Case#: MPS I_Case 02, female newborn

DiseaseAssertion: MPS type I, MPS I, MPS-I, attenuated MPS I

FamilyInfo: MPS I_Case 02 and MPS I_Case 03 are twins

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText: This proband is believed to be an affected MPS-patient however, the proband did not have any obvious clinical symptoms to date (up to two years of age). The paper states that this attenuated MPS I case will need a long term follow up.

CaseEnzymeAssay: Proband identified by newborn screening. alpha-L-iduronidase activity in dried blood spot sample is 0.59 umole/L/Hr; this is below the study's DBS enzyme activity cutoff value of 3 umol/L/h

CaseUrineGAGs: Urine DMB GAG ratio is 204.7mg/mmol creatinine. 99.60 ug/ml dermatan sulfate in urine (<0.41 ug/ml is the reference cutoff for dermatan sulfate in this study). 13.31 ug/ml heparan sulfate in urine (<0.8 ug/ml is the reference cutoff for heparan sulfate in this study). 0.83 ug/ml keratan sulfate in urine.

CaseERT: Don't know (would assume no since the proband is a newborn)

CaseBMT: Don't know (would assume no since the proband is a newborn)

Variant1: c.1037T>G, p.L346R

Variant1ClinVarID: 11927

Variant1CAID: CA256128

Variant2: c.1091C>T, p.T364M

Variant2ClinVarID: 11925

Variant2CAID: CA256126

AdditionalVariants: No additional variants mentioned

ParentalGenotype: No parental testing results are available

PreviouslyPublished No statement from the author indicating the proband is previously published. Since this is a newborn study, I strongly believe this is the proband’s first time being published.

Case#: MPS I_Case 03, female newborn

DiseaseAssertion: MPS type I, MPS I, MPS-I, attenuated MPS I

FamilyInfo: MPS I_Case 03 and MPS I_Case 02 are twins

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText: This proband is believed to be an affected MPS-patient however, the proband did not have any obvious clinical symptoms to date (up to two years of age). The paper states that this attenuated MPS I case will need a long term follow up.

CaseEnzymeAssay: Proband identified by newborn screening. alpha-L-iduronidase activity in dried blood spot sample is 0.51 umole/L/Hr; this is below the study's DBS enzyme activity cutoff value of 3 umol/L/h

CaseUrineGAGs: Urine DMB GAG ratio is 239.3 mg/mmol creatinine. 41.04 ug/ml dermatan sulfate in urine (<0.41 ug/ml is the reference cutoff for dermatan sulfate in this study). 2.93 ug/ml ug/ml heparan sulfate in urine (<0.8 ug/ml is the reference cutoff for heparan sulfate in this study). 0.00 ug/ml keratan sulfate in urine.

CaseERT: Don't know (would assume no since the proband is a newborn)

CaseBMT: Don't know (would assume no since the proband is a newborn)

Variant1: c.1037T>G, p.L346R

Variant1ClinVarID: 11927

Variant1CAID: CA256128

Variant2: c.1091C>T, p.T364M

Variant2ClinVarID: 11925

Variant2CAID: CA256126

AdditionalVariants: No additional variants mentioned

ParentalGenotype: No parental testing results are available

PreviouslyPublished No statement from the author indicating the proband is previously published. Since this is a newborn study, I strongly believe this is the proband’s first time being published.

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: T364M

Variant1ClinVarID: 11925

Variant1CAID: CA256126

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: Patient 55, 6 months old (age at report), female, Indian

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

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

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.589G>A (p.Gly197Ser)

Variant1ClinVarID: 1526094

Variant1CAID: CA355961839

Variant2: c.1091C>T (p.Thr364Met)

Variant2ClinVarID: 11925

Variant2CAID: CA256126

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Infant #10, female.

DiseaseAssertion: MPS-I

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 0.70 IDUA enzyme activity (Ref. 5.9–27.8 μmol/g protein/h)

CaseUrineGAGs: DMB/Cre. Ratio - 204.70, DS - 176.96, HS - 28.51, KS - 1.78 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.1037T>G (p.L346R)

Variant1ClinVarID: 11927

Variant1CAID: CA256128

Variant2: c.1091C>T (p.T364M) Article has (p.364M) which appears to be a typo.

Variant2ClinVarID: 11925

Variant2CAID: CA256126

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Infant #11, female.

DiseaseAssertion: MPS-I

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 0.80 IDUA enzyme activity (Ref. 5.9–27.8 μmol/g protein/h)

CaseUrineGAGs: DMB/Cre. Ratio - 239.25, DS - 296.10, HS - 33.55, KS - 1.37 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.1037T>G (p.L346R)

Variant1ClinVarID: 11927

Variant1CAID: CA256128

Variant2: c.1091C>T (p.T364M) Article has (p.364M) which appears to be a typo.

Variant2ClinVarID: 11925

Variant2CAID: CA256126

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 6, female, twin of Patient 5 (see Table 1)

DiseaseAssertion: MPS I

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: Low IDUA enzyme activity 0.75 (Ref. 4.87 ~ 54.70 μmol/g protein/h)

CaseUrineGAGs: Positive GAG tests

CaseERT: N/A

CaseBMT: N/A

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

Variant1ClinVarID: 11927

Variant1CAID: CA256128

Variant2: c.1091C>T (p.T364M)

Variant2ClinVarID: 11925

Variant2CAID: CA256126

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 5, female, twin of Patient 6 (see Table 1)

DiseaseAssertion: MPS I

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: Low IDUA enzyme activity 0.81 (Ref. 4.87 ~ 54.70 μmol/g protein/h)

CaseUrineGAGs: Positive GAG tests

CaseERT: N/A

CaseBMT: N/A

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

Variant1ClinVarID: 11927

Variant1CAID: CA256128

Variant2: c.1091C>T (p.T364M)

Variant2ClinVarID: 11925

Variant2CAID: CA256126

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Newborn 5, female, 1.4 months, Taiwan

DiseaseAssertion: MPS1

FamilyInfo: proband is a twin with newborn 6, who has the same genotype

CasePresentingHPOs:

CaseHPOFreeText: IDUA enzyme activity in leukocytes= 0.81 (Ref. 4.87 ~ 54.70 μmol/g protein/h, with cut-off values of < 3.0), positive GAG tests (GAG tests including GAG quantification (DMB/Cre ratio), 2-dimensional electrophoresis, and quantitative analyses of GAG-derived disaccharides (DS and HS) by tandem mass spectrometry assay). DS=99.61 (ug/mL), HS=13.31 (ug/mL)-average DS and HS values of the normal population were 0.17 (±0.23) and 0.11 (±0.21), respectively

CaseNotHPOs:

CaseNotHPOFreeText:

PreviouslyPublished: n/a

Variant: c.1037 T > G (p.L346R)  +  c.1091C > T (p.T364M)

ClinVar: 11925

CAID: CA256126

SupplementalData: n/a

Case#: TW1-2 ID number, Table S1.1 of Supplementary Material. Female, 1-2 years old (age at first symptoms), 3 years and 2 months old (age at diagnosis). Stored Frozen (-20ºC).

DiseaseAssertion: Severe MPS-I

FamilyInfo: Twin of patient TW1-3.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: 615 fmol/punch

CaseERT: N/A

CaseBMT: N/A

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

Variant1ClinVarID: 11927

Variant1CAID: CA256128

Variant2: c.1091C>T (p.T364M)

Variant2ClinVarID: 11925

Variant2CAID: CA256126

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: TW1-3 ID number, Table S1.1 of Supplementary Material. Female, 1-2 years old (age at first symptoms), 1 year and 6 months old (age at diagnosis). Stored Frozen (-20ºC)

DiseaseAssertion: Severe MPS-I

FamilyInfo: Twin of patient TW1-2.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: 589 fmol/punch

CaseERT: N/A

CaseBMT: N/A

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

Variant1ClinVarID: 11927

Variant1CAID: CA256128

Variant2: c.1091C>T (p.T364M)

Variant2ClinVarID: 11925

Variant2CAID: CA256126

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Annotating here since the article is a PDF.

Case#: Lin ERT Proband, 3yo at dx, male, Taiwan

DiseaseAssertion: MPS1 H/S

FamilyInfo:

CasePresentingHPOs: HP:0002094, HP:0030828, HP:0002870, HP:0001640, HP:0001712, HP:0005133, HP:0001654, HP:0005145, HP:0008155, HP:0002653, HP:0002829, HP:0001376, HP:0002751, HP:0004348, HP:0007957, HP:0007663, HP:0002167, HP:0032341, HP:0410042

CaseHPOFreeText: Positive urine MPS screening test, blood IDUA activity=0.4 umol/h per mg protein (normal range 10-35). ERT improved cardiopulmonary status, joint range of motion, mobility, bone and joint pain, kyphoscoliosis, bone mineral density, sleep quality, corneal clouding and visual acuity, speech fluency, forced vital capacity and liver size, and resulted in 80.2% reduction in urinary GAG excretion. Cardiopulmonary failure

CaseNotHPOs:

CaseNotHPOFreeText:

PreviouslyPublished: n/a

Variant: T364M homozygous

ClinVar: 11925

CAID: CA256126

SupplementalData: n/a

Transfection into COS-7 cells showed that this variant has 1.2% IDUA activity compared to WT

Case#: Patient W2, 10 years old, Chinese. The patient had normal intelligence based on their performance in school.

DiseaseAssertion: MPS1-H/S

FamilyInfo: Maternal and paternal DNA were interpreted.

CasePresentingHPOs: Short stature, coarse facial features, severe skeletal deformities (HP:0004322, HP:0000280, HP:0000924)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1091C>T (p.T364M)

Variant1ClinVarID: 11925

Variant1CAID: CA256126

Variant2: c.1091C>T (p.T364M)

Variant2ClinVarID: 11925

Variant2CAID: CA256126

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Expression in COS-7 cells resulted in 85.6 nmol/h/mg protein IDUA activity (1.3% of normal).

Unable to annotate on PDF.

Case#: Lee-Chen Patient W2, 10yo, male, Chinese

DiseaseAssertion: MPS1

FamilyInfo: Variant was paternally inherited and the mother was no mentioned, but it was said that there may have been a "de novo deletion or gene conversion event" that resulted in apparent homozygosity

CasePresentingHPOs: HP:0004322, HP:0000280, HP:0011842

CaseHPOFreeText:

CaseNotHPOs: HP:0001249

CaseNotHPOFreeText:

PreviouslyPublished: n/a

Variant: T364M homozygous

AdditionalVariants: Proband is also homozygous for polymorphisms (A314, T388, T410, and R489) as well as R105Q, A361T, and V454I

ClinVar: 11925

CAID: CA256126

SupplementalData: n/a

Proband KH7 was 10yo at report, has the Hurler/Scheie phenotype, and has this variant but a second variant does not appear to have been detected.

Proband KH6 was 6yo at report, has the Hurler/Scheie phenotype, and has this variant but a second variant does not appear to have been detected.

Proband KH3 was 13yo at report, has the Hurler phenotype, and has this variant in compound heterozygosity with second missense variant on exon 3, but that variant is not provided.

Proband KH8 was 20yo at report, has the Hurler phenotype, and has this variant in compound heterozygosity with 704ins5 (CTGCT)

Proband KH9 was 11yo at report, has the Hurler phenotype, and has this variant in compound heterozygosity with 704ins5 (CTGCT)

Proband KH4 was 6yo at report, has the Hurler phenotype, and has this variant in compound heterozygosity with 704ins5 (CTGCT)

This variant is mentioned as one that causes an intermediate phenotype of MPS1 with a reference to a paper (PMID: 9391892) where it was previously reported. No new cases or experiments.

The paper mentions this variant, but only in review of the cases that exist in the literature for Chinese MPS1 patients. Will annotate the case in the original publication.