Case#: Patient 22, female, 4 years (age at presentation).

DiseaseAssertion: MPS1-H/S

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

CasePresentingHPOs: Corneal clouding, coarse facial features, dystosis multiplex, hepatomegaly, joint stiffness, sleep disturbance, splenomegaly (HP:0007957, HP:0000256, HP:0000943, HP:0002240, HP:0001387, HP:0002360, 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.1469T>C (p.L490P)

Variant1ClinVarID: 11919

Variant1CAID: CA220503

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

Variant2ClinVarID: 556406

Variant2CAID: CA355966010

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 50, male, Han origin, 5 years 6 months old (age at diagnosis)

DiseaseAssertion: MPS1-H/S

FamilyInfo: N/A

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

CaseHPOFreeText: N/A

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

CaseNotHPOFreeText: Cardiac disease

CaseEnzymeAssay: IDUA activity 0.8 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: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 12, female, Han origin, 13 years old (age at diagnosis)

DiseaseAssertion: MPS1-S

FamilyInfo: N/A

CasePresentingHPOs: Joint stiffness, Hepatosplenomegaly (HP:0001387, HP:0001433)

CaseHPOFreeText: Cardiac disease

CaseNotHPOs: Global Developmental Delay, Macrocephaly, Mongolian macula, Hernia, Airway obstruction (HP:0001263, HP:0000256, HP:0011369, HP:0100790, HP:0006536)

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: IDUA activity 0.0 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.536C>G (p.S633L)

Variant1ClinVarID: 556406

Variant1CAID: CA355966010

Variant2: c.536C>G (p.S633L)

Variant2ClinVarID: 556406

Variant2CAID: CA355966010

AdditionalVariants: N/A

ParentalGenotype: Father - c.536C>G, Mother - c.536C>G. The transmission of sequence variations found in each patient was inferred by sequencing the corresponding exons of the patient's parents - confirmed by parental testing.

PreviouslyPublished N/A

Case#: Patient 15, male, Han origin, 6 years old (age at diagnosis)

DiseaseAssertion: MPS1-H/S

FamilyInfo: N/A

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

CaseHPOFreeText: N/A

CaseNotHPOs: Global Developmental Delay (HP:0001263)

CaseNotHPOFreeText: Cardiac disease

CaseEnzymeAssay: IDUA activity 1.4 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.349delT (p.Tyr117ThrfsTer16)

Variant1ClinVarID: 1451219

Variant1CAID: CA2573137553

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 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 5, female, Han origin, 11 years old (age at diagnosis)

DiseaseAssertion: MPS1-H/S

FamilyInfo: N/A

CasePresentingHPOs: Macrocephaly, Joint stiffness, Mongolian macula, Hepatosplenomegaly, Airway obstruction (HP:0000256, HP:0001387, HP:0011369, HP:0001433, HP:0006536)

CaseHPOFreeText: Cardiac disease

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

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: IDUA activity 1.3 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.536C>G (p.T179R)

Variant1ClinVarID: 556358

Variant1CAID: CA355961718

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 47, female, Han origin, 4 years old (age at diagnosis)

DiseaseAssertion: MPS1-H/S

FamilyInfo: N/A

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

CaseHPOFreeText: Cardiac disease

CaseNotHPOs: Global Developmental Delay, Macrocephaly, Mongolian macula, Hernia (HP:0001263, HP:0000256, HP:0011369, HP:0100790)

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: IDUA activity 0.9 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: N/A

Variant1ClinVarID: N/A

Variant1CAID: N/A

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

Variant2ClinVarID: 556406

Variant2CAID: CA355961718

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 57, female, Han origin, 2 years old (age at diagnosis)

DiseaseAssertion: MPS1-H/S

FamilyInfo: N/A

CasePresentingHPOs: Joint stiffness (HP:0001387)

CaseHPOFreeText: N/A

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

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.1262T>C (p.L421P)

Variant1ClinVarID: 1328979

Variant1CAID: CA355963724

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 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#: 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: S633L

Variant1ClinVarID: 556406

Variant1CAID: CA355966010

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: Patient 46, 9 years old (age at report), female, Indian

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

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

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1898C>T (p.Ser633Leu)

Variant1ClinVarID: 556406

Variant1CAID: CA355966010

Variant2: c.1898C>T (p.Ser633Leu)

Variant2ClinVarID: 556406

Variant2CAID: CA355966010

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 60, 14 years old (age at report), male, Indian

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: Coarse facial features, hepatosplenomegaly, joint contractures, corneal clouding, dysostosis multiplex, intellectual disability, hernia (HP:0000280, HP:0001433, HP:0002828, HP:0007957, HP:0000943, HP:0001249, HP:0100790)

CaseHPOFreeText: Cardiac disease

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.1181_1189dup (p.Ala394_Leu396dup)

Variant1ClinVarID: 3720561

Variant1CAID: CA549264540

Variant2: c.1898C>T (p.Ser633Leu)

Variant2ClinVarID: 556406

Variant2CAID: CA355966010

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 45, 10 years old (age at report), male, Indian

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

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

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 2.0% (Range of residual enzyme activity: 0.0%-4.8%)

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1898C>T (p.Ser633Leu)

Variant1ClinVarID: 556406

Variant1CAID: CA355966010

Variant2: c.1898C>T (p.Ser633Leu)

Variant2ClinVarID: 556406

Variant2CAID: CA355966010

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

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

DiseaseAssertion: MPS-I

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1898C>T (p.S633L)

Variant1ClinVarID: 556406

Variant1CAID: CA355966010

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Family 27, Pakistan

DiseaseAssertion: MPS1-S

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: The Scheie phenotype is characterized by aortic valve disease, corneal clouding, limited skeletal problems, but no mental retardation. This is a general assessment and 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.

α-L-iduronidase activity in COS-7 cells transiently transfected with wild-type or mutagenised cDNAs. α-L-iduronidase activity: 5.4 nmol/h/mg cell protein; values are the means of two experiments.

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1898C>T (p.S633L)

Variant1ClinVarID: 556406

Variant1CAID: CA355966010

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

Variant2ClinVarID: 556406

Variant2CAID: CA355966010

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A