https://gnomad.broadinstitute.org/variant/chr12-6022833-A-G?dataset=gnomad_r4

Variant: c.3485C > T, p.(Pro1162Leu)

HGVS: NM_000552.5:c.3485C>T (p.Pro1162Leu)

ClinVarID: 256669

CAID: CA6402756

gnomAD: MAF of 0.2076 (7087/34136 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6022793-G-A?dataset=gnomad_r4

Variant: c.3486A > G, p.(Pro1162 =)

HGVS: NM_000552.5:c.3486A>G (p.Pro1162=)

ClinVarID: 256670

CAID: CA6402755

gnomAD: MAF of 0.2083 (7074/33968 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6022792-T-C?dataset=gnomad_r4

Variant: c.4414G > C p.(Asp1472His)

HGVS: NM_000552.5:c.4414G>C (p.Asp1472His)

ClinVarID: 256679

CAID: CA6402534

gnomAD: MAF of 0.5076 (38011/74882 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6019004-C-G?dataset=gnomad_r4

Variant: c.6554G > A, p.(Arg2185Gln)

HGVS: NM_000552.5:c.6554G>A (p.Arg2185Gln)

ClinVarID: 100443

CAID: CA228748

gnomAD: MAF of 0.1927 (14427/74878 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-5993906-C-T?dataset=gnomad_r4

Case: Patient 38, Family R (Table 1.), F/51, Afro-Caribbean

DiseaseAssertion: VWD2A (IIE)

FamilyInfo: Patient 36 (M/22, Afro-Caribbean) and Patient 37 (M/20, Afro-Caribbean) also from Family R. (Table 1.)

ParentalGenotype(s): NA

CasePresentingHPOs:

CaseHPOFreeRext: BAT = 6, FVIII:C (IU/dL) = 30, VWF:Ag (IU/dL) = 20, VWF:Act (IU/dL) = 14

CaseNOTHPOs:

CaseNOTHPOFreeText: Blood group O+

CasePreviousTesting:

GenotypingMethod: All samples were analyzed by captured-based high throughput sequencing which was performed with a custom-design of the VWF gene provided by Twist BioScience (San Francisco, USA). It comprised all 52 exons, intronic flanking regions, promoter and 3’UTR region of the VWF gene. Libraries were prepared by using the Twist NGS target enrichment solution (Twist BioScience) according to the manufacturer protocol. Samples were analyzed on a NovaSeq 6000 sequencer (Illumina) with a median read depth of 2500X by using the 300-cycle S1 NovaSeq 6000seq reagent kit with 150-bp paired-end reads. The raw data were analyzed with Mutect21 and Vardict2 tools. The inhouse NGSreport software (CHU Lille) was used for data visualization, sequences check and conservation of variants with high quality metrics. In some cases, patients genomic DNA was screened for sequence variations (large deletions, insertions and duplications) by Multiplex Ligation-dependent Probe Amplification (MCR Holland).

PreviouslyPublished: NA

Gene: VWF

Variant: c.1530G > A, p.(Val510 =) p.

HGVS: NM_000552.5:c.1530G>A (p.Val510=)

ClinVarID:

CAID: CA6403368

gnomAD: MAF of 0.00002198 (2/91004 alleles) in South Asian population https://gnomad.broadinstitute.org/variant/chr12-6062957-C-T?dataset=gnomad_r4

Variant: c.1892C > T, p.(Ala631Val)

HGVS: NM_000552.5:c.1892C>T (p.Ala631Val)

ClinVarID: 422844

CAID: CA6403245

gnomAD: MAF of 0.001908 (137/71810 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6056910-G-A?dataset=gnomad_r4

Variant: c.2220G > A, p.(Met740Ile)

HGVS: NM_000552.5:c.2220G>A (p.Met740Ile)

ClinVarID: 100206

CAID: CA201316

gnomAD: MAF of 0.1816 (13626/75022 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6046784-C-T?dataset=gnomad_r4

Variant: c.2451T > A, p.(His817Gln)

HGVS: NM_000552.5:c.2451T>A (p.His817Gln)

ClinVarID: 100224

CAID: CA228345

gnomAD: MAF of 0.1150 (8626/75016 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6036483-A-T?dataset=gnomad_r4

Variant: c.3445T > C, p.(Cys1149Arg)

HGVS: NM_000552.5:c.3445T>C (p.Cys1149Arg)

ClinVarID: 309

CAID: CA228410

gnomAD: MAF of 0.000003160 (1/316464 alleles) in European (non-Finnish) population https://gnomad.broadinstitute.org/variant/chr12-6022833-A-G?dataset=gnomad_r4

Variant: c.4414G > C p.(Asp1472His)

HGVS: NM_000552.5:c.4414G>C (p.Asp1472His)

ClinVarID: 256679

CAID: CA6402534

gnomAD: MAF of 0.5076 (38011/74882 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6019004-C-G?dataset=gnomad_r4

Case: Patient 15, Family J (Table 1.), F/64, Afro-Caribbean

DiseaseAssertion: Indeterminate effect of the VWF defect due to ISTH BAT at 0

FamilyInfo: Patient 14 (M/36, Afro-Carribean) also from Family J. (Table 1.)

ParentalGenotype(s): NA

CasePresentingHPOs:

CaseHPOFreeRext: BAT =0, FVIII:C (IU/dL) = 110, VWF:Ag (IU/dL) = 102, VWF:Act (IU/dL) = 40

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: All samples were analyzed by captured-based high throughput sequencing which was performed with a custom-design of the VWF gene provided by Twist BioScience (San Francisco, USA). It comprised all 52 exons, intronic flanking regions, promoter and 3’UTR region of the VWF gene. Libraries were prepared by using the Twist NGS target enrichment solution (Twist BioScience) according to the manufacturer protocol. Samples were analyzed on a NovaSeq 6000 sequencer (Illumina) with a median read depth of 2500X by using the 300-cycle S1 NovaSeq 6000seq reagent kit with 150-bp paired-end reads. The raw data were analyzed with Mutect21 and Vardict2 tools. The inhouse NGSreport software (CHU Lille) was used for data visualization, sequences check and conservation of variants with high quality metrics. In some cases, patients genomic DNA was screened for sequence variations (large deletions, insertions and duplications) by Multiplex Ligation-dependent Probe Amplification (MCR Holland).

PreviouslyPublished: NA

Gene: VWF

Variant: c.3505T > A, p.(Cys1169Ser)

HGVS: NM_000552.5:c.3505T>A (p.Cys1169Ser)

ClinVarID:

CAID: CA383511219

gnomAD:

Case: Patient 52, Family S (Table 1.), F/48, Afro-Caribbean

DiseaseAssertion: VWD1

FamilyInfo: Patient 39 (F/76, Afro-Caribbean), Patient 40 (F/38, Afro-Caribbean)and Patient 41 (m/63, Afro Caribbean) also from Family S. (Table 1.)

ParentalGenotype(s): NA

CasePresentingHPOs:

CaseHPOFreeRext: BAT = 4, FVIII:C (IU/dL) = NA, VWF:Ag (IU/dL) = 30, VWF:Act (IU/dL) = 30

CaseNOTHPOs:

CaseNOTHPOFreeText: Blood group O+

CasePreviousTesting:

GenotypingMethod: All samples were analyzed by captured-based high throughput sequencing which was performed with a custom-design of the VWF gene provided by Twist BioScience (San Francisco, USA). It comprised all 52 exons, intronic flanking regions, promoter and 3’UTR region of the VWF gene. Libraries were prepared by using the Twist NGS target enrichment solution (Twist BioScience) according to the manufacturer protocol. Samples were analyzed on a NovaSeq 6000 sequencer (Illumina) with a median read depth of 2500X by using the 300-cycle S1 NovaSeq 6000seq reagent kit with 150-bp paired-end reads. The raw data were analyzed with Mutect21 and Vardict2 tools. The inhouse NGSreport software (CHU Lille) was used for data visualization, sequences check and conservation of variants with high quality metrics. In some cases, patients genomic DNA was screened for sequence variations (large deletions, insertions and duplications) by Multiplex Ligation-dependent Probe Amplification (MCR Holland).

PreviouslyPublished: NA

Gene: VWF

Variant: deletion of exons 9-10

HGVS: NM_000552.5:c.1030_1317del (p.Gly344_Arg439del)

ClinVarID:

CAID: CA3260663889

gnomAD:

Variant: c.4414G > C p.(Asp1472His)

HGVS: NM_000552.5:c.4414G>C (p.Asp1472His)

ClinVarID: 256679

CAID: CA6402534

gnomAD: MAF of 0.5076 (38011/74882 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6019004-C-G?dataset=gnomad_r4