PMID: 10735634

Gene: IDUA

Disease: MPS1

Inheritance: Autosomal recessive

Case#: Patient F (female), diagnosed at 4 years and 6 months on the basis of clinical findings, an elevated urinary glycosaminoglycan level, and low α-l-iduronidase activity in leukocytes. Patient F was 104.0 cm tall (75th percentile).

DiseaseAssertion: MPS1-H/S

FamilyInfo: The patient is an older sibling who was diagnosed with the disease and has an affected younger brother.

CasePresentingHPOs: Coarse facial features, joint stiffness, thick skin, corneal clouding, hepatosplenomegaly, dysostosis multiplex (HP:0000280, HP:0001387, HP:0001072, HP:0007957, HP:0001433, HP:0000943)

CaseHPOFreeText: Moderate mitral insufficiency with thickened valve leaflets and anterior edge prolapse; mild left atrium thickening and increased pulmonary pressure were also present. Radiographic skeletal examination showed several signs of hip hypoplasia, ovoid shape of lumbar vertebral bodies, V-shaped distal ulnar and radial extremities, and short and broad metacarpal bones. Although she had normal intelligence, she developed obstructive hydrocephalus, which required shunting at 7 months of age.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: Low α-l-iduronidase activity in leukocytes

CaseUrineGAGs: Elevated urinary glycosaminoglycan levels

CaseERT: Yes - Patient F started laronidase at 5 years of age, also at the standard dose. After 5 years of therapy, she was 138.0 cm tall (90th percentile), her liver and spleen volume had normalized, her skin had become less thickened, and her shoulder flexion and extension were moderately improved. Her dysostosis multiplex, cardiac function, and corneal clouding (visual acuity: 10/10) had stabilized but were not improved.

CaseBMT: N/A

Variant1: c.12205G>A (p.W402X)

Variant1ClinVarID: 11908

Variant1CAID: CA220498

Variant2: c.1603C>T (p.L535F)

Variant2ClinVarID: 638076

Variant2CAID: CA355965038

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 27, female, Han origin, 9 years old (age at diagnosis)

DiseaseAssertion: MPS1-H/S

FamilyInfo: N/S

CasePresentingHPOs: Joint stiffness, Mongolian macula, Hepatosplenomegaly, Airway obstruction (HP:0001387, HP:0011369, HP:0001433, HP:0006536)

CaseHPOFreeText: N/A

CaseNotHPOs: Global Developmental Delay, Macrocephaly, Hernia (HP:0001263, HP:0000256, HP:0100790)

CaseNotHPOFreeText: Cardiac disease

CaseEnzymeAssay: IDUA activity 3.4 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.98A>C (p.H33P)

Variant1ClinVarID: N/A

Variant1CAID: CA355945475

Variant2: c.1402+2T>G

Variant2ClinVarID: 553131

Variant2CAID: CA355964392

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 21, female, Han origin, 10 years old (age at diagnosis)

DiseaseAssertion: MPS1-S

FamilyInfo: N/A

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

CaseHPOFreeText: N/A

CaseNotHPOs: Global Developmental Delay, Macrocephaly, Mongolian macula (HP:0001263, HP:0000256, HP:0011369)

CaseNotHPOFreeText: Cardiac disease

CaseEnzymeAssay: IDUA activity 0.2 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.1898C>T (p.S633L)

Variant1ClinVarID: 556406

Variant1CAID: CA355966010

Variant2: c.536C>G (p.T179R)

Variant2ClinVarID: 556358

Variant2CAID: CA355961718

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 36, female, Han origin, 5 years old (age at diagnosis)

DiseaseAssertion: MPS1-H/S

FamilyInfo: N/A

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

CaseHPOFreeText: N/A

CaseNotHPOs: Global Developmental Delay, Mongolian macula, Hernia, (HP:0001263, HP:0011369, HP:0100790)

CaseNotHPOFreeText: Cardiac disease

CaseEnzymeAssay: IDUA activity 1.5 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.159C>A (p.C53X)

Variant1ClinVarID: 1458768

Variant1CAID: N/A

Variant2: c.1037T>G (p.L346R)

Variant2ClinVarID: 11927

Variant2CAID: CA256128

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 54, male, Han origin, age of diagnosis not available

DiseaseAssertion: N/A

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: IDUA activity 0.6 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.236C>T (p.A79V)

Variant1ClinVarID: 1458769

Variant1CAID: CA356987

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 43, male, Han origin, 5 years old (age at diagnosis)

DiseaseAssertion: MPS1-H/S

FamilyInfo: N/A

CasePresentingHPOs: Joint stiffness, Mongolian macula, Hepatosplenomegaly, Hernia, Airway obstruction (HP:0001387, HP:0011369, HP:0001433, HP:0100790, HP:0006536)

CaseHPOFreeText: N/A

CaseNotHPOs: Global Developmental Delay, Macrocephaly (HP:0001263, HP:0000256)

CaseNotHPOFreeText: Cardiac disease

CaseEnzymeAssay: IDUA activity 1.5 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.300-3C>G

Variant1ClinVarID: 551563

Variant1CAID: CA549265042

Variant2: c.530dupT (p.Glu178ArgfsTer5) (Paper refers to the variant as c.531dupT, there is a typo in the article where all duplication variants are one base pair off)

Variant2ClinVarID: N/A

Variant2CAID: CA2586973520

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

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 No. 2 (Table 1), Arabic Druze ethnic group, male, 1.15 years old (age at time of gene therapy), 100 IQ score, 2.40 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.192C>A (p.Y64X)

Variant1ClinVarID: 11914

Variant1CAID: CA256113

Variant2: c.192C>A (p.Y64X)

Variant2ClinVarID: 11914

Variant2CAID: CA256113

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient No. 7 (Table 1), Black race, male, 1.71 years (age at time of gene therapy), 80 IQ score, 1.73 years since gene therapy (1.5 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.923_926delTGCC (p.L308HfsX8)

Variant1ClinVarID: N/A

Variant1CAID: N/A

Variant2: c.923_926delTGCC (p.L308HfsX8)

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

PMID: 34788506

Gene: IDUA

Disease: MPS1

Inheritance: Autosomal recessive

Case#: Patient 32, 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.1205G>A (p.W402X)

Variant1ClinVarID: 11908

Variant1CAID: CA220498

Variant2: c.1225G>A (p.G265R)

Variant2ClinVarID: 1084956

Variant2CAID: CA91169920

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 82, Turkey

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.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 10, 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.1205G>A (p.W402X)

Variant1ClinVarID: 11908

Variant1CAID: CA220498

Variant2: c.1603C>T (p.L535F)

Variant2ClinVarID: 638076

Variant2CAID: CA355865038

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 65, Spain

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.979G>C (p.A327P)

Variant1ClinVarID: 167190

Variant1CAID: CA234128

Variant2: c.1154C>G (p.P385R)

Variant2ClinVarID: 556024

Variant2CAID: CA355963438

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Family E proband, female, 18 months old (age of diagnosis), 11 years old (age of death), Tunisia.

DiseaseAssertion: MPS1-H

FamilyInfo: No affected family members (See Fig. 1), parents were 1st degree relatives (See Table 1). The family benefited from a prenatal diagnosis showing a normal enzymatic activity (3.5 nmol/h/mg) (usual values: 1-5).

CasePresentingHPOs: HP:0001999, HP:0030799, HP:0002652, HP:0000687, HP:0030812, HP:0012471, HP:0000574, HP:0001537, HP:0001653, HP:0002673, HP:0001433, HP:0001640, HP:0004322 (Abnormal facial shape, scaphocephaly, skeletal dysplasia, widely spaced teeth, enlarged tonsils, thick lips, bushy eyebrows, umbilical hernia, mitral valve regurgitation, coax valga, hepatosplenomegaly, cardiomegaly, short stature

CaseHPOFreeText: Compression of the medulla

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: IDUA activity (0.5 nmol/h/mg) (usual values: 1-5 nmol/h/mg).

CaseUrineGAGs: glycosaminoglycans (125 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.530T>C (p.F177S)

Variant1ClinVarID: N/A

Variant1CAID: CA355961706

Variant2: c.530T>C (p.F177S)

Variant2ClinVarID: N/A

Variant2CAID: CA355961706

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 42, 1 years old (age at report), female, Indian

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

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

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 3.1% (Range of residual enzyme activity: 0.0%-4.8%)

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1855C>T (p.Arg619Ter)

Variant1ClinVarID: 280976

Variant1CAID: CA2802455

Variant2: c.1855C>T (p.Arg619Ter)

Variant2ClinVarID: 280976

Variant2CAID: CA2802455

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 37, 1 years old (age at report), female, Indian

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

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

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 4.8% (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 28, 8 months old (age at report), female, Indian

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: Coarse facial features, hepatosplenomegaly, corneal clouding, dysostosis multiplex (HP:0000280, HP:0001433, HP:0007957, HP:0000943)

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.1273delC (p.His425Thrfs*15)

Variant1ClinVarID: 3391381

Variant1CAID: CA2586965976

Variant2: c.1273delC (p.His425Thrfs*15)

Variant2ClinVarID: 556156

Variant2CAID: CA2586965976

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 50, 2 years old (age at report), female, Indian

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: Coarse facial features, hepatosplenomegaly, corneal clouding, recurrent infections, hernia (HP:0000280, HP:0001433, HP:0007957, HP:0002719, HP:0100790)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 2.2% (Range of residual enzyme activity: 0.0%-4.8%)

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.238G>T (p.Val80Phe)

Variant1ClinVarID: N/A

Variant1CAID: CA355946451

Variant2: c.784delC (p.His262Thrfs*55)

Variant2ClinVarID: 956890

Variant2CAID: CA2802083

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 10, 1 years old (age at report), male, Indian

DiseaseAssertion: MPS1-H

FamilyInfo: Sibling of patient 11

CasePresentingHPOs: Coarse facial features, recurrent infections, dysostosis multiplex, intellectual disability, hernia (HP:0000280, HP:0002719, HP:0000943, HP:0001249, HP:0100790)

CaseHPOFreeText: Cardiac disease

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.531C>G (p.Phe177Leu)

Variant1ClinVarID: 2432729

Variant1CAID: CA2801983

Variant2: c.531C>G (p.Phe177Leu)

Variant2ClinVarID: 2432729

Variant2CAID: CA2801983

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 30, 8 years old (age at report), male, Indian

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: Coarse facial features, hepatosplenomegaly, joint contractures, corneal clouding, recurrent infections, dysostosis multiplex, intellectual disability (HP:0000280, HP:0001433, HP:0002828, HP:0007957, HP:0002719, HP:0000943, HP:0001249)

CaseHPOFreeText: Cardiac disease

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.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 51, 2 years old (age at report), female, Indian

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: Coarse facial features, hepatosplenomegaly, joint contractures, dysostosis multiplex (HP:0000280, HP:0001433, HP:0002828, HP:0000943)

CaseHPOFreeText: Cardiac disease

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 2.4% (Range of residual enzyme activity: 0.0%-4.8%)

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.265G>C in the article - incorrect variant but unknown what the correct nomenclature is. Could be c.265C>G (p.Arg89Gly) or c.266G>C (p.Arg89Pro)

Variant1ClinVarID: N/A

Variant1CAID: N/A

Variant2: c.779C>T (p.Ser260Phe)

Variant2ClinVarID: 3895951

Variant2CAID: CA355962251

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: D349N

Variant1ClinVarID: 92623

Variant1CAID: CA220497

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: H82Q

Variant1ClinVarID:

Variant1CAID: CA355946477

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: M133I

Variant1ClinVarID:

Variant1CAID: CA91166179

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: No additional case information provided.

DiseaseAssertion: Not specified

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: Abnormal

CaseUrineGAGs: Normal

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1225G>A (p.G409R)

Variant1ClinVarID: 1084956

Variant1CAID: CA91169920

Variant2: c.1757C>T (p.S386F)

Variant2ClinVarID: 571910

Variant2CAID: CA2802396

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: No additional case information provided.

DiseaseAssertion: Not specified

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: Abnormal

CaseUrineGAGs: Normal

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1148G>A (p.R383H)

Variant1ClinVarID: 558189

Variant1CAID: CA2802205

Variant2: c.112C>A (p.R89S)

Variant2ClinVarID: 2432781

Variant2CAID: CA355945526

AdditionalVariants: c.250G>A (p.G48S), ClinVarID:726495, CAID:CA2801152

ParentalGenotype: N/A

PreviouslyPublished N/A

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: Abnormal

CaseUrineGAGs: Normal

CaseERT: N/A

CaseBMT: N/A

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

Variant1ClinVarID: 11909

Variant1CAID: CA220498

Variant2: c.1577T>C (p.L526P)

Variant2ClinVarID: 567566

Variant2CAID: CA2802300

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient #3 (see Table 2), male, 15 months old (age at diagnosis), 5 years old (age at report).

DiseaseAssertion: MPS-I

FamilyInfo: Born to a consanguineous family

CasePresentingHPOs: Macrocephaly, corneal clouding, hearing loss (HP:0000256, HP:0007957, HP:0000365)

CaseHPOFreeText: Normal intelligence

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: α-L-iduronidase 15.6 pmol/spot. The activity of this enzyme is below its reference (200–2600 pmol/spot).

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1A>C (p.M1L)

Variant1ClinVarID: 550458

Variant1CAID: CA355945204

Variant2: c.469T>C (p.S157P)

Variant2ClinVarID: N/A

Variant2CAID: CA355961573

AdditionalVariants: N/A

ParentalGenotype: Variant c.1A>C was paternally inherited and variant c.469T>C was maternally inherited.

PreviouslyPublished N/A

1 individual was reported to have this variant from the cohort UK cohort of 145 people.

Genotype: NM_000203.3 c.1205G>A p.(Trp402Ter) c.1728-1G>C

HPOFreeText: Phenotype: Sev: 1 (H) "classification of a “severe” phenotype was based on the presence of one or more of the following: presentation with clinical features of MPS I and diagnosis before 12 months of age; significant developmental delay in a child with clinical features of MPS I under 30 months of age; sibling of a child with MPS I also classified as “severe phenotype.”"

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

Case#: <0.1% residual activity at 37 °C

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: <0.1 nmol/mg/h IDUA activity at 37 °C

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.134del12 on paper but nomenclature is c.46_57del (p.Ser16_Ala19del)

Variant1ClinVarID: 92643

Variant1CAID: CA220509

Variant2: c.134del12 on paper but nomenclature is c.46_57del (p.Ser16_Ala19del)

ClinVarID: 92643

Variant2CAID: CA220509

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Family 9, 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.208C>T (p.Q70X)

Variant1ClinVarID: 11909

Variant1CAID: CA204563

Variant2: c.540_544del (p.W180X); c.628del5 in the paper

Variant2ClinVarID: 3775043

Variant2CAID: CA2573332240

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Family 21, Pakistan

DiseaseAssertion: MPS1-H/S

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

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.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#: Infant #7, female.

DiseaseAssertion: MPS-I

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 21.60 IDUA enzyme activity (Ref. 5.9–27.8 μmol/g protein/h)

CaseUrineGAGs: DMB/Cre. Ratio - 26.82, DS - 0.20, HS - 0.01, KS - 6.49 GAG quantifications (DMB/Cre ratio) and the normal reference values based on the age groups: <6 mos: <70.68 mg /mmol cre.; 6 mos–2 yrs: <46.80 mg /mmol cre.; 2–17 yrs: <20.98 mg /mmol cre.; and >18 yrs: <12.62 mg /mmol cre. Quantitative analyses of GAG-derived disaccharides (DS, S, or KS) by tandem mass spectrometry assay. The normal cut-off values: DS < 0.80 μg/mL; HS < 0.78 μg/mL; and KS < 7.90 μg/mL.

CaseERT: N/A

CaseBMT: N/A

Variant1: c.76G>A (p.A26T)

Variant1ClinVarID: 712785

Variant1CAID: CA280110

Variant2: c.911delT (p.V304Gfs*13)

Variant2ClinVarID: 1184991

Variant2CAID: CA2573052265

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Pt2, Male, 15 months (diagnosis), 15 months (onset)

DiseaseAssertion: Hurler Syndrome

FamilyInfo: N/A Pedigree (Figure 4Pt2)

CasePresentingHPOs: HP:0000280, HP:0000365, HP:0001654, HP:0100814, (Coarse face, Hearing Loss, Valvular heart disease, Dermal melanocytosis)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0007957, HP:0001387, HP:0001433, (Cornea clouding, Joint stiffness, Hepatosplenomegaly)

CaseNotHPOFreeText: Long bone deformation, Spinal deformation, Inguinal or Umbilical hernia

CaseEnzymeAssay: α-L-iduronidase 0.06 (dried blood spots, normal >1.32 µM/h)

CaseUrineGAGs: Urine heparan sulfate 55.44 (mg/mmol creatinine) {0.65-3.51}

CaseERT: N/A

CaseBMT: N/A

GenotypingMethod: Not Provided.

Variant1: c.1190-10C>A

Variant1ClinVarID: 950888

Variant1CAID: CA1139658405

Variant2: c.1190-10C>A

Variant2ClinVarID: 950888

Variant2CAID: CA1139658405

AdditionalVariants: N/A

ParentalGenotype: Both parents are homozygous for not having the c.1190-10C>A variant (figure 4 Pt 2)

PreviouslyPublished: N/A

Case#: Pt1, Male, 20 months (diagnosis), 20 months (onset)

DiseaseAssertion: Hurler Syndrome

FamilyInfo: N/A Pedigree (Figure 4Pt1)

CasePresentingHPOs: HP:0000280, HP:0007957, HP:0001654, HP:0100814, (Coarse face, Cornea clouding, Valvular heart disease, Dermal melanocytosis)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0001387, HP:0000365, HP:0001433, (Joint stiffness, Hearing loss, Hepatosplenomegaly)

CaseNotHPOFreeText: Long bone deformation, Spinal deformation, Inguinal or umbilical hernia

CaseEnzymeAssay: α-L-iduronidase 0.17 (dried blood spots, normal >1.32 µM/h)

CaseUrineGAGs: Urine heparan sulfate 8.26 (mg/mmol creatinine) {<0.67}

CaseERT: N/A

CaseBMT: N/A

GenotypingMethod: Not Provided.

Variant1: c.1190-10C>A

Variant1ClinVarID: 950888

Variant1CAID: CA1139658405

Variant2: c.1190-10C>A

Variant2ClinVarID: 950888

Variant2CAID: CA1139658405

AdditionalVariants: N/A

ParentalGenotype: Both parents are homozygous for not having the c.1190-10C>A variant (figure 4 Pt 1)

PreviouslyPublished: N/A

Case#: Patient 1, male, 1 year old (age at diagnosis), 2 years old (age when deceased - due to a severe respiratory infection)

DiseaseAssertion: MPS I-H

FamilyInfo: Parents had a consanguineous marriage

CasePresentingHPOs: Coarse facial features, corneal clouding, hepatosplenomegaly, skeletal dysplasia, global developmental delay (HP:0000280, HP:0007957, HP:0001433, HP:0002652, HP:0001263)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.252insC (current nomenclature: c.252dup)

Variant1ClinVarID: N/A

Variant1CAID: CA3060586149

Variant2: c.252insC (current nomenclature: c.252dup)

Variant2ClinVarID: N/A

Variant2CAID: CA3060586149

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.1858G>T (p.V620F)

Variant1ClinVarID: 1067173

Variant1CAID: CA355965934

Variant2: c.1858G>T (p.V620F)

Variant2ClinVarID: 1067173

Variant2CAID: CA355965934

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.1205G>A (p.W402X)

Variant1ClinVarID: 11908

Variant1CAID: CA220498

Variant2: c.1650+5G>A

Variant2ClinVarID: 92634

Variant2CAID: CA220504

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: P2, Female, 8.7 years (diagnosed), 10.7 (report), 21 kg (weight), 122 cm (height), Algerian

DiseaseAssertion: Scheie Syndrome

FamilyInfo: Parents are consanguineous

CasePresentingHPOs: HP:0001999, HP:0000943, HP:0001387, HP:0000365, HP:0007957, HP:0000238 (Facial Dysmorphic Features, Multiple Dysostosis, Hernia(Ombelical), Deafness(bilateral transmission), Corneal Opacity, Hydrocephalus)

CaseHPOFreeText: Chronic Rhinorrhea, Cardiac Manifestations(Mitral Insufficiency & Aortic Insufficiency)

CaseNotHPOs: HP:0001249, HP:0002240 (Mental Retardation, Joint Stiffness)

CaseNotHPOFreeText: HM/HSM

CaseEnzymeAssay: IDUA Enzyme activity 0 (% to the reference range mean)

CaseUrineGAGs: GAG quantitation 47 (fold change to the reference range mean according to age)

CaseERT: N/A

CaseBMT: N/A

GenotypingMethod: Direct DNA Fragments Sequencing

Variant1: c.1598C>G (p.Pro533Arg)

Variant1ClinVarID: 11910

Variant1CAID: CA256112

Variant2: c.1598C>G (p.Pro533Arg)

Variant2ClinVarID: 11910

Variant2CAID: CA256112

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

PMID: 32162878

Gene: IDUA

Disease: MPS1

Inheritance: Autosomal recessive

Case#: PKMPS1P2a, 8 years old (age at presentation), female, Pakastani

DiseaseAssertion: MPS-IH

FamilyInfo: Proband has an affected younger brother (PKMPS1P2b)

CasePresentingHPOs: On and off snoring, nasal congestion, failure to thrive, abdominal distension, recurrent respiratory infections, hepatomegaly (HP:0025267, HP:0001742, HP:0001508, HP:0003270, HP:0002788, HP:0002240)

CaseHPOFreeText: A liver span of 2 cm with firm consistency and a smooth surface. Smooth muscle infections.

CaseNotHPOs: Vomiting, headache (HP:0002013, HP:0002315)

CaseNotHPOFreeText: Fever, difficulty walking, normal facial features and normal eyes.

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.908T>C (p.L303P)

Variant1ClinVarID: N/A

Variant1CAID: CA355962537

Variant2: c.908T>C (p.L303P)

Variant2ClinVarID: N/A

Variant2CAID: CA355962537

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 9 (see Table 1), 5 years old - deceased (age at report), 1 year old (age at onset), female, height of 102 cm, weight of 18 kg, located at Mahdia: Touristic region.

DiseaseAssertion: MPS1 - severe

FamilyInfo: Parents were 1st cousins (see Table 2), aged 50 yrs (M) and 62 yrs (F).

CasePresentingHPOs: HP:0004322, HP:0010864, HP:0001537, HP:0000687, HP:0030812, HP:0001999, HP:0007957, HP:0000943 (Short stature, severe intellectual disability, umbilical hernia, widely spaced teeth, enlarged tonsils, facial dysmorphia, corneal clouding, dysostosis multiplex)

CaseHPOFreeText: Pigmented skin

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: IDUA activity 0.020 μKat/kg

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

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 4 (see Table 1), 9 years - deceased (age at report), 7 months (age at onset), male, height of 107 cm, weight of 19 kg, location at Gabes: Industrial region.

DiseaseAssertion: MPS1 - severe

FamilyInfo: One affected siblings (Patient 5), parents were 1st cousins (see Table 2) aged 55 yrs (M) and 65 yrs (F).

CasePresentingHPOs: HP:0004322, HP:0001999, HP:0000924, HP:0007957, HP:0001537, HP:0010864 (Short stature, abnormal facial shape, skeletal abnormality, corneal clouding, umbilical hernia, severe intellectual disability)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: IDUA activity: 0.018 μKat/kg

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1598C>G (p.P533R)

Variant1ClinVarID: 11910

Variant1CAID: CA256112

Variant2: c.1598C>G (p.P533R)

Variant2ClinVarID: 11910

Variant2CAID: CA256112

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Female, 6 years old (age of onset), 8 years old (age at report). Developmentally normal at 6 years old but had a 1-year long history of painful and stiff joints. Her weight was in the 5th percentile, height in the 3rd percentile, and head circumference in the 10th percentile for her age group.

DiseaseAssertion: MPS1-S

FamilyInfo: The patient's parents are second cousins. She has two healthy brothers.

CasePresentingHPOs: Joint stiffness, recurrent otitis media, snoring, joint contractures, carpal tunnel syndrome (HP:0001387, HP:0000403, HP:0025267, HP:0100790, HP:0012185)

CaseHPOFreeText: Painful joints affecting the hands, wrists, knees, elbows, and shoulders. At 8 years old, she had second and third finger numbness. Flexion contractures in distal and proximal interphalangeal joints, wrists, and restricted joint mobility was observed. Echocardiogram showed thickening of the mitral and aortic valves, and brain magnetic resonance imaging demonstrated increased signal in the white matter surrounding dilated perivascular spaces.

CaseNotHPOs: Coarse facial features, cardiac murmurs, hernias (HP:0000256, HP:0030148, HP:0100790)

CaseNotHPOFreeText: Organomegaly

CaseEnzymeAssay: 1 nmol/h/mg (reference range, 14-41 nmol/h/mg)

CaseUrineGAGs: Excess heparan and dermatan sulfate

CaseERT: Enzyme replacement therapy was initiated. Improvements in hand mobility and joint size were noted, as well as less joint discomfort.

CaseBMT: N/A

Variant1: c.1039A>C (p.S347R)

Variant1ClinVarID: 1067172

Variant1CAID: CA355963126

Variant2: c.1039A>C (p.S347R)

Variant2ClinVarID: 1067172

Variant2CAID: CA355963126

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

annotating here sice the article is only available as a PDF.

Case#: Clarke Patient 3

DiseaseAssertion: MPS I, severe

FamilyInfo: father and mother were het carriers

CasePresentingHPOs:

CaseHPOFreeText: severe clinical phenotype with presentation in the first year of life and currently at age two has received bone marrow transplantation

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: SSCP, restriction enzyme digestion

PreviouslyPublished: n/a

Variant: c.820G>T (p.Glu274Ter); Q70X phase confirmed

CAID: CA355962341

SupplementalData: n/a

Case#: Patient 1, Turkish

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.1A>C (p.M1L)

Variant1ClinVarID: 550458

Variant1CAID: CA355945204

Variant2: c.1A>C (p.M1L)

Variant2ClinVarID: 550458

Variant2CAID: CA355945204

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: 22-month-old Norwegian female patient

DiseaseAssertion: MPS-H

FamilyInfo: Mother and father received parental testing.

CasePresentingHPOs: Joint stiffness (HP:0001387)

CaseHPOFreeText: She had a tendency to fall without normal protective reactions. Typical facial appearance and other clinical findings were suggestive of MPS I Hurler, and this diagnosis was also supported by X-ray images which showed characteristic skeletal changes. Motor development appeared slightly delayed, while intellectual development was considered to be normal.

CaseNotHPOs: Corneal clouding (HP:0007957)

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 0.006 μmol phenol/18 h/mg protein. Normal range of IDUA activity (n = 52, healthy volunteers): 0.143–0.351 μmol phenol/18 h/mg protein.

CaseUrineGAGs: Urinary GAG excretion - 101 mg GAG/mmol creatinine. The patient demonstrated increased excretion of GAGs, which were identified as HS and DS. Normal age adjusted range of urinary GAG excretion: 14–34 mg GAG/mmol creatinine.

CaseERT: The patient was initiated on enzyme replacement therapy (ERT) with weekly infusions of recombinant α-l-iduronidase 100 IE/kg

CaseBMT: The patient successfully received hematopoietic stem cell transplantation (HSCT) 4 months after ERT.

Variant1: c.1727+3G>C

Variant1ClinVarID: 4817926

Variant1CAID: CA91171181

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

Variant2ClinVarID: 11909

Variant2CAID: CA204563

AdditionalVariants: N/A

ParentalGenotype: Mother: c.208C>T (p.Q70X); 0.071 μmol phenol/18 h/mg protein (IDUA activity). Father: c.1727+3G>C; 0.079 μmol phenol/18 h/mg protein (IDUA activity).

PreviouslyPublished N/A

PMID: 25864295

Gene: IDUA

Disease: MPS1

Inheritance: Autosomal recessive

Case#: Patient 8, male

DiseaseAssertion: MPS I

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: Low IDUA enzyme activity 1.50 (Ref. 4.87 ~ 54.70 μmol/g protein/h)

CaseUrineGAGs: Negative GAG tests

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1081G>A (p.A361T)

Variant1ClinVarID: 92624

Variant1CAID: CA145865

Variant2: c.1395delC (p.G466Afs*?)

Variant2ClinVarID: 929236

Variant2CAID: CA549264595

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 15 (see Table 2), 38 weeks, 1 day (Gestational age)

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: Inguinal hernia (HP:0000023)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 0.23 nmol x mg-1 × hr-1

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.494-1G > A

Variant1ClinVarID: 557942

Variant1CAID: CA355961634

Variant2: c.494-1G > A

Variant2ClinVarID: 557942

Variant2CAID: CA355961634

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 26, male, 1 year (age at presentation).

DiseaseAssertion: MPS1-H

FamilyInfo: Consanguinity in the family not present for this patient.

CasePresentingHPOs: Corneal clouding, coarse facial features, dysostosis multiplex, hepatomegaly, intellectual disabilities, splenomegaly (HP:0007957, HP:0000256, HP:0000943, HP:0002240, HP:0010864, 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.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#: 14, Male, 0.7 years (diagnosed), 8.5 years (report), 9.5 kg (weight), 73 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 0.6 (μmol/spot.20h)

CaseUrineGAGs: Quantitative urinary GAG 6.4 (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#: 9, Female, 0.7 years (diagnosed), 1.2 years (report), 6.8 kg (weight), 69 cm (height), Iranian

DiseaseAssertion: Hurler-Scheie Syndrome

FamilyInfo: Parents are consanguineous

CasePresentingHPOs: HP:0100790 (Hernia)

CaseHPOFreeText: HM/HSM, 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: Cardiac Manifestations

CaseEnzymeAssay: IDUA activity 0.97 (μmol/spot.20h)

CaseUrineGAGs: Quantitative urinary GAG 7.21 (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#: Patient 108, Central district of the Russian Federation

DiseaseAssertion: MPS1, Severe

FamilyInfo:

CasePresentingHPOs:

CaseHPOFreeText: IdA activity in DBS=0,01 DBS, severe phenotype, hyperexcretion of urine heparan and dermatan sulfate

CaseNotHPOs:

CaseNotHPOFreeText:

CasePreviousTesting: Electrophoresis of urine GAGs and measurement of lysosomal enzyme activity in peripheral blood leukocytes or DBSs were performed for all patients with suspected MPS I

GenotypingMethod: The 14 exons and exon–intron boundaries of the IDUA gene were amplified from DNA samples. Sanger sequencing of each one of the 14 exons was performed. PCR products containing mutations were re-sequenced in both directions. The mutations were further confirmed where possible by restriction analysis (data not shown).

PreviouslyPublished:

Variant: NM_000203.5:c.[208C>T];[1029C>A]

ClinVar: 222997

CAID: CA356984

SupplementalData: n/a

PMID: 19783188

Gene: IDUA

Disease: MPS1

Inheritance: Autosomal recessive

Case#: Patient 7, born in 2005 (paper published in 2017), 16 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: 62.57 ng/mol (34.3 weight matched enzyme reference assay)

CaseUrineGAGs: 0.59 DS/CS

CaseERT: No

CaseBMT: Yes, Cord

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

Variant1ClinVarID: 11908

Variant1CAID: CA220498

Variant2: c.386-2A>G

Variant2ClinVarID: 222994

Variant2CAID: CA356991

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 2, born in 2000 (paper published in 2017), 18 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: 28 ng/mol (38 weight matched enzyme reference assay)

CaseUrineGAGs: 0.36 DS/CS

CaseERT: No

CaseBMT: Yes, MUD

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

Variant1ClinVarID: 11908

Variant1CAID: CA220498

Variant2: c.979G>C (p.A327P)

Variant2ClinVarID: 167190

Variant2CAID: CA234128

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 1 (see Table 2), female, 18.6 years old (age at report), 5.9 years (years of treatment), 6 surgeries.

DiseaseAssertion: MPS1-HS

FamilyInfo: N/A

CasePresentingHPOs: HP:0002176, HP:0002360 (Spinal cord compression, sleep abnormality)

CaseHPOFreeText: Psychiatric problems

CaseNotHPOs: HP:0000238 (Hydrocephalus)

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.63delC (p.P22Rfs*86) Known HGVS nomenclature is c.65del as there is a run of 5 C's.

Variant2ClinVarID: 929238

Variant2CAID: CA437911597

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: OS of sibship 7, female, 4.3 years old (age at diagnosis), 4.5 years old (age at ERT enrollment), 5.5 years (duration of ERT)

DiseaseAssertion: MPS1-HS

FamilyInfo: Affected YS (YS of sibship 7)

CasePresentingHPOs: HP:0007957, HP:0000943, HP:0002828, HP:0001263, HP:0001270 (Corneal opacity, dysostosis, joint contractures, cognitive impairment, motor impairment)

CaseHPOFreeText: Cardiac disease, somatic impairment

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: Yes - After 5 years of ERT, cardiac symptoms stabilized, and musculoskeletal symptoms, motor development, and corneal clouding progressed.

CaseBMT: N/A

Variant1: c.1598C>G (p.P533R)

Variant1ClinVarID: 11910

Variant1CAID: CA256112

Variant2: (L564fsx) No CDNA change provided.

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 3

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.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

PMID: 39645522

Gene: IDUA

Disease: MPS1

Inheritance: Autosomal recessive

Case: P87, Chinese, female, 27yo

DiseaseAssertion: VWD1

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type O blood, bleeding score = 3; VWF:Ag (%) = 55.9, VWF:RCo (%) = 55.8, FVIII:C (%) = 70.1, VWF:CB (%) = 61.3, VWFpp (%) = 88.0, VWF:RCo/VWF:Ag = 1.0, VWF:CB/VWF:Ag = 1.1, VWFpp/VWF:Ag = 1.6, FVIII:C/VWF:Ag = 1.3

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.6860G>A (p.Arg2287Gln)

HGVS: NM_000552.3:c.6860G>A (p.Arg2287Gln)

ClinVarID: NA

CAID: CA6401877; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA6401877

gnomAD: MAF = 0.005415 (108/19946 alleles) in the East Asian population; https://gnomad.broadinstitute.org/variant/12-6094770-C-T

Case: P2, Chinese, female, 3yo

DiseaseAssertion: VWD1

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type O blood, bleeding score = 4; VWF:Ag (%) = 55.0, VWF:RCo (%) = 53.0, FVIII:C (%) = 59.0, VWF:CB (%) = 47.0, VWFpp (%) = 57.4, VWF:RCo/VWF:Ag = 1.0, VWF:CB/VWF:Ag = 0.9, VWFpp/VWF:Ag = 1.0, FVIII:C/VWF:Ag = 1.1

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.6104G>A (p.Gly2035Asp)

HGVS: NM_000552.3:c.6104G>A (p.Gly2035Asp)

ClinVarID: NA

CAID: CA6402069; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA6402069

gnomAD: MAF = 0.005613 (112/19954 alleles; 2 homozygotes) in the East Asian population; https://gnomad.broadinstitute.org/variant/12-6103733-C-T

Case: P32, Chinese, male, 3yo

DiseaseAssertion: VWD1

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: patient coexisting with severe haemophilia A; type O blood, bleeding score = 3; VWF:Ag (%) = 51.3, VWF:RCo (%) = 50.7, FVIII:C (%) = 1.0, VWF:CB (%) = 50.3, VWFpp (%) = 49.2, VWF:RCo/VWF:Ag = 1.0, VWF:CB/VWF:Ag = 1.0, VWFpp/VWF:Ag = 1.0, FVIII:C/VWF:Ag = 0.0

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.646G>A (p.Glu216Lys)

HGVS: NM_000552.5(VWF):c.646G>A (p.Glu216Lys)

ClinVarID: 870925; https://www.ncbi.nlm.nih.gov/clinvar/variation/870925/

CAID: NA

gnomAD: 0.001353 (27/19952 alleles) in East Asian population; https://gnomad.broadinstitute.org/variant/12-6204637-C-T?dataset=gnomad_r2_1

MultipleGeneVariants

Gene: F8

Variant: p.Arg446Ter - Unregistered Variant

Case: P71, Chinese, female, 23yo

DiseaseAssertion: VWD1

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type O blood, bleeding score = 1; VWF:Ag (%) = 57.9, VWF:RCo (%) = 55.6, FVIII:C (%) = 71.3, VWF:CB (%) = 69.7, VWFpp (%) = 66.9, VWF:RCo/VWF:Ag = 1.0, VWF:CB/VWF:Ag = 1.2, VWFpp/VWF:Ag = 1.2, FVIII:C/VWF:Ag = 1.2

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.4850A>G (p.Lys1617Arg)

HGVS: NM_000552.3:c.4850A>G (p.Lys1617Arg)

ClinVarID: NA

CAID: CA6402448; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA6402448

gnomAD: MAF = 0.0002507 (5/19942 alleles) in the East Asian population; https://gnomad.broadinstitute.org/variant/12-6127734-T-C

Case: P7, Chinese, female, 27yo

DiseaseAssertion: VWD1

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type O blood, bleeding score = 9; VWF:Ag (%) = 5.4, VWF:RCo (%) = 5.3, FVIII:C (%) = 28, VWF:CB (%) = 4.1, VWFpp (%) = 4.8, VWF:RCo/VWF:Ag = 1.0, VWF:CB/VWF:Ag = 0.8, VWFpp/VWF:Ag = 0.9, FVIII:C/VWF:Ag = 5.2, RIPA (1.2 mg/ml, %) = 73.3

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant 1: c.711C>G (p.Cys237Trp)

HGVS: NM_000552.3:c.711C>G (p.Cys237Trp)

ClinVarID: NA

CAID: CA383509260; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA383509260

gnomAD: absent

Variant: c.1109+47T>A - Unregistered Variant

HGVS: NA

ClinVarID: NA

CAID: NA

gnomAD: NA

Case: P10, Chinese, male, 5yo

DiseaseAssertion: VWD1

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type A blood, bleeding score = 2; VWF:Ag (%) = 4.2, VWF:RCo (%) = 3.8, FVIII:C (%) = 30.1, VWF:CB (%) = 3.5, VWFpp (%) = 4.1, VWF:RCo/VWF:Ag = 0.9, VWF:CB/VWF:Ag = 0.8, VWFpp/VWF:Ag = 1.0, FVIII:C/VWF:Ag = 7.4, RIPA (1.2 mg/ml, %) = 40.1

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant 1: c.7199delA (p.Asn2400Thrfs*4) - Unregistered Variant

HGVS: NA

ClinVarID: NA

CAID: NA

gnomAD: NA

Variant 2: c.8155+5G>C - Unregistered Variant

HGVS: NA

ClinVarID: NA

CAID: NA

gnomAD: NA

Case: P6, Chinese, male, 57yo

DiseaseAssertion: VWD2A

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type AB blood, bleeding score = 15; VWF:Ag (%) = 18.5, VWF:RCo (%) = 5.8, FVIII:C (%) = 39.0, VWF:CB (%) = 4.9, VWFpp (%) = 36.4, VWF:RCo/VWF:Ag = 0.3, VWF:CB/VWF:Ag = 0.3, VWFpp/VWF:Ag = 2.0, FVIII:C/VWF:Ag = 2.1

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.3920T>G (p.Leu1307Arg)

HGVS: NM_000552.5:c.3920T>G (p.Leu1307Arg)

ClinVarID: NA

CAID: CA383506205; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA383506205

gnomAD: absent

Case: P72, Chinese, female, 25yo

DiseaseAssertion: VWD2B

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type A blood, bleeding score = 7; VWF:Ag (%) = 31.1, VWF:RCo (%) = 10.5, FVIII:C (%) = 44.8, VWF:CB (%) = 5.4, VWFpp (%) = 73, VWF:RCo/VWF:Ag = 0.3, VWF:CB/VWF:Ag = 0.2, VWFpp/VWF:Ag = 2.3, FVIII:C/VWF:Ag = 1.4, RIPA (0.5 mg/ml, %) = 8.7, PLT(×109/l) = 181

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.3939G>C (p.Trp1313Cys)

HGVS: NM_000552.4(VWF):c.3939G>C (p.Trp1313Cys)

ClinVarID: 287; https://www.ncbi.nlm.nih.gov/clinvar/variation/287/

CAID: NA

gnomAD: absent

Case: P77, Chinese, female, 10yo

DiseaseAssertion: VWD3

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type B blood, bleeding score = 7; VWF:Ag (%) = 3.0, VWF:RCo (%) = 2.7, FVIII:C (%) = 6.8, VWF:CB (%) = 2.1, VWFpp (%) = 3.2, VWF:RCo/VWF:Ag = 0.9, VWF:CB/VWF:Ag = 0.7, VWFpp/VWF:Ag = 1.1, FVIII:C/VWF:Ag = 2.3

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant 1: c.6771C>A (p.Cys2257Ter)

HGVS: NM_000552.5:c.6771C>A (p.Cys2257Ter)

ClinVarID: NA

CAID: CA383489897; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA383489897

gnomAD: absent

Variant 2: c.8116-2delA - unregistered variant

HGVS: NA

ClinVarID: NA

CAID: NA

gnomAD: NA

Case: P34, Chinese, female, 34yo

DiseaseAssertion: VWD2B

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type O blood, bleeding score = 13; VWF:Ag (%) = 20.2, VWF:RCo (%) = 6.9, FVIII:C (%) = 32.9, VWF:CB (%) = 4.8, VWFpp (%) = 54.5, VWF:RCo/VWF:Ag = 0.3, VWF:CB/VWF:Ag = 0.2, VWFpp/VWF:Ag = 2.7, FVIII:C/VWF:Ag = 1.6, RIPA (0.5 mg/ml, %) = 65.1, PLT(×109/l) = 153

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

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: P61, Chinese, female, 34yo

DiseaseAssertion: VWD1

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type O blood, bleeding score = 2; VWF:Ag (%) = 57.6, VWF:RCo (%) = 57.8, FVIII:C (%) = 76.2, VWF:CB (%) = 67.4, VWFpp (%) = 62.7, VWF:RCo/VWF:Ag = 1.0, VWF:CB/VWF:Ag = 1.2, VWFpp/VWF:Ag = 1.1, FVIII:C/VWF:Ag = 1.3

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.-128G>A

HGVS: NM_000552.3:c.-128G>A

ClinVarID: NA

CAID: CA603092904; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA603092904

gnomAD: MAF = 0.001182 (1/846 alleles) in Latino/Admixed American population; https://gnomad.broadinstitute.org/variant/12-6233714-C-T

Case: P27, Chinese, female, 3yo

DiseaseAssertion: VWD2N

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type B blood, bleeding score = 6; VWF:Ag (%) = 9.5, VWF:RCo (%) = 8.9, FVIII:C (%) = 6.5, VWF:CB (%) = 6.9, VWFpp (%) = 10.8, VWF:RCo/VWF:Ag = 0.9, VWF:CB/VWF:Ag = 0.7, VWFpp/VWF:Ag = 1.1, FVIII:C/VWF:Ag = 0.7, VWF: FVIIIB (%) = 0.0

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant 1: c.2396G>A (p.Cys799Tyr)

HGVS: NM_000552.5:c.2396G>A (p.Cys799Tyr)

ClinVarID: NA

CAID: CA232300402; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA232300402

gnomAD: absent

Variant 2: c.3197_3201del - unregistered variant

HGVS: NA

ClinVarID: NA

CAID: NA

gnomAD: NA

Case: P36, Chinese, male, 56yo

DiseaseAssertion: VWD3

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type A blood, bleeding score = 10; VWF:Ag (%) = 1.0, VWF:RCo (%) = 0.9, FVIII:C (%) = 4.1, VWF:CB (%) = 0.9, VWFpp (%) = 0.9, VWF:RCo/VWF:Ag = 0.9, VWF:CB/VWF:Ag = 0.9, VWFpp/VWF:Ag = 0.9, FVIII:C/VWF:Ag = 4.1

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.5870delA - unregistered variant

HGVS: NA

ClinVarID: NA

CAID: NA

gnomAD: NA

Case: P83, Chinese, male, 5yo

DiseaseAssertion: VWD1

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: patient coexisting with mild haemophilia A; type O blood, bleeding score = 3; VWF:Ag (%) = 44.5, VWF:RCo (%) = 36.7, FVIII:C (%) = 12.6, VWF:CB (%) = 49.2, VWFpp (%) = 35.2, VWF:RCo/VWF:Ag = 0.8, VWF:CB/VWF:Ag = 1.1, VWFpp/VWF:Ag = 0.8, FVIII:C/VWF:Ag = 0.3

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.6104G>A (p.Gly2035Asp)

HGVS: NM_000552.3:c.6104G>A (p.Gly2035Asp)

ClinVarID: NA

CAID: CA6402069; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA6402069

gnomAD: MAF = 0.005613 (112/19954 alleles; 2 homozygotes) in the East Asian population; https://gnomad.broadinstitute.org/variant/12-6103733-C-T

Multiple Gene Variants

Gene: F8

Variant: c.943G>T (p.Ala315Ser)

HGVS: NM_000132.3:c.943G>T (p.Ala315Ser)

ClinVarID: NA

CAID: CA414917823; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA414917823

gnomAD: absent

Case: P29, Chinese, male, 10yo

DiseaseAssertion: VWD2M

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type B blood, bleeding score = 5; VWF:Ag (%) = 13.9, VWF:RCo (%) = 5.9, FVIII:C (%) = 37.8, VWF:CB (%) = 17.4, VWFpp (%) = 31.3, VWF:RCo/VWF:Ag = 0.4, VWF:CB/VWF:Ag = 1.3, VWFpp/VWF:Ag = 2.3, FVIII:C/VWF:Ag = 2.7

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.3943C>T (p.Arg1315Cys)

HGVS: NM_000552.4(VWF):c.3943C>T (p.Arg1315Cys)

ClinVarID: 100310; https://www.ncbi.nlm.nih.gov/clinvar/variation/100310/

CAID: NA

gnomAD: absent

Case: P22, Chinese, male, 22yo

DiseaseAssertion: VWD3

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type O blood, bleeding score = 10; VWF:Ag (%) = 1.4, VWF:RCo (%) = 1.2, FVIII:C (%) = 5.1, VWF:CB (%) = 1.3, VWFpp (%) = 1.0, VWF:RCo/VWF:Ag = 0.9, VWF:CB/VWF:Ag = 0.9, VWFpp/VWF:Ag = 0.7, FVIII:C/VWF:Ag = 3.6

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.8116–2delA - Unregistered variant

HGVS: NA

ClinVarID: NA

CAID: NA

gnomAD: NA

Case: P42, Chinese, male, 10yo

DiseaseAssertion: VWD1

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type O blood, bleeding score = 1; VWF:Ag (%) = 41.9, VWF:RCo (%) = 33.9, FVIII:C (%) = 54.7, VWF:CB (%) = 46.8, VWFpp (%) = 34.6, VWF:RCo/VWF:Ag = 1.0, VWF:CB/VWF:Ag = 1.1, VWFpp/VWF:Ag = 0.8, FVIII:C/VWF:Ag = 1.3

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.-672C>T

HGVS: NA

ClinVarID: NA

CAID: NA

gnomAD: NA

Case: P33, Chinese, female, 35yo

DiseaseAssertion: VWD3

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type A blood, bleeding score = 10; VWF:Ag (%) = 0.5, VWF:RCo (%) = <0.5, FVIII:C (%) = 5.0, VWF:CB (%) = <0.5, VWFpp (%) = <0.5, VWF:RCo/VWF:Ag = NA, VWF:CB/VWF:Ag = NA, VWFpp/VWF:Ag = NA, FVIII:C/VWF:Ag = 10.0

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.813C>G (p.Tyr271Ter)

HGVS: NM_000552.5:c.813C>G (p.Tyr271Ter)

ClinVarID: NA

CAID: CA383508522; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA383508522

gnomAD: MAF = 0.0001088 (2/18380 alleles) in the East Asian popualtion; https://gnomad.broadinstitute.org/variant/12-6184562-G-C

Case#: p.P1162L, Female, Age 52, African American

Disease Assertion: Normal Variant

Family Info: Two family members tested with normal clinical phenotype

Parental Genotype: Not listed

CasePresentingHPOs:

CaseHPOFreeText: VWF:RCo/VWF:Ag Ratio 0.50, VWF:GPIbM 98

CaseNotHPOs: HP:0040240

(Increased Ratio of VWF Propeptide to VWF antigen)

CaseNotHPOFreeText:bleeding score 2, VWF:Ag 144 IU/dL, VWF:RCo 72 IU/dL, normal multimer distribution

ProteinExpression:

CasePreviousTesting: VWF Sequencing

Gene:VWF

Variant: NM_000552.4(VWF):c.3485C>T (p.Pro1162Leu)

ClinVar: 256669 ClinVarID

CAID: CA6402756

CAID

gnomAD: MAF of 0.2207 (2023/9166 alleles) in the African American population.

gnomAD

Case#: p.I1453N, Male, Age 25, Caucasian

Disease Assertion: VWD2M

FamilyInfo: No affected family members enrolled in study

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: bleeding score 11, VWF:RCo/VWF:Ag ratio 0.55, VWF:Ag 20 IU/dL, VWF:RCo 11 IU/dL,

CaseNotHPOs:HP:0040240

(Increased Ratio of VWF Propeptide to VWF antigen)

CaseNotHPOFreeText: Normal multimer distribution

Protein Expression: N/A

CasePreviousTesting: VWF sequencing

Gene: VWF

Variant: NM_000552.4:c.4358T>A (p.Ile1453Asn)

ClinVar: N/A

CAID: CA383502477

CAID

gnomAD: N/A

Case#: p.D1283Y, Female, Age 85, Caucasian

Disease Assertion: VWD2M

FamilyInfo: Single affected family member with similar bleeding score

Parental Genotype: Not listed

CasePresentingHPOs:

CaseHPOFreeText: VWF:RCo/ VWF:Ag ratio 0.34, bleeding score 12, VWF:RCo 12 IU/dL, VWF:Ag 25 IU/dL

CaseNotHPOs: HP:0040240

(Increased Ratio of VWF Propeptide to VWF antigen)

CaseNotHPOFreeText: Normal multimer distribution

Protein Expression: N/A

CasePreviousTesting: VWF Sequencing

Gene: VWF

Variant: NM_000552.4:c.3847G>T (p.Asp1283Tyr)

ClinVar: N/A

CAID: CA383506819

CAID

gnomAD: N/A

Case#: 35003, Age 75, Female, Blood Type A- (Table S3)

Disease Assertion: VWD 1

FamilyInfo: The patient is one of two members in Family# 3502.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: VWF:Ag: 6.6, VWF:RCo: 8.5, FVIII:C:13, VWF:CB: 11

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.3614G>A (p.Arg1205His)

ClinVar: 308 ClinVar

CAID: CA114160 CAID

gnomAD: N/A

Case#: 13001, Age 61, Female, Blood Type O+ (Table S3)

Disease Assertion: VWD 1

FamilyInfo: The patient was the only member of Family# 1301.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding Score 27, VWF:Ag: 11, VWF:RCo: 9.7, FVIII:C: 36, VWF:CB: 12

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.7985A>G

ClinVar: N/A

CAID: CA383487641 CAID

gnomAD: N/A

Case#: 02042, Age 41, Male, Blood Type: O+ (Table S3)

Disease Assertion: VWD 1

FamilyInfo: Family#: 0215; 5 Members of the family were included in the study. 1 was diagnosed type 3 (patient 02039) and the other 4 were carriers for VW

Parental Genotype: Not listed

CasePresentingHPOs:

CaseHPOFreeText: VWF:Ag: 25, VWF:RCo: 21, FVIII:C:77, VWF:CB: 27

CaseNotHPOs:

CaseNotHPOFreeText: Bleeding score 1

Protein Expression:

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.1109G>A

ClinVar: N/A

CAID:CA6403559

CAID

gnomAD: MAF of 0.000008802 (1/113608 alleles) in the European (non-Finnish population). gnomAD