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  1. Last 7 days
    1. TTL Overexpression Rescues Hypertrophy in Cardiomyocytes Derived From an HCM hiPSC Line

      Case1: HCM patient-derived cell line UKEi070-A (demographics not reported in this paper) DiseaseAssertion: HCM

      ParentalTesting: CasePresentingHPOs: HP:0001639 CaseHPOFreeText: CaseNotHPOs: CaseNotHPOFreeText: CasePreviousTesting: Genotyping Method: Not reported in this paper; it references a previously established patient-derived cell line. FunctionalAnalysis: The variant is reported to cause MYBPC3 protein haploinsufficiency in cardiomyocytes. In this study, TTL overexpression normalized cell hypertrophy in the HCM cell model. Variant: NM_000256.3:c.2308G>A (heterozygous; the paper reports the splice consequence as p.Asp770Serfs98X) ClinVar: 36604 CAID: gnomAD: NR AdditionalInfo: The paper uses patient-derived induced pluripotent stem cell cardiomyocytes; it does not provide the patient’s age, sex, or pedigree.

    1. A 50-year-old male with a prior clinical diagnosis of hypertrophic cardiomyopathy presented with monomorphic ventricular tachycardia.

      Case1: 50 year old male DiseaseAssertion: HCM; hydroxychloroquine cardiotoxicity FamilyInfo: Six children undergoing predictive testing for the familial MYBPC3 variant; family history not reported ParentalTesting: CasePresentingHPOs: HP:0001639 CaseHPOFreeText: Monomorphic ventricular tachycardia, dyspnea, nausea, vomiting, biventricular hypertrophy, systolic dysfunction, cardiogenic shock CaseNotHPOs: CaseNotHPOFreeText: CasePreviousTesting: Prior CMR showed nonobstructive HCM; cardiomyopathy gene panel identified the variant Genotyping Method: Cardiomyopathy gene panel FunctionalAnalysis: Altered splicing with exon 30 skipping; authors describe a nonfunctional protein or premature stop codon Variant: c.3330+5G>C ClinVar: 42706 CAID: gnomAD: 0.03% (as reported in the article) AdditionalInfo: Long-term hydroxychloroquine exposure for malaria prophylaxis; biopsy findings were consistent with both HCM and hydroxychloroquine cardiotoxicity

    1. 3.1.2 Patient 2—heart transplanted DCM and intronic MYBPC3 variant

      Case2: 12-year-old boy (Patient 2) DiseaseAssertion: DCM FamilyInfo: Family history unremarkable. ParentalTesting: The MYBPC3 variant was inherited from his father. The father’s cardiac phenotype is not reported. CasePresentingHPOs: HP:0001644, HP:0003546 CaseHPOFreeText: Severely depressed biventricular function; heart transplantation for decompensated heart failure. CaseNotHPOs: CaseNotHPOFreeText: CasePreviousTesting: Previous WES was negative; the variant’s intronic region was not adequately covered. Genotyping Method: Whole-genome sequencing (WGS; Illumina NovaSeq 6000; aligned to hg19/GRCh37). FunctionalAnalysis: SpliceAI predicted a potential splicing effect; no functional assay in this patient is reported. Variant: NM_000256.3:c.1224-80G>A (heterozygous intronic variant) ClinVar: 693982 CAID: CA221697326 gnomAD: 0.0000637 AdditionalInfo: The authors classified the variant as a VUS in this DCM case because evidence for a MYBPC3–DCM relationship is limited. ClinVar currently reports a pathogenic/likely pathogenic aggregate classification, primarily in relation to HCM. Reanalysis found no second MYBPC3 variant.

  2. Oct 2026
    1. 203

      Case#: 203 6.1yrs male, age at initial diagnosis 4.9 yrs DiseaseAssertion: MPS IH-S FamilyInfo:Nil CasePresentingHPOs: CaseHPOFreeText: CaseNotHPOs: CaseNotHPOFreeText: CaseEnzymeAssay: IDUA activity: low leukocyte IDUA enzyme activity CaseUrineGAGs: CaseERT: 1.7 yrs on ERT, then study drug, valanafusp alpha, also called AGT-181 for 12 months

      CaseBMT: No PreviouslyPublished Don't know Variant1:p.R621X Variant1ClinVarID: 11917 Variant1CAID: Variant2:IVS9-12_4delCAGGCCCCG . However the sequence at this location corresponds to "cccgccccg" Variant2ClinVarID: Variant2CAID:

    2. 211

      Case#: 211 2.5 yrs male, age at initial diagnosis 2.4 yrs DiseaseAssertion: MPS IH FamilyInfo:Nil CasePresentingHPOs: CaseHPOFreeText: CaseNotHPOs: CaseNotHPOFreeText: CaseEnzymeAssay: IDUA activity: low leukocyte IDUA enzyme activity CaseUrineGAGs: CaseERT: Nil, study drug, valanafusp alpha, also called AGT-181 for 12 months

      CaseBMT: No PreviouslyPublished Don't know Variant1:p.G208D Variant1ClinVarID: 554590 Variant1CAID: Variant2:p.G208D Variant2ClinVarID: 554590 Variant2CAID:

    3. 215

      Case#: 215 12.1 yrs male, age at initial diagnosis 3.6 yrs DiseaseAssertion: MPS IH FamilyInfo:Nil CasePresentingHPOs: CaseHPOFreeText: CaseNotHPOs: CaseNotHPOFreeText: CaseEnzymeAssay: IDUA activity: low leukocyte IDUA enzyme activity CaseUrineGAGs: CaseERT: 5.6 yrs, then study drug, valanafusp alpha, also called AGT-181 for 12 months

      CaseBMT: No PreviouslyPublished Don't know Variant1:p.P533R Variant1ClinVarID: 11910 Variant1CAID: CA256112 Variant2:p.G208D Variant2ClinVarID: 554590 Variant2CAID:

    4. 213

      Case#: 213 15.7 yrs male, age at initial diagnosis 3.7 yrs DiseaseAssertion: MPS IH-S FamilyInfo:Nil CasePresentingHPOs: CaseHPOFreeText: CaseNotHPOs: CaseNotHPOFreeText: CaseEnzymeAssay: IDUA activity: low leukocyte IDUA enzyme activity CaseUrineGAGs: CaseERT: 12 yrs, then study drug, valanafusp alpha, also called AGT-181 for 12 months Variant1: p.R383H Variant1ClinVarID: 558189 Variant1CAID: Variant2:p.W402X Variant2ClinVarID: 11908 Variant2CAID: CA220498 AdditionalVariants: NA ParentalGenotype: NA PreviouslyPublished:NA

    1. 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

    2. Case#: Patient D4, Druze religious group, located in lower Galilee.

      DiseaseAssertion: N/A

      FamilyInfo: May have relation with Patient D5 due to being located in the same village. Parents were found to be heterozygous for the mutation.

      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.1096A>C (p.T366P)

      Variant1ClinVarID: 11916

      Variant1CAID: CA:256117

      Variant2: N/A

      Variant2ClinVarID: N/A

      Variant2CAID: N/A

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished N/A

    3. Case#: Patient D5, Druze religious group, located in lower Galilee.

      DiseaseAssertion: N/A

      FamilyInfo: May have relation with Patient D5 due to being located in the same village. Parents were found to be heterozygous for the mutation.

      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.1096A>C (p.T366P)

      Variant1ClinVarID: 11916

      Variant1CAID: CA:256117

      Variant2: N/A

      Variant2ClinVarID: N/A

      Variant2CAID: N/A

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished N/A

    4. Case#: Patient M2, Muslim religious group, located in lower Galilee.

      DiseaseAssertion: MPS1-H

      FamilyInfo: Parents of M2 were found to be heterozygous for this mutation.

      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.1096A>C (p.T366P)

      Variant1ClinVarID: 11916

      Variant1CAID: CA:256117

      Variant2: N/A

      Variant2ClinVarID: N/A

      Variant2CAID: N/A

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished N/A

    5. Case#: Patient D3, Druze religious group, located in lower Galilee.

      DiseaseAssertion: MPS-H

      FamilyInfo: Parents were heterozygous for the same mutation.

      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.1096A>C (p.T366P)

      Variant1ClinVarID: 11916

      Variant1CAID: CA256117

      Variant2: N/A

      Variant2ClinVarID: N/A

      Variant2CAID: N/A

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished N/A

    6. D5

      Case#: Patient D5, Druze religious group, located in lower Galilee.

      DiseaseAssertion: N/A

      FamilyInfo: May have relation with Patient D5 due to being located in the same village. Parents were found to be heterozygous for the mutation.

      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.1096A>C (p.T366P)

      Variant1ClinVarID: 11916

      Variant1CAID: CA:256117

      Variant2: N/A

      Variant2ClinVarID: N/A

      Variant2CAID: N/A

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished N/A

    7. M3)

      Case#: Patient M3, Muslim religious group, located in Gaza. The cells of the patient were listed in the catalog of the Human Genetic Mutant Cell Repository as "Hurler/Scheie". However, the patient at age 6 years had been described as having a typical MPS1-H phenotype except for apparently normal intelligence (measured across a language barrier).

      DiseaseAssertion: MPS1-H/S or MPS1-H

      FamilyInfo: Parents were found to have both mutations were found in heterozygous form in the DNA. Affected brother deceased at age 9.

      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.1225G>A (p.G409R)

      Variant1ClinVarID: 1084956

      Variant1CAID: CA91169920

      Variant2: (p.X654C)

      Variant2ClinVarID: N/A

      Variant2CAID: N/A

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished N/A

    8. M1

      Case#: Patient M1, Muslim 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.192C>A (p.Y64X)

      Variant1ClinVarID: 11914

      Variant1CAID: N/A

      Variant2: N/A

      Variant2ClinVarID: N/A

      Variant2CAID: N/A

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished N/A

    9. D4

      Case#: Patient D4, Druze religious group, located in lower Galilee.

      DiseaseAssertion: N/A

      FamilyInfo: May have relation with Patient D5 due to being located in the same village. Parents were found to be heterozygous for the mutation.

      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.1096A>C (p.T366P)

      Variant1ClinVarID: 11916

      Variant1CAID: CA:256117

      Variant2: N/A

      Variant2ClinVarID: N/A

      Variant2CAID: N/A

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished N/A

    1. In family B

      Case#: Patient 2 of family B: Female DiseaseAssertion:MPS1 FamilyInfo:Consanguinity Yes CasePresentingHPOs: NA CaseHPOFreeText: CaseNotHPOs: CaseNotHPOFreeText: CaseEnzymeAssay: enzyme values lower than the cut-off values CaseUrineGAGs: NA CaseERT: NA CaseBMT:Nil Variant1:c.1469T>C ,Leu490Pro Variant1ClinVar ID: 11919 Variant1CAID: Variant2:c.1469T>C ,Leu490Pro Variant2ClinVarID:11919 Variant2CAID: AdditionalVariants:Nil ParentalGenotype:NA PreviouslyPublishedNA

    1. three siblings

      Case#: Eldest child, female, age at diagnosis and onset are unknown, age at treatment is 6, age at report is 11 DiseaseAssertion: MPS1 FamilyInfo: All 3 cases are siblings CasePresentingHPOs: HP:0000280, HP:0008800, HP:0010501, HP:0006467, HP:0001659, HP:0001653, HP:0001634 (Coarse facial features, Limited hip movement, Limited shoulder movement, Limitation of knee mobility, Aortic regurgitation, Mitral regurgitation, Mitral valve prolapse) CaseHPOFreeText: Corneal clouding CaseNotHPOs: N/A CaseNotHPOFreeText: N/A CaseEnzymeAssay: N/A CaseUrineGAGs: N/A CaseERT: Yes CaseBMT: Don't know Variant1: p.Leu490Pro Variant1ClinVarID: 11919 Variant1CAID: Variant2: p.Leu490Pro Variant2ClinVarID: 11919 Variant2CAID: AdditionalVariants: N/A ParentalGenotype: N/A PreviouslyPublished N/A

    2. three siblings

      Case#: Youngest child, Female, age at diagnosis and onset are unknown, age at treatment is 4 months, age at report is 5 years, 4 months DiseaseAssertion: MPS1 FamilyInfo: All 3 cases are siblings CasePresentingHPOs: N/A CaseHPOFreeText: Mild corneal clouding, this study is to examine the efficacy of enzyme replacement therapy at different stages of teh disease, and it is assumed this patient is not yet old enough to have develped symptoms CaseNotHPOs: N/A CaseNotHPOFreeText: N/A CaseEnzymeAssay: N/A CaseUrineGAGs: N/A CaseERT: Yes CaseBMT: Don't know Variant1: p.Leu490Pro Variant1ClinVarID: 11919 Variant1CAID: Variant2: p.Leu490Pro Variant2ClinVarID: 11919 Variant2CAID: AdditionalVariants: N/A ParentalGenotype: N/A PreviouslyPublished N/A

    3. three siblings

      Case#: Middle child, Male, age at diagnosis and onset are unknown, age at treatment is 2.5 years, age at report is 7.5 years DiseaseAssertion: MPS1 FamilyInfo: All 3 cases are siblings CasePresentingHPOs: HP:0001634, HP:0001653 (mitral valve prolapse, mitral regurgitation) CaseHPOFreeText: Mild corneal clouding CaseNotHPOs: N/A CaseNotHPOFreeText: N/A CaseEnzymeAssay: N/A CaseUrineGAGs: N/A CaseERT: Yes CaseBMT: Don't know Variant1: p.Leu490Pro Variant1ClinVarID: 11919 Variant1CAID: Variant2: p.Leu490Pro Variant2ClinVarID: 11919 Variant2CAID: AdditionalVariants: N/A ParentalGenotype: N/A PreviouslyPublished N/A

    1. CasePT-104: United States

      CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

      HPOsFreeText: N/A

      CaseNotHPOs: HP:0001650, HP:0001658 (Aortic valve stenosis, Myocardial infarction)

      NotHPOsFreeText: N/A

      CaseAddInfo:


      CaseGenotypingMethod: DNA was collected from the participants using blood samples. 18 genes suspected on contributing to HCM were targeted and sequenced. The variants were then located and filtered for pathogenicity.


      Variant: NM_000257.3:c.4399C>G (p.Leu1467Val)

      ClinVar: 43015 https://www.ncbi.nlm.nih.gov/clinvar/variation/43015/

      gnomAD: South Asian 1.111e-3, Overall 1.352e-4 https://gnomad.broadinstitute.org/variant/14-23886482-G-C

    1. 1

      Case1: Male, 0.5 yr onset, 2.5 yr diagnosis, 10.04 yr report

      CasePresentingHPOs: HP:0001371 (Contractures)

      HPOsFreeText: Wheelchair used, FVC z-score sitting -0.25 (97% pred), FVC z-score supine -1.12 (87% pred), 65% MRC Scale, 530 CK U/l, 9.1 GAA activity (nmol/h/mg)^h from cultured fibroblasts

      NotHPOsFreeText: No respiratory support

    2. 7

      Case7: Male, 1 yr onset, 2 yr diagnosis, 13.7 yr report

      CasePresentingHPOs: HP:0002650 (Scoliosis)

      HPOsFreeText: Respiratory support at night, FVC z-score sitting -4.08 (54% pred), FVC z-score supine -5.4 (39% pred), 87% MRC Scale, 548 CK U/l, 17.9 GAA activity (nmol/h/mg)^h from cultured fibroblasts

      NotHPOsFreeText: No wheelchair used

    1. Patient 5

      Case5: Female, Caucasian, United States, 2 months onset and diagnosis, 0.4 years report

      CasePresentingHPOs: HP:0011968, HP:0011469, HP:0012378, HP:0004347, HP:0010453 (Feeding difficulties, Nasal regurgitation, Fatigue, Weakness of muscles of respiration, Pelvic bone asymmetry)

      HPOsFreeText: Difficulty in lying supine while eating, sleeping and self-limited gasping episodes was observed, PT evaluation showed mild consistent asymmetry with increased lateral head tilt to the right, Tendency towards flexion/abduction/external rotation positioning of lower extremities was noted, Slight lateral thigh grooves reflected early IT band tightness with decreased posterior weight shift and propping on forearms in prone, AIMS score was at 10th percentile for chronological age and 25th to 50th percentile for corrected age, ALT 27 U/L (Normal 5–40 U/L), AST 36 U/L (Normal 15–41 U/L), ALP 352 U/L (Normal 24–170 U/L), Urinary Glc4 4.1 mmol/mol creatinine (Normal ≤8.3 mmol/mol creatinine)

      CaseNotHPOs: HP:0002033, HP:0002015, HP:0004323, HP:0003808 (Poor suck, Poor swallowing, Abnormality of body weight, Abnormal muscle tone)

      NotHPOsFreeText: CK levels, ECG, and ECHO have consistently been within normal limits, Had normal passive ranges of motion and appropriate weight bearing through lower extremities in supported standing

    2. Patient 4

      Case4: Female, Caucasian, United States, 1 month onset, 6 months diagnosis, 1.1 years report

      CasePresentingHPOs: HP:0003236, HP:0012378, HP:0006589, HP:0003725 (Increased serum CK, Fatigue, Flaring of lower rib cage, Firm muscles)

      HPOsFreeText: HyperCKemia present in the first month (505 IU/L; Normal 30–279 IU/L) but normalized spontaneously at 4 months (188 IU/L), PT assessment revealed subtle motor signs including preferred position of ring sitting with hips in flexion/abduction/external rotation and bilateral IT band tightness, Imbalanced trunk flexion, Decreased use of abdominals and excessive use of spinal extension, Asymmetry was noted in reaching objects in prone and weight shifting with lateral flexion and shortening on the left at the neck and trunk, AIMS score was at the 25th percentile and GMFM was 22.14%, Urinary Glc4 4.8 mmol/mol creatinine (Normal ≤8.3 mmol/mol creatinine)

      CaseNotHPOs: HP:0003690 (Limb muscle weakness)

      NotHPOsFreeText: She had no head lag when pulled to sit and the ability to transfer objects and bring them to midline

    3. Patient 1

      Case1: Male, Caucasian, United States, Birth onset

      CasePresentingHPOs: HP:0008872, HP:0002100, HP:0001508, HP:0008947, HP:0001655, HP:0003236, HP:0200136, HP:0001290, HP:0002835, HP:0002194 (Feeding difficulties in infancy, Recurrent aspiration pneumonia, Poor weight gain, Infantile muscular hypotonia, Patent foramen ovale, Increased serum CK, Oropharyngeal dysphagia, Low muscle tone, Aspiration, Delayed gross motor development)

      HPOsFreeText: HyperCKemia was present since the early neonatal period (378 IU/L, day 8 of life; N: 60–305 IU/L), ERT at a dose of 20 mg/kg every 2 weeks was initiated at age 1 month, CK levels were normalized on ERT by age 4 months (80 IU/L), Flexion/abduction/ external rotation positioning of lower extremities, iliotibial (IT) band tightness, lack of independent sitting, AIMS score between 10th and 25th percentile, GMFM at 23.16%, At age 23 months, he had achieved significant motor milestones; started sitting with support at 10 months and without support at 12 months, pulled to stand at 12 months, walked at 15 months and could feed himself with an immature pincer grasp. Swallow study was normal, ALT 26 U/L (Normal 5–40 U/L), AST 45 U/L (Normal 15–41 U/L), ALP 211 U/L (Normal 24–170 U/L), Urinary Glc4 3.7 mmol/mol creatinine (Normal ≤8.3 mmol/mol creatinine)

      CaseNotHPOs: HP:0011675, HP:0002910 (ECG abnormality, Elevated hepatic transaminases)

      NotHPOsFreetext:

      CaseAddInfo: Older brother of Patient 2, Late-Onset Pompe Disease

    4. Patient 2

      Case2: Male, Caucasian, United States, Birth onset

      CasePresentingHPOs: HP:0001290, HP:0200136, HP:0002033, HP:0003236, HP:0001655, HP:0002058, HP:0002194, HP:0002421, HP:0000467, HP:0002015 (Generalized hypotonia, Oral-pharyngeal dysphagia, Poor suck, Increased serum CK, Patent foramen ovale, Myopathic face, Delayed gross motor development, Poor head control, Neck muscle weakness, Dysphagia)

      HPOsFreeText: hyperCKemia at 435 IU/L on day of life 4, Patent foramen ovale detected at birth by ECHO but resolved spontaneously, PT evaluation at age 2 months revealed flexion/abduction/external rotation positioning of lower extremities with tightness bilaterally in hip flexors, hamstrings, and IT bands, Had a tendency to remain on toes when held in supported standing with additional support required for weight bearing through lower extremities, Had difficulty lifting his head in prone, with asymmetric head lift to 45 degrees, and an inability to maintain head in midline when supine, AIMS score at age 2 months was between 10–25th percentile, ALT 41 U/L (Normal 5–40 U/L), AST 33 U/L (Normal 15–41 U/L), ALP 239 U/L (Normal 24–170 U/L), Urinary Glc4 4.5 mmol/mol creatinine (Normal ≤8.3 mmol/mol creatinine)

      CaseNotHPOs: HP:0011016 (Abnormality of urine glucose concentration)

      NotHPOsFreeText:

      CaseAddInfo: Younger brother of Patient 1, Late-Onset Pompe Disease

    5. Patient 7

      Case7: Female, Caucasian, United States, 6 months diagnosis, 8 months report

      CasePresentingHPOs: HP:0001643, HP:0006699, HP:0006682, HP:0003722, HP:0008969 (Patent ductus arteriosus, Premature atrial contractions, Premature ventricular contractions, Neck flexor weakness, Leg muscle stiffness)

      HPOsFreeText: At 6 months head lag during pull to sit was noted, Had predominant overall flexion position of lower extremities with a tendency towards hip flexion/abduction/external rotation, with lateral thigh grooves suggestive of bilateral IT band tightness, AIMS score was between 10th and 25th percentile for chronological age and 50th percentile for her corrected age adjusted for prematurity while GMFM score was 16.55%, ALT 37 U/L (Normal 5–40 U/L), AST 53 U/L (Normal 15–41 U/L), ALP 174 U/L (Normal 24–170 U/L)

      CaseNotHPOs: HP:0003236, HP:0001712, HP:0001290 (Increased serum CK, Left ventricular hypertrophy, Decreased muscle tone)

      NotHPOsFreeText: Other evaluations including pulmonary, speech, and swallow were normal

    6. Patient 6

      Case6: Male, Caucasian, United States, 1 month onset, 6 months diagnosis, 8 months report

      CasePresentingHPOs: HP:0003236, HP:0001655, HP:0003701, HP:0006589, HP:0003093, (Increased serum CK, Patent foramen ovale, Proximal muscle weakness, Flaring of lower rib cage, Limited hip extension,

      HPOsFreeText: HyperCKemia was noticed in the first month (438 U/L; Normal 60–305) but normalized spontaneously by age 6 months, flexion/abduction/external rotation positioning of lower extremities and with bilateral IT band tightness was revealed at the same time, also had decreased active use of abdominal oblique muscles with a lack of active trunk rotation, Decreased active use of lower abdominal muscles with inability to achieve a posterior pelvic tilt in supine, AIMS score was at 1st percentile for age and GMFM was at 12.3%, ALT 30 U/L (Normal 5–40 U/L), AST 90 U/L (Normal 15–41 U/L), ALP 249 U/L (Normal 24–170 U/L), Urinary Glc4 2.6 mmol/mol creatinine (Normal ≤8.3 mmol/mol creatinine)

      CaseNotHPOs: HP:0001712, HP:0001290 (Left ventricular hypertrophy, Decreased muscle tone)

      NotHPOsFreeText: Other evaluations including cardiac, pulmonary, speech, and swallow were normal

    1. one confirmed LOPD patient

      Case1: Female, 55 years report, 25 years onset, Brazil, African

      CasePresentingHPOs: HP:0003325, HP:0003236, HP:0003148, HP:0100284, HP:0011807, HP:0003326, HP:0008994, HP:0002527, HP:0003551, HP:0002015, HP:0000822, HP:0000819, HP:0003119, HP:0003707, HP:0003391, HP:0003327, HP:0001315, HP:0002515, HP:0010546 (Limb-girlde muscle weakness, Increased serum CK, Elevated serum acid phosphatase, EMG: myotonic discharges, Type 1 muscle fiber atrophy, Myalgia, Proximal muscle weakness in lower limbs, Falls, Difficulty climbing stairs, Dysphagia, Hypertension, Diabetes mellitus, Dyslipidemia, Calf muscle pseudohypertrophy, Gowers sign, Axial muscle weakness, Reduced deep tendon reflexes, Waddling gait, Muscle fibrillation)

      HPOsFreeText: Serum CK 1467 U/L (normal: ≤ 200U/L), NaG/AaGIA ratio 40.4, %INH 87.2, GAA activity 4.2% from dried blood spot, Falls occurring mainly when walking for long distances, Normal Mini-Mental State Examination score (27/30), Mild symmetrical weakness in proximal muscles in the lower limbs (Medical Research Council grade 4), Needle electromyography revealed motor unit potentials with low amplitude and short duration in the iliopsoas muscle associated with fibrillation and short myotonic discharge potentials in lumbar paraspinal muscles

      CaseNotHPOs: HP:0001270 (Motor delay)

      NotHPOsFreeText: Muscle biopsy with the absence of vacuolar myopathy

      CaseAddInfo: Late-Onset Pompe Disease, One sister diagnosed with LOPD based on low GAA activity and shared genetic variants but no other known relatives with the condition

    1. 3

      Case3: Male, 19 years report, Italy

      CasePresentingHPOs: HP:0003551 (Difficulty climbing stairs)

      HPOsFreeText: Height is 1.78 m, Weight is 60 kg, BMI is 18.9 kg/cm2, 7 years on ERT, Forced Vital Capacity at 107%

      CaseNotHPOs: HP:0002098 (Respiratory distress)

      NotHPOsFreeText: Nocturnal non-invasive ventilation

      CaseAddInfo: Late Onset Pompe Disease

    2. 1

      Case1: Female, 46 years report, Italy

      CasePresentingHPOs: HP:0003551 (Difficulty climbing stairs)

      HPOsFreeText: Height is 1.64 m, Weight is 50 kg, BMI is 18.6 kg/cm2, 2 years on ERT, Forced Vital Capacity at 108%

      CaseNotHPOs: HP:0002098 (Respiratory distress)

      NotHPOsFreeText: Nocturnal non-invasive ventilation

      CaseAddInfo: Late Onset Pompe Disease

    1. II

      CaseII: Adult onset, 71 years diagnosis

      CasePresentingHPOs: HP:0003701, HP:0003326, HP:0003236, HP:0003198 (Proximal muscle weakness, Myalgia, Increased serum CK, Myopathy)

      HPOsFreeText: Plasma CK 5–10× Normal, GAA activity from dried blood spot: 0%, 6-Minute Walking Test: 40 min, Forced Vital Capacity Seated: 850 (22%)

      CaseNotHPOs: HP:0002795 (Abnormal respiration)

      CaseAddInfo: Late-Onset Pompe Disease

    2. 1

      CaseV,1: Adolescent onset, 42 years diagnosis

      CasePresentingHPOs: HP:0003701, HP:0003236, HP:0003388, HP:0003326 (Proximal muscle weakness, Increased serum CK, Easy fatigability, Myalgia)

      HPOsFreeText: Plasma CK 5-10× Normal, Vacuoles in histology, 6-Minute Walking Test: 135 min, Forced Vital Capacity Seated: 950 (20%), GAA activity from dried blood spot: 0.20%

      CaseNotHPOs: HP:0002795 (Abnormal respiration)

      CaseAddInfo: Late-Onset Pompe Disease

    3. 3

      CaseV,3: Child onset, 45 years diagnosis

      CasePresentingHPOs: HP:0003701, HP:0003236 (Proximal muscle weakness, Increased serum CK)

      HPOsFreeText: Plasma CK 2.5-5× Normal, GAA activity from dried blood spot: 0.08%, 6-Minute Walking Test: 566 min

      CaseNotHPOs: HP:0002795 (Abnormal respiration)

      CaseAddInfo: Late-Onset Pompe Disease

    4. III

      CaseIII: Adult onset, 63 years diagnosis

      CasePresentingHPOs: HP:0003701, HP:0003388, HP:0003236, HP:0003198, HP:0002460, HP:0002015 (Proximal muscle weakness, Easy fatigability, Increased serum CK, Myopathy, Distal muscle weakness, Dysphagia)

      HPOsFreeText: Plasma CK 2.5–5× Normal, GAA activity from muscle: 11.7%

      CaseNotHPOs: HP:0002795 (Abnormal respiration)

      CaseAddInfo: Late-Onset Pompe Disease

    5. I

      CaseI: Early adult onset, 49 years diagnosis

      CasePresentingHPOs: HP:0003701, HP:0003388, HP:0003236, HP:0003198 (Proximal muscle weakness, Easy fatigability, Increased serum CK, Myopathy)

      HPOsFreeText: Plasma CK 5–10× Normal, GAA activity from lymphocytes: 14.2%

      CaseNotHPOs: HP:0002795 (Abnormal respiration)

      CaseAddInfo: Late-Onset Pompe Disease

    6. 2

      CaseV,2: Adult onset, 33 years diagnosis

      CasePresentingHPOs: HP:0003701, HP:0003236, HP:0003388 (Proximal muscle weakness, Increased serum CK, Easy fatigability)

      HPOsFreeText: Plasma CK 5-10× Normal, 6-Minute Walking Test: 566 min, Forced Vital Capacity Seated: 3000 (90%), GAA activity from dried blood spot: 0.20%

      CaseNotHPOs: HP:0002795 (Abnormal respiration)

      CaseAddInfo: Late-Onset Pompe Disease

    1. 9

      Case9: Male, 40 years onset, 45 years diagnosis, 74 years report, France

      CasePresentingHPOs: HP:0002540, HP:0002878, HP:0004887 (Inability to walk, Respiratory failure, Respiratory failure requiring assisted ventilation)

      HPOsFreeText: Lost ambulation at 50 years, Started invasive ventilation at 67 years, Started ERT given every other week at a dose of 20 mg/kg at 70 years for 43 months, Peak Anti-rhGAA antibodies at 1:409,600, Time off ventilation stayed constant at 0 min, Total Motor Function Measure from 29 to 26, 6MWT stayed constant at 0 meters

      CaseNotHPOs: HP:0030148 (Heart murmur)

      NotHPOsFreeText: No adverse reaction to ERT was recorded

      CaseAddInfo: Late Onset Pompe Disease

    2. 12

      Case12: Male, 35 years onset, 50 years diagnosis, 61 years report, France

      CasePresentingHPOs: HP:0002540, HP:0002878, HP:0004887 (Inability to walk, Respiratory failure, Respiratory failure requiring assisted ventilation)

      HPOsFreeText: Lost ambulation at 48 years, Started invasive ventilation at 35 years, Started ERT given every other week at a dose of 20 mg/kg at 56 years for 49 months, Peak Anti-rhGAA antibodies at 1:1600, FVC at 0 (L / % expected), MIP at 22 (cm H2O), MEP at 28 (cm H2O), Time off ventilation stayed constant at 0 min, 6MWT stayed constant at 0 meters

      CaseNotHPOs: HP:0030148 (Heart murmur)

      NotHPOsFreeText: No adverse reaction to ERT was recorded

      CaseAddInfo: Late Onset Pompe Disease

    3. 3

      Case3: Male, 28 years onset, 30 years diagnosis, 69 years report, France

      CasePresentingHPOs: HP:0002540, HP:0002878, HP:0004887, HP:0002093 (Inability to walk, Respiratory failure, Respiratory failure requiring assisted ventilation, Respiratory insufficency)

      HPOsFreeText: Lost ambulation at 58 years, Started invasive ventilation at 28 years, Started ERT given every other week at a dose of 20 mg/kg at 68 years for 11 months, Peak Anti-rhGAA antibodies at 1:1600, FVC at 0.45/13 (L / % expected), MIP at 17 (cm H2O), MEP at 29 (cm H2O), Time off ventilation stayed constant at 0, Total Motor Function Measure from 31 to 27

      CaseNotHPOs: HP:0030148 (Heart murmur)

      NotHPOsFreeText: No adverse reaction to ERT was recorded

      CaseAddInfo: Late Onset Pompe Disease, Patient died before publication

    1. 62-year-old man

      Case1: Male, 62 years report

      CasePresentingHPOs: HP:0002091, HP:0002878, HP:0003701, HP:0040047, HP:0002098, HP:0100786, HP:0006510, HP:0005978, HP:0000822, HP:0003124, HP:0001677, HP:0003236, HP:0004324, HP:0002329, HP:0030207, HP:0002098, HP:0040047, HP:0100750, HP:0002097, HP:0007269, HP:0040046 (Restrictive lung disease, Respiratory failure, Proximal muscle weakness, Abnormality of the right hemidiaphragm, Shortness of breath, Hypersomnia, Chronic obstructive pulmonary disease, Diabetes mellitus Type II, Hypertension, Hypercholesterolemia, Coronary artery disease, Elevated serum creatine kinase, Increased body weight, Drowsiness, Paradoxical respiration, Respiratory distress, Abnormality of the right hemidiaphragm, Atelectasis, Emphysema, Spinal muscular atrophy, Abnormality of the left hemidiaphragm)

      HPOsFreeText: Hypercapnic respiratory failure, Chronic phrenic neuropathy bilaterally, Long history of apparently idiopathic right hemidiaphragm paralysis, Underwent muscle biopsy and electromyography, both of which showed nonspecific myopathic features associated with mild denervation, On presentation, the patient's vital signs were a temperature of 36.5 °C (97.7 °F); heart rate, 94 beats/minute; blood pressure, 104/70 mm Hg; respiratory rate, 22 breaths/minute; oxygen saturation, 90% when receiving 2 L of supplemental oxygen per minute; and body mass index, 29.9 kg/m2, Decreased air entry bilaterally, Laboratory values were: Hemoglobin, 120 g/L; platelets, 279 × 109/L; white blood cells, 7.7 × 109/L; sodium, 140 mmol/L; potassium, 5.1 mmol/L; bicarbonate, 40 mmol/L; serum urea nitrogen, 3.6 mmol/L; creatinine, 70.7 μmol/L; and calcium, 2.48 mmol/L, Fatty atrophy of rotator cuff musculature, Tests for resting room-air arterial blood gases showed a pH of 7.29; PCO2, 89.4 mm Hg; PO2, 67.6 mm Hg; and serum bicarbonate, 43 mmol/L, Right diaphragm paralysis, Electromyography showed complete absence of phrenic compound muscle action potentials bilaterally. No activation of motor unit potentials was seen within the diaphragm, either with respiration or with volitional effort. Ultrasonography showed that the left hemidiaphragm was hyperechoic, 0.14 cm thick at functional residual capacity (FRC), with a thickening ratio of 1.1 (the thickening ratio is thickness at total lung capacity/thickness at FRC). The right hemidiaphragm was hyperechoic, 0.15 cm thick at FRC, with thickening ratio of 0.9. (Normal thickness is >0.15 cm, normal thickening ratio is >1.2.) The aldolase concentration was slightly increased at 9 U/L (reference level, <7.7 U/L). To complete the evaluation for rarer causes of diaphragmatic dysfunction, neurology services requested testing for inherited neuropathies. Three weeks later, the patient's serum GAA level was 1.0 nmol/mL/hour (reference level, >7.4 nmol/mL/hour)

      CaseNotHPOs: HP:0003549 (Abnormality of connective tissue)

      NotHPOsFreeText: The following tests were within reference range: creatine kinase, thyroid function tests, erythrocyte sedimentation rate, serum and protein electrophoresis, antinuclear antibody profile, and anti-Jo antibodies

      CaseAddInfo: Ex-Smoker with 40–80 pack-years of smoking, Medications at presentation to facility included aspirin, clopidogrel, simvastatin, diltiazem, sitagliptin, metformin, budesonide and formoterol inhaler, tiotropium bromide inhaler, and albuterol inhaler

    1. 1

      Case1: Female, 12 years report, 3 years onset, 12 years diagnosis

      CasePresentingHPOs: HP:0003325, HP:0002093, HP:0002650 (Limb-girdle muscle weakness, Respiratory insufficiency, Scoliosis)

      HPOsFreeText: 730 CK (U/L), Normal Heart, 0 GAA activity (µmol/L/h), Showed respiratory involvement and required nocturnal non-invasive ventilation, An ambulant patient with 284 m six minute walk distance at the time of diagnosis

      CaseNotHPOs: HP:0003457, HP:0001627 (EMG abnormality, Abnormality of the heart)

      NotHPOsFreeText: Muscle weakness confined to limb-girdle muscles

    1. 4

      Case4: 0.5 years diagnosis, Germany

      CasePresentingHPOs: HP:0031185, HP:0001635, HP:0001252, HP:0001324, HP:0003236, HP:0001639 (Increased NT-proBNP level, Cardiac failure, Muscular hypotonia, Muscle weakness, Increased serum CK, Hypertrophic cardiomyopathy)

      HPOsFreeText: 3924 BNP (pg/ml), 7.68 IVS (d) z score, 6.42 IVS (s) z score, Heart Failure at NYHA Class 3

      NotHPOsFreeText: No left-ventricular outflow tract obstruction

      CaseAddInfo: Infantile-Onset Pompe Disease

    1. 1117

      Case1117: Male, 35 years onset, Welsh/English, Caucasian

      CasePresentingHPOs: HP:0003560, HP:0005110 (Muscular dystrophy, Atrial fibrillation)

      HPOsFreeText: 1,000 –2000's CK level, Immunohistochemistry: dystrophin, sarcoglycans, merosin

      CaseNotHPOs: HP:0009051, HP:0002540 (Increased muscle glycogen content, Non-ambulatory)

    1. Patient Number 3

      Case3: Male, 35 years report, 5 years onset, Algeria, African

      CasePresentingHPOs: HP:0003323, HP:0003749, HP:0002355, HP:0007340, HP:0008956, HP:0003484, HP:0003236, HP:0003198 (Progressive muscle weakness, Pelvic girdle muscle weakness, Difficulty walking, Lower limb muscle weakness, Proximal lower limb amyotrophy, Upper limb muscle weakness, Increased serum CK, Myopathy)

      HPOsFreeText: At grade 3 of Vignos and Walton scales, CK rate was 5 times the normal value and AST and ALT were normal, EMG was compatible with a myopathic disorder, GAA activity measured in leukocytes was significantly decreased

      CaseNotHPOs: HP:0003115, HP:0003116, HP:0001270, HP:0001290, HP:0002240, HP:0001640, HP:0005952, HP:0002540 (Abnormal ECG, Abnormal echocardiography, Motor delay, Generalized hypotonia, Hepatomegaly, Cardiomegaly, Decreased pulmonary function, Non-ambulatory)

    1. 15

      Patient15: Male, 21 years report, 2 years onset

      CasePresentingHPOs: N/A

      HPOsFreeText: GAA activity 4.7% from a dried blood spot

      CaseNotHPOs: HP:0002098, HP:0001324, HP:0001640, HP:0002240 (Respiratory distress, Muscle weakness, Cardiomegaly, Hepatomegaly)

      NotHPOsFreeText: No wheelchair needed, Respiratory Assistance not needed

      CaseAddInfo: LOPD

    1. The affected patient

      Case1: Male, French-Canadian, 18 years onset, 54 years diagnosis and report

      CasePresentingHPOs: HP:0008994, HP:0000822, HP:0003119, HP:0004398, HP:0007185, HP:0009109, HP:0002094, HP:0012764, HP:0002098 (Proximal muscle weakness in lower limbs, High blood pressure, dyslipidemia, Peptic ulcer, Loss of consciousness, Denervation of the diaphragm, Dyspnea, Orthopnea, Shortness of breath)

      HPOsFreeText: Dependent on continuous positive airway pressure or bilevel positive airway pressure when he is lying flat or sleeping because of previous intubation and tracheostomy, GAA activity measured from dried blood spot was 0.87 pmol/h/punch (Normal 4.96 - 27.3)

      CaseAddInfo: Late Onset Pompe Disease, The patient’s mother had six miscarriages and died at age 75 of lung cancer and his father died of cardiac problems in his early sixties, It appears that no other family members, including his parents and two siblings, were affected, patient had a previous appendectomy, He has no allergies, stopped smoking in 2002, and denied any alcohol or drug use

    1. 1

      Case#: 1, Female, 0.6 years (diagnosed), 5.2 years (report), 15 kg (weight), 75 cm (height), Iranian

      DiseaseAssertion: Hurler Syndrome

      FamilyInfo: Parents are not consanguineous

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

      CaseHPOFreeText: HM/HSM, Cardiac Manifestations (mitral stenosis)

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

      CaseNotHPOFreeText: Chronic Rhinorrhea

      CaseEnzymeAssay: IDUA activity 1.02 (μmol/spot.20h)

      CaseUrineGAGs: Quantitative urinary GAG 11.14 (mg/gCr)

      CaseERT: N/A

      CaseBMT: N/A

      GenotypingMethod: Sanger Sequencing

      Variant1: p.D257A

      Variant2: N/A

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished: N/A

    2. 4

      Case#: 4, Female, 0.3 years (diagnosed), 7.2 years (report), 23 kg (weight), 112 cm (height), Iranian

      DiseaseAssertion: Hurler 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: Chronic Rhinorrhea, Cardiac Manifestations

      CaseEnzymeAssay: IDUA activity 1.27 (μmol/spot.20h)

      CaseUrineGAGs: Quantitative urinary GAG 13.27 (mg/gCr)

      CaseERT: N/A

      CaseBMT: N/A

      GenotypingMethod: Sanger Sequencing

      Variant1: p.D257A

      Variant2: N/A

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished: N/A

    3. 11

      Case#: 11, Female, 0.5 years (diagnosed), 6.2 years (report), 14.5 kg (weight), 100 cm (height), Iranian

      DiseaseAssertion: Hurler Syndrome

      FamilyInfo: Parents are not consanguineous

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

      CaseHPOFreeText: HM/HSM, Chronic Rhinorrhea

      CaseNotHPOs: HP:0000238 (Hydrocephalus)

      CaseNotHPOFreeText: Cardiac Manifestations

      CaseEnzymeAssay: IDUA activity 1.04 (μmol/spot.20h)

      CaseUrineGAGs: Quantitative urinary GAG 7.82 (mg/gCr)

      CaseERT: N/A

      CaseBMT: N/A

      GenotypingMethod: Sanger Sequencing

      Variant1: p.D301E

      Variant2: N/A

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished: N/A

    4. 16

      Case#: 16, Male, 0.6 years (diagnosed), 5.5 years (report), 11.0 kg (weight), 66 cm (height), Iranian

      DiseaseAssertion: Hurler Syndrome

      FamilyInfo: Parents are consanguineous

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

      CaseHPOFreeText: HM/HSM

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

      CaseNotHPOFreeText: Chronic Rhinorrhea, Cardiac Manifestations

      CaseEnzymeAssay: IDUA activity 0.89 (μmol/spot.20h)

      CaseUrineGAGs: Quantitative urinary GAG 8.5 (mg/gCr)

      CaseERT: N/A

      CaseBMT: N/A

      GenotypingMethod: Sanger Sequencing

      Variant1: p.D301E

      Variant2: N/A

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished: N/A

    1. Q70X

      Case#: Family 11, 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: N/A

      Variant2ClinVarID: N/A

      Variant2CAID: N/A

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished N/A

    2. H240R

      Case#: Family 29, UK

      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: 5.6 nmol/h/mg cell protein; values are the means of two experiments.

      CaseUrineGAGs: N/A

      CaseERT: N/A

      CaseBMT: N/A

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

      Variant1ClinVarID: 11908

      Variant1CAID: CA220498

      Variant2: c.719A>G (p.H240R)

      Variant2ClinVarID: 947028

      Variant2CAID: CA355962127

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished N/A

    3. Q70X

      Case#: Family 19, Slovenia

      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: N/A

      Variant2ClinVarID: N/A

      Variant2CAID: N/A

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished N/A

    4. R619X

      Case#: Family 5, 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.1855C>T (p.R619X)

      Variant2ClinVarID: 280976

      Variant2CAID: CA2802455

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished N/A

    1. 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: E182K

      Variant1ClinVarID: 2856554

      Variant1CAID: CA2739269988

      Variant2: N/A

      Variant2ClinVarID: N/A

      Variant2CAID: N/A

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished: N/A

    2. 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: N350I

      Variant1ClinVarID:

      Variant1CAID: CA355963160

      Variant2: N/A

      Variant2ClinVarID: N/A

      Variant2CAID: N/A

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished: N/A

    3. 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: S260F

      Variant1ClinVarID:

      Variant1CAID: CA355962251

      Variant2: N/A

      Variant2ClinVarID: N/A

      Variant2CAID: N/A

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished: N/A

    4. 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: F602I

      Variant1ClinVarID:

      Variant1CAID: CA355965569

      Variant2: N/A

      Variant2ClinVarID: N/A

      Variant2CAID: N/A

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished: N/A

    5. 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: A300T

      Variant1ClinVarID: 11923

      Variant1CAID: CA121772

      Variant2: N/A

      Variant2ClinVarID: N/A

      Variant2CAID: N/A

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished: N/A

    6. 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: W626R

      Variant1ClinVarID:

      Variant1CAID: CA355965965

      Variant2: N/A

      Variant2ClinVarID: N/A

      Variant2CAID: N/A

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished: N/A

    7. Pro533Arg

      Case#: Variant not associated with a proband in this paper.

      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: Pro533Arg

      Variant1ClinVarID: 11910

      Variant1CAID: CA256112

      Variant2: N/A

      Variant2ClinVarID: N/A

      Variant2CAID: N/A

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished: N/A

    8. 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: C205Y

      Variant1ClinVarID: 1468875

      Variant1CAID: CA355961928

      Variant2: N/A

      Variant2ClinVarID: N/A

      Variant2CAID: N/A

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished: N/A

    9. 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

    10. 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: T366P

      Variant1ClinVarID: 11916

      Variant1CAID: CA256117

      Variant2: N/A

      Variant2ClinVarID: N/A

      Variant2CAID: N/A

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished: N/A

    1. sibling who initiated ERT at 2.5 years

      Case#: YS2 of sibship 5 (see Table 1), female, 0.1 years old (age at diagnosis), 2.5 years old (age at ERT enrollment), 8.8 years (duration of ERT)

      DiseaseAssertion: MPS1-HS

      FamilyInfo: Two affected siblings (OS and YS1 of sibship 5)

      CasePresentingHPOs: HP:0007957, HP:0002828, HP:0001270 (Corneal opacity, joint contractures, motor delay)

      CaseHPOFreeText: Cardiac disease, ocular disease, organomegaly

      CaseNotHPOs: HP:0000943 (Dysostosis)

      CaseNotHPOFreeText: N/A

      CaseEnzymeAssay: N/A

      CaseUrineGAGs: N/A

      CaseERT: Yes - Organomegaly and motor function delays improved, cardiac symptoms remained stable, and mild joint contractures developed. Pulmonary function was between 70 and 94 % of normal at T2.

      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

    2. older sibling

      Case#: OS of sibship 3, female, 1 year old (age at diagnosis), 12 years old (age at ERT enrollment), 8 years (duration of ERT)

      DiseaseAssertion: MPS1-HS

      FamilyInfo: Affected female YS (YS of sibship 1)

      CasePresentingHPOs: HP:0007957, HP:0000943, HP:0002828, HP:0001263, HP:0010862, HP:0002194 (Corneal opacity, dysostosis, joint contractures, cognitive delay, delayed fine motor development, delayed gross motor development)

      CaseHPOFreeText: Cardiac disease, moderate musculoskeletal disease

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CaseEnzymeAssay: N/A

      CaseUrineGAGs: N/A

      CaseERT: Yes - After ERT all existing symptoms persisted or progressed in this sibling except for improvement in organomegaly.

      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

    1. MPS-I patients 296

      Case#: Patient 296, female, northern European origin, 8 months (age of diagnosis), 4 years and 9 months (age of death)

      DiseaseAssertion: MPS1-H, severe

      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.1614del (delG1702)

      Variant2ClinVarID: 167191

      Variant2CAID: CA234129

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished N/A

    1. 40/M

      Case#: Patient 40, male, Han origin, 11 months 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: Cardiac disease

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      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.300-1G>C

      Variant1ClinVarID: N/A

      Variant1CAID: CA355960962

      Variant2: c.123G>A (p.W41X)

      Variant2ClinVarID: 2734632

      Variant2CAID: CA355945567

      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

    2. 33/M

      Case#: Patient 33, male, Han origin, 7 year 5 months 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 0.7 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.792+1G>C

      Variant1ClinVarID: N/A

      Variant1CAID: : CA355962280

      Variant2: c.236C>T (p.A79V)

      Variant2ClinVarID: 1458769

      Variant2CAID: CA356987

      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

    3. 31/F

      Case#: Patient 31, female, Han origin, 9 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 1.3 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.1037T>G (p.L346R)

      Variant1ClinVarID: 11927

      Variant1CAID: CA256128

      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 by parental testing.

      PreviouslyPublished N/A

    4. 3/M

      Case#: Patient 3, male, Han origin, 1 year and 5 months old (age at diagnosis).

      DiseaseAssertion: MPS1-H/S

      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: Cardiac disease

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CaseEnzymeAssay: IDUA activity 1.0 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.T179R)

      Variant1ClinVarID: 556358

      Variant1CAID: CA355961718

      Variant2: c.236C>T (p.A79V)

      Variant2ClinVarID: 1458769

      Variant2CAID: CA356987

      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

    1. 15

      Case#: Patient 15, born in 2001 (paper published in 2017), 13 months (age at first treatment), 2 years 9 months (age at last 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: 25 ng/mol (56 weight matched enzyme reference assay)

      CaseUrineGAGs: 0.80 DS/CS

      CaseERT: No

      CaseBMT: Yes, from mother

      Variant1: c.783delC is not a known variant in IDUA; there is a C at position 783 but the only known variants are c.784del

      Variant1ClinVarID: N/A

      Variant1CAID: N/A

      Variant2: c.783delC; same as above

      Variant2ClinVarID: N/A

      Variant2CAID: N/A

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished N/A

    2. 22

      Case#: Patient 22, born in 1995 (paper published in 2017), 8 months (age at first treatment). 2 years and 2 months (age at last 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: 49.94 ng/mol (38.49 weight matched enzyme reference assay)

      CaseUrineGAGs: 0.43 DS/CS

      CaseERT: No

      CaseBMT: Yes, Sib

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

      Variant1ClinVarID: 11909

      Variant1CAID: CA204563

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

      Variant2ClinVarID: 11909

      Variant2CAID: CA204563

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished N/A

    1. 3

      Case#: Patient 3, male, brother of Patient 7 (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 1.60 (Ref. 4.87 ~ 54.70 μmol/g protein/h)

      CaseUrineGAGs: Positive GAG tests

      CaseERT: N/A

      CaseBMT: N/A

      Variant1: c.300-3C>G

      Variant1ClinVarID: 551563

      Variant1CAID: CA549265042

      Variant2: c.1874A>C (p.Y625S)

      Variant2ClinVarID: 2910181

      Variant2CAID: CA355965961

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished N/A

    2. 4

      Case#: Patient 4, male

      DiseaseAssertion: MPS I

      FamilyInfo: N/A

      CasePresentingHPOs: N/A

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CaseEnzymeAssay: Low IDUA enzyme activity 2.06 (Ref. 4.87 ~ 54.70 μmol/g protein/h)

      CaseUrineGAGs: Negative GAG tests

      CaseERT: N/A

      CaseBMT: N/A

      Variant1: c.355G>T (p.D119Y)

      Variant1ClinVarID: 2432701

      Variant1CAID: CA2801882

      Variant2: c.617C>T (p.S206L)

      Variant2ClinVarID: 1436435

      Variant2CAID: CA2802033

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished N//A

    1. Hurler disease

      Case#: Patient 58, 6 years old (age at report), male, Indian

      DiseaseAssertion: MPS1-H

      FamilyInfo: Sibling of Patient 59

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

      CaseHPOFreeText: N/A

      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.1044C>G (p.Asn348Lys)

      Variant1ClinVarID: 557870

      Variant1CAID: CA2802172

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

      Variant2ClinVarID: 11910

      Variant2CAID: CA256112

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished N/A

    2. Hurler disease

      Case#: Patient 43, 2 years old (age at report), male, Indian

      DiseaseAssertion: MPS1-H

      FamilyInfo: N/A

      CasePresentingHPOs: Coarse facial features, hepatosplenomegaly, joint contractures, corneal clouding, intellectual disability, hernia (HP:0000280, HP:0001433, HP:0002828, HP:0007957, HP:0001249, 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.1862C>T (p.Arg621Leu) - There seems to be a typo, either c.1862G>T (p.Arg621Leu) or c.1861C>T (p.Arg621Ter). Unknown which variant is being referred.

      Variant1ClinVarID: N/A

      Variant1CAID: N/A

      Variant2: c.1862C>T (p.Arg621Leu) - There seems to be a typo, either c.1862G>T (p.Arg621Leu) or c.1861C>T (p.Arg621Ter). Unknown which variant is being referred.

      Variant2ClinVarID: N/A

      Variant2CAID: N/A

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished N/A

    3. Hurler disease

      Case#: Patient 34, 5 years old (age at report), female, 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: 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.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

    4. Hurler disease

      Case#: Patient 48, 6 years old (age at report), male, Indian

      DiseaseAssertion: MPS1-H

      FamilyInfo: N/A

      CasePresentingHPOs: Hepatosplenomegaly, joint contractures, corneal clouding, recurrent infections (HP:0001433, HP:0002828, HP:0007957, HP:0002719)

      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.(972+1_973-1)(1959?)del in the paper, unsure how to write this in current nomenclature.

      Variant1ClinVarID: N/A

      Variant1CAID: N/A

      Variant2: c.(972+1_973-1)(1959?)del in the paper, unsure how to write this in current nomenclature.

      Variant2ClinVarID: N/A

      Variant2CAID: N/A

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished N/A

    5. Hurler disease

      Case#: Patient 25, 28 years old (age at report), female, Indian

      DiseaseAssertion: MPS1-H

      FamilyInfo: N/A

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

      CaseHPOFreeText: Cardiac disease

      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.1148G>A (p.Arg388His)

      Variant1ClinVarID: 558189

      Variant1CAID: CA2802205

      Variant2: c.1148G>A (p.Arg388His)

      Variant2ClinVarID: 558189

      Variant2CAID: CA2802205

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished N/A

    6. Hurler disease

      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

    1. Scheie

      Case#: Patient 14 (group 2), Poland, male 5 years old (age at diagnosis), 15 years old (age at baseline), 19 years old (current age)

      DiseaseAssertion: MPS1-S

      FamilyInfo: N/A

      CasePresentingHPOs: Limitation of join mobility, joint stiffness (HP:0001376, HP:0001387)

      CaseHPOFreeText: Patients in group 2 had normal mental development or only slightly delayed mental development and, therefore, could undergo active physical rehabilitation.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CaseEnzymeAssay: Diagnosis of MPS I was confirmed by the biochemical determination of α-L-iduronidase activity deficiency in leukocytes and by molecular analysis.

      CaseUrineGAGs: N/A

      CaseERT: Yes, weekly infusions for 52-208 weeks (depending on the patient)

      CaseBMT: N/A

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

      Variant1ClinVarID: 11909

      Variant1CAID: CA204563

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

      Variant2ClinVarID: 638074

      Variant2CAID: CA2802098

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished N/A

    1. 36

      Case#: Patient 36 (Table 3)

      DiseaseAssertion: Attenuated naïve MPS 1

      FamilyInfo: N/A

      CasePresentingHPOs: N/A

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CaseEnzymeAssay: 7 nmol/h/mg per DBS (dried blood spots) determined during NBS. 13 DBS protein concentration determined by Immuno-SRM (pmol/L). 125.50 relative protein abundance, expressed as the ratio between IDUA/GAA (amol / fmol) in buccal swabs.

      CaseUrineGAGs: N/A

      CaseERT: Yes

      CaseBMT: N/A

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

      Variant1ClinVarID: 11909

      Variant1CAID: CA204563

      Variant2: c.1070C>T (p.P357L)

      Variant2ClinVarID: 1683228

      Variant2CAID: CA91169110

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished N/A

    2. 26

      Case#: Patient 26 (Table 3)

      DiseaseAssertion: Severe naïve MPS 1

      FamilyInfo: N/A

      CasePresentingHPOs: N/A

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CaseEnzymeAssay: N/A

      CaseUrineGAGs: N/A

      CaseERT: Yes

      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

    3. 38

      Case#: Patient 38 (Table 3)

      DiseaseAssertion: Severe MPS 1

      FamilyInfo: N/A

      CasePresentingHPOs: N/A

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CaseEnzymeAssay: 59.4 DBS protein concentration determined by Immuno-SRM (pmol/L).

      CaseUrineGAGs: N/A

      CaseERT: Yes

      CaseBMT: N/A

      Variant1: c.1205G>A (p.W402X) Listed in Table 3 as c.12095G>A

      Variant1ClinVarID: 11908

      Variant1CAID: CA220498

      Variant2: c.1205G>A (p.W402X) Listed in Table 3 as c.12095G>A

      Variant2ClinVarID: 11908

      Variant2CAID: CA220498

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished N/A

    4. 40

      Case#: Patient 40 (Table 3)

      DiseaseAssertion: Severe MPS 1

      FamilyInfo: N/A

      CasePresentingHPOs: N/A

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CaseEnzymeAssay: 7 nmol/h/mg per DBS (dried blood spots) determined during NBS. 469.4 DBS protein concentration determined by Immuno-SRM (pmol/L). 15.98 relative protein abundance, expressed as the ratio between IDUA/GAA (amol / fmol) in buccal swabs.

      CaseUrineGAGs: N/A

      CaseERT: Yes

      CaseBMT: N/A

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

      Variant1ClinVarID: 11908

      Variant1CAID: CA220498

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

      Variant2ClinVarID: 11908

      Variant2CAID: CA220498

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished N/A

    1. c.531C>G

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

      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.531C>G (p.P177L)

      Variant1ClinVarID: 2432729

      Variant1CAID: CA2801983

      Variant2: N/A

      Variant2ClinVarID: N/A

      Variant2CAID: N/A

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished N/A

    2. c.898G>A

      Case#: Functional assay variant with a clinical significance of having conflicting interpretations.

      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.898G>A (p.A300T)

      Variant1ClinVarID: 11923

      Variant1CAID: CA121772

      Variant2: N/A

      Variant2ClinVarID: N/A

      Variant2CAID: N/A

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished N/A

    3. c.1706C>T

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

      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.1706C>T (p.S569L)

      Variant1ClinVarID: N/A

      Variant1CAID: CA355965250

      Variant2: N/A

      Variant2ClinVarID: N/A

      Variant2CAID: N/A

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished N/A

    4. c.719A>G

      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.719A>G (p.H240R)

      Variant1ClinVarID: 947028

      Variant1CAID: CA355962127

      Variant2: N/A

      Variant2ClinVarID: N/A

      Variant2CAID: N/A

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished N/A

    1. 22

      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

    2. 28

      Case#: Patient 28, female, 2 months (age at presentation).

      DiseaseAssertion: MPS1-H

      FamilyInfo: Consanguinity in the family present for this patient. Sister is unaffected.

      CasePresentingHPOs: Coarse facial features, dysostosis multiplex, global developmental delay, hepatomegaly, joint contractures, splenomegaly (HP:0000256, HP:0000943, HP:0001263, 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.1855C>T (p.R619X)

      Variant1ClinVarID: 280976

      Variant1CAID: CA2802455

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

      Variant2ClinVarID: 280976

      Variant2CAID: CA2802455

      AdditionalVariants: N/A

      ParentalGenotype: Mother and father are both carriers but does not specify for which variants.

      PreviouslyPublished N/A

    3. 30

      Case#: Patient 30, female, 3 years (age at presentation).

      DiseaseAssertion: MPS1-H/S

      FamilyInfo: Consanguinity in the family present for this patient. Family had a prenatal diagnosis "CVS-unaffected"

      CasePresentingHPOs: Corneal clouding, coarse facial features, dysostosis multiplex, hepatomegaly, joint stiffness, splenomegaly, short stature, umbilical hernia (HP:0007957, HP:0000256, HP:0000943, HP:0002240, HP:0001387, HP:0001744, HP:0004322, 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.1861C>T (p.R621X)

      Variant1ClinVarID: 11917

      Variant1CAID: CA256118

      Variant2: c.1861C>T (p.R621X)

      Variant2ClinVarID: 11917

      Variant2CAID: CA256118

      AdditionalVariants: N/A

      ParentalGenotype: Mother and father are both carriers but does not specify for which variants.

      PreviouslyPublished N/A

    1. c.1240_1240delA

      Case#: No additional case information provided

      DiseaseAssertion: N/A

      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.1240_1240delA (p.S414AfsTer26)

      Variant1ClinVarID: N/A

      Variant1CAID: CA645372298

      Variant2: c.614G>A (p.C205X)

      Variant2ClinVarID: 1468875

      Variant2CAID: CA355961928

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished N/A

    2. c.41T > G

      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: Not detectable

      CaseUrineGAGs: N/A

      CaseERT: N/A

      CaseBMT: N/A

      Variant1: c.41T>G (p.L14R)

      Variant1ClinVarID: N/A

      Variant1CAID: CA355945322

      Variant2: c.386-2A>G

      Variant2ClinVarID: 222994

      Variant2CAID: CA356991

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished N/A

    3. To assess the potential utility of these genotype–phenotype relationships, the associations suggested were applied to test cohort derived from a previously published cohort of MPS I patients (Beesley et al., 2001). This study described the variants identified in a cohort of 85 families with MPS I, and identified nine common variants. Phenotypic information was available for a subset of individuals in whom neither or only one variant was a common variant. Up to date genotypes and phenotypic classification was obtained for 31 such individuals in whom both IDUA variants were identified (Clare Beesley, personal communication), and this was used as the test cohort (Supp. Table S5).

      This variant can be found in supp table s5, mentioned from a previous publication (Beesley et al., 2001).

    4. c.506_513delinsGGAA

      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: Not detectable

      CaseUrineGAGs: N/A

      CaseERT: N/A

      CaseBMT: N/A

      Variant1: c.506_513delinsGGAA (p.L169RfsTer24)

      Variant1ClinVarID: N/A

      Variant1CAID: CA645372296

      Variant2: c.506_513delinsGGAA (p.L169RfsTer24)

      Variant2ClinVarID: N/A

      Variant2CAID: CA645372296

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished N/A

    1. P3-IDUAMNorth AfricaMorocco1.774.4IDUAc.1598C > G/wtp.Pro533Arg/wtMissenseHurler/wt

      Case#: P3-IDUA, M, North Africa, Morocco DiseaseAssertion: MPS1 - Hurler/wt FamilyInfo: CasePresentingHPOs: CaseHPOFreeText: CaseNotHPOs: CaseNotHPOFreeText: CaseEnzymeAssay: NBS 1.77 triplex / 4.4 single CaseUrineGAGs: CaseERT: CaseBMT: Variant1: c.1598C>G Variant1ClinVarID: 11910 Variant1CAID: CA256112 Variant2: wt Variant2ClinVarID: Variant2CAID:<br /> AdditionalVariants: ParentalGenotype: PreviouslyPublished

    1. Case#: TW1-1 ID number, Table S1.1 of Supplementary Material. Stored Frozen (-20ºC). Other identifying factors N/A

      DiseaseAssertion: Severe MPS-I

      FamilyInfo: N/A

      CasePresentingHPOs: N/A

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CaseEnzymeAssay: N/A

      CaseUrineGAGs: 301 fmol/punch

      CaseERT: N/A

      CaseBMT: N/A

      Variant1: c.1874A>C (p.Y625S)

      Variant1ClinVarID: 2910181

      Variant1CAID: CA355965961

      Variant2: c.300-3C>G

      Variant2ClinVarID: 551563

      Variant2CAID: CA549265042

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished N/A

    2. Case#: MN-400 ID number, Table S1.1 of Supplementary Material. Female, 1.5 months old (age at diagnosis). Stored frozen (-20ºC) 0.7 yr

      DiseaseAssertion: Severe MPS-I

      FamilyInfo: N/A

      CasePresentingHPOs: N/A

      CaseHPOFreeText: Probable heart features, small curve in the spine

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CaseEnzymeAssay: N/A

      CaseUrineGAGs: 1632 fmol/punch

      CaseERT: N/A

      CaseBMT: N/A

      Variant1: N/A

      Variant1ClinVarID: N/A

      Variant1CAID: N/A

      Variant2: N/A

      Variant2ClinVarID: N/A

      Variant2CAID: N/A

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished N/A

    3. Case#: NY-605 ID number, Table S1.1 of Supplementary Material. Additional health information not provided.

      DiseaseAssertion: Severe MPS-I

      FamilyInfo: N/A

      CasePresentingHPOs: N/A

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CaseEnzymeAssay: N/A

      CaseUrineGAGs: 1412 fmol/punch

      CaseERT: N/A

      CaseBMT: N/A

      Variant1: N/A

      Variant1ClinVarID: N/A

      Variant1CAID: N/A

      Variant2: N/A

      Variant2ClinVarID: N/A

      Variant2CAID: N/A

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished N/A

    4. Case#: NJ-500 ID number, Table S1.1 of Supplementary Material. Male, 1 year and 4 months (age at first symptoms), 1 year and 4 months old (age at diagnosis). Stored ambient 3 yr

      DiseaseAssertion: Severe MPS-I

      FamilyInfo: N/A

      CasePresentingHPOs: Macrocephaly, umbilical hernia, hypertension (HP:0000256, HP:0001537, HP:0000822)

      CaseHPOFreeText: Some heart issues

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CaseEnzymeAssay: N/A

      CaseUrineGAGs: 1343 fmol/punch

      CaseERT: N/A

      CaseBMT: N/A

      Variant1: N/A

      Variant1ClinVarID: N/A

      Variant1CAID: N/A

      Variant2: N/A

      Variant2ClinVarID: N/A

      Variant2CAID: N/A

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished N/A

    1. missense mutations

      Case#: Patient 61, Spain

      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.1475G>C (p.R492P)

      Variant1ClinVarID: 11918

      Variant1CAID: CA256120

      Variant2: N/A

      Variant2ClinVarID: N/A

      Variant2CAID: N/A

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished N/A

    2. distinct mutant IDUA alleles

      Case#: Patient 23, 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

    3. distinct mutant IDUA alleles

      Case#: Patient 92, Turkey, patient belong to the same geographical region as patients 86, 90, and 98

      DiseaseAssertion: MPS1-H/S - S (Unsure what this phenotype means)

      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.494-1G>A

      Variant1ClinVarID: 557942

      Variant1CAID: CA355961634

      Variant2: c.826G>A (p.E276K)

      Variant2ClinVarID: 3233261

      Variant2CAID: CA355962355

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished N/A

    1. Case#: Patient 3, male, 12.2 months (age at HSCT), 8.5 months (age at ERT).

      DiseaseAssertion: MPS1-H

      FamilyInfo: N/A

      CasePresentingHPOs: N/A

      CaseHPOFreeText: RSV pneumonitis, pneumothoraces

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CaseEnzymeAssay: 0.14 (at diagnosis), 49.9 (after HSCT) Units not provided.

      CaseUrineGAGs: N/A

      CaseERT: Yes - 96 days duration

      CaseBMT: Yes - MUD (matched unrelated donor) with stem cells sourcing from the PBSC (peripheral blood stem cells)

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

      Variant1ClinVarID: 11908

      Variant1CAID: CA220498

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

      Variant2ClinVarID: 11908

      Variant2CAID: CA220498

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished N/A

    2. Case#: Patient 7, female, 13.2 months (age at HSCT), 10.2 months (age at ERT).

      DiseaseAssertion: MPS1-H

      FamilyInfo: N/A

      CasePresentingHPOs: N/A

      CaseHPOFreeText: Norovirus gastroenteritis

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CaseEnzymeAssay: 0.09 (at diagnosis), 17.1 (after ERT) Units not provided.

      CaseUrineGAGs: N/A

      CaseERT: Yes - 113 days duration

      CaseBMT: Yes - MUD (matched unrelated donor) with stem cells sourcing from the CB (cord blood)

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

      Variant1ClinVarID: 11908

      Variant1CAID: CA220498

      Variant2: N/A

      Variant2ClinVarID: N/A

      Variant2CAID: N/A

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished N/A

    3. Case#: Patient 4, female, 8.3 months (age at HSCT), 4.5 months (age at ERT).

      DiseaseAssertion: MPS1-H

      FamilyInfo: N/A

      CasePresentingHPOs:

      CaseHPOFreeText: Cy-induced acute cardiomyopathy

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CaseEnzymeAssay: 0.31 (at diagnosis), 15.7 (after HSCT) Units not provided.

      CaseUrineGAGs: N/A

      CaseERT: Yes - 114 days duration

      CaseBMT: Yes - MUD (matched unrelated donor) with stem cells sourcing from the BM (bone marrow).

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

      Variant1ClinVarID: 11909

      Variant1CAID: CA204563

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

      Variant2ClinVarID: 11908

      Variant2CAID: CA220498

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished N/A

    4. Case#: Patient 2, male, 11.5 months (age at HSCT), 9.2 months (age at ERT)

      DiseaseAssertion: MPS1-H

      FamilyInfo: N/A

      CasePresentingHPOs: Renal tubular acidosis (HP:0001947)

      CaseHPOFreeText: Veno occlusive disease (VOD), skin graft-versus-host disease (GVHD)

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CaseEnzymeAssay: 0.22 (at diagnosis), 27.6 (after HSCT) Units not provided.

      CaseUrineGAGs: N/A

      CaseERT: Yes - 64 days duration

      CaseBMT: Yes - MUD (matched unrelated donor) with stem cells sourcing from the CB (cord blood)

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

      Variant1ClinVarID: 11908

      Variant1CAID: CA220498

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

      Variant2ClinVarID: 11908

      Variant2CAID: CA220498

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished N/A

    1. 9/m

      Case#: 9, Male, Han Chinese

      DiseaseAssertion: Hurler Syndrome

      FamilyInfo: Not Provided

      CasePresentingHPOs: HP:0001249, HP:0007957, HP:0001433 (Mental Retardation (severe), Corneal Clouding, Hepatosplenomegaly)

      CaseHPOFreeText: Skeletal Deformities

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CaseEnzymeAssay: 0 Leukocyte IDUA activity (nmol/h/mg protein) (isolated leukocytes in the latter)

      CaseUrineGAGs: N/A

      CaseERT: N/A

      CaseBMT: N/A

      GenotypingMethod: Using the artificial substrate 4-methyl-umbelliferyl α-L-iduronide (Sigma)

      Variant1: c.1190-1G>A

      Variant1ClinVarID: 1204494

      Variant1CAID: CA355963511

      Variant2: c.792+1G>T

      Variant2ClinVarID: N/A

      Variant2CAID: CA355962278

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished N/A

    2. 4/m

      Case#: 4, Male, Han Chinese

      DiseaseAssertion: Hurler Syndrome

      FamilyInfo: Not Provided

      CasePresentingHPOs: HP:0001249, HP:0007957, HP:0001433 (Mental Retardation (severe), Corneal Clouding, Hepatosplenomegaly)

      CaseHPOFreeText: Skeletal Deformities

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CaseEnzymeAssay: 0 Leukocyte IDUA activity (nmol/h/mg protein) (isolated leukocytes in the latter)

      CaseUrineGAGs: N/A

      CaseERT: N/A

      CaseBMT: N/A

      GenotypingMethod: Using the artificial substrate 4-methyl-umbelliferyl α-L-iduronide (Sigma)

      Variant1: c.792+1G>T

      Variant1ClinVarID: N/A

      Variant1CAID: CA355962278

      Variant2: c.792+1G>T

      Variant2ClinVarID: N/A

      Variant2CAID: CA355962278

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished N/A

    1. 16/M

      Case#: 16, Male, Infancy (onset), 2,5 years (diagnosed), 3 years (report), deceased (at 5y)

      DiseaseAssertion: Hurler Syndrome

      FamilyInfo: Not Provided

      CasePresentingHPOs: HP:0000256, HP:0002240, HP:0000158, HP:0000280, HP:0000943, HP:0007957 (Macrocephaly (hydrocephalus), Hepatomegaly (moderate), Large Tongue, Coarse Facial Features, Dysostosis Multiplex, Corneal Clouding)

      CaseHPOFreeText: (Mental Development (Delayed since infancy; developmental quotient 68 at 3y), Mild LV Hypertrophy, Frequent respiratory infections, After ERT: decreased illness (obstructive bronchitis), decreased organomegaly, increased mobility)

      CaseNotHPOs: HP:0004322, HP:0001744 (Short Stature, Splenomegaly)

      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.A327P

      Variant1ClinVarID: 167190

      Variant1CAID: CA234128

      Variant2: c.1727+2T>G (splicing error)

      Variant2ClinVarID: N/A

      Variant2CAID: CA355965300

      AdditionalVariants: p.Q33H

      ParentalGenotype: N/A

      PreviouslyPublished N/A

    2. 5/M

      Case#: 5, Male, 1 year (onset), 3 years (diagnosed), 3 years (report)

      DiseaseAssertion: Hurler Syndrome

      FamilyInfo: Not Provided

      CasePresentingHPOs: HP:0001387, HP:0002240, HP:0001744, HP:0000501, HP:0000280, HP:0000943, HP:0007957 (Joint Stiffness, Hepatomegaly (moderate), Splenomegaly (moderate), Glaucoma, Coarse Facial Features, Dysostosis Multiplex, Corneal Clouding)

      CaseHPOFreeText: Mental Development (delayed since 2y), LV hypertrophy (at 3y)

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CaseEnzymeAssay: N/A

      CaseUrineGAGs: N/A

      CaseERT: N/A

      CaseBMT: N/A

      GenotypingMethod: Not Provided

      Variant1: p.W402X

      Variant1ClinVarID: 11908

      Variant1CAID: CA220498

      Variant2: p.V620F

      Variant2ClinVarID: 1067173

      Variant2CAID: CA355965934

      AdditionalVariants: p.R105Q, p.N181, p.A314, p.T410, p.V454I, p.R489

      ParentalGenotype: N/A

      PreviouslyPublished N/A

    3. 19/F

      Case#: 19, Female, infancy (onset), 3 years (diagnosed), 17 years (report)

      DiseaseAssertion: Hurler Syndrome

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0004322, HP:0001387, HP:0002240, HP:0001744, HP:0001537, HP:0001007, HP:0000158, HP:0000280, HP:0000943, HP:0007957 (Short Stature, Joint Stiffness, Hepatomegaly (severe), Splenomegaly(severe), Umbilical Hernia, Hirsutism, Large Tongue, Coarse Facial Features, Dysostosis Multiplex, Corneal Clouding)

      CaseHPOFreeText: (Mental Development (delayed), Systolic murmur 3/6/combined defect of mitral valve)

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CaseEnzymeAssay: N/A

      CaseUrineGAGs: N/A

      CaseERT: N/A

      CaseBMT: N/A

      GenotypingMethod: Not Provided

      Variant1: p.H539T (fsX21)

      Variant1ClinVarID: N/A

      Variant1CAID: N/A

      Variant2: c.1650+5G>A (splicing error)

      Variant2ClinVarID: 92634

      Variant2CAID: CA220504

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

      ParentalGenotype: N/A

      PreviouslyPublished N/A

    1. MPS I_Case 02

      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.

    1. PKMPS1P7

      Case#: PKMPS1P7, 10 months old (age at presentation), 2.4 years old (age at report), male, Pakastani. He underwent ventriculoperitoneal shunting at the age of 18 months due to significant hydrocephalus.

      DiseaseAssertion: MPS-I

      FamilyInfo: Parents had a consanguineous marriage

      CasePresentingHPOs: Coarse facial features, macrocephaly, rhinorrhea, hydrocephalus, mild to moderate developmental delay, umbilical hernia (HP:0000256, HP:0000256, HP:0031417, HP:0000238, HP:0001263, HP:0001537)

      CaseHPOFreeText: Poor growth potential, widening of the wrist and elbow. The abdomen was distended. The liver span was 3 cm.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CaseEnzymeAssay: N/A

      CaseUrineGAGs: N/A

      CaseERT: N/A

      CaseBMT: N/A

      Variant1: c.784delC (p.H262Tfs*55)

      Variant1ClinVarID: 956890

      Variant1CAID: CA2802083

      Variant2: c.784delC (p.H262Tfs*55)

      Variant2ClinVarID: 956890

      Variant2CAID: CA2802083

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished N/A

    2. PKMPS1P12

      Case#: PKMPS1P12, 2.6 years old (age at presentation), male, Pakastani

      DiseaseAssertion: MPS-I

      FamilyInfo: Born to a non-consanguineous couple

      CasePresentingHPOs: Significant developmental delay, stridor, coarse facial features, recurrent chest infections, umbilical hernia, corneal clouding (HP:0001263, HP:0010307, HP:0000256, HP:0002783, HP:0001537, HP:0007957)

      CaseHPOFreeText: Running nose, skeletal stigmata were consistent with MPS1, and a liver span on 3 cm.

      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

    1. Case#: Patient W3, 10 years old, Chinese. The patient had normal intelligence based on their performance in school.

      DiseaseAssertion: MPS1-H/S

      FamilyInfo: Patient received the p.M1I mutation from their mother and received the p.Y343X from their father.

      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: Expression of Y343X in COS-7 cells showed retention of a very low level of IDUA activity

      CaseUrineGAGs: N/A

      CaseERT: N/A

      CaseBMT: N/A

      Variant1: c.3G>A (p.M1I)

      Variant1ClinVarID: 557150

      Variant1CAID: CA355945212

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

      Variant2ClinVarID: 222997

      Variant2CAID: CA356984

      AdditionalVariants: The patient has one IDUA allele with the variant c.3G>A (p.M1I) and an in frame deletion of the whole of exon 2, whereas the other allele has Y343X (an in frame deletion of nucleotides 1061-1117 in exon 8).

      ParentalGenotype: Maternal - p.M1I, Paternal - p.Y343X

      PreviouslyPublished N/A

    1. two boys

      Case#: Boy 3, male, 5 years old, born of normal pregnancy with a birth weight of 3,200 grams

      DiseaseAssertion: MPS-I H/S

      FamilyInfo: Boy 1 was born to a Chinese family of five members, with a total of 3 boys. Genetic testing was conducted on all 5 family members. The first and third child (boy 1 and boy 3) have MPS I. The second son had a normal phenotype and genotype.

      CasePresentingHPOs: N/A

      CaseHPOFreeText: Lesions (similar to elder brother; noted at 3 years old)

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CaseEnzymeAssay: 3.29 nmol/h/mg (reference range >21)

      CaseUrineGAGs: Positive for urinary polysaccharide toluidine blue staining test

      CaseERT: N/A

      CaseBMT: N/A

      Variant1: c.265C>T (p.R89W)

      Variant1ClinVarID: 580286

      Variant1CAID: CA2801156

      Variant2: c.1633G>T (p.E545X)

      Variant2ClinVarID: N/A

      Variant2CAID: CA355965099

      AdditionalVariants: N/A

      ParentalGenotype: Mother carries c.265C>T and father carries c.1633G>T.

      PreviouslyPublished N/A

    1. Hurler

      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: 0.2 ± 0.1 nmol/mg/h IDUA activity at 37 °C

      CaseUrineGAGs: N/A

      CaseERT: N/A

      CaseBMT: N/A

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

      Variant1ClinVarID: 11909

      Variant1CAID: CA204563

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

      ClinVarID: 11909

      Variant2CAID: CA204563

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished N/A

    2. Scheie

      Case#: 0.3% residual activity at 37 °C

      DiseaseAssertion: MPS1-S

      FamilyInfo: N/A

      CasePresentingHPOs: N/A

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CaseEnzymeAssay: 0.8 ± 0.1 nmol/mg/h IDUA activity at 37 °C

      CaseUrineGAGs: N/A

      CaseERT: N/A

      CaseBMT: N/A

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

      Variant1ClinVarID: 167190

      Variant1CAID: CA234128

      Variant2: c.1148G>A (p.R383H)

      ClinVarID: 558189

      Variant2CAID: CA2802205

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished N/A

    1. 3.3.1. Severe patients There were 115 individual genotypes represented in the 380 patients with a severe phenotype and two reported alleles; 31 genotypes were recurrent and 84 genotypes unique (Table 3). The most common genotypes in severe patients were W402X/W402X (109/380; 28.7%), W402X/Q70X (61/380; 16.1%) and Q70X/Q70X (24/380; 6.3%). In total, these two nonsense variants defined the genotypes of 51% (194/380) of severe patients. Of severe patients, 67.6% (257/380) were either homozygous or compound heterozygous for two variants predicted to severely disrupt gene transcription or translation (eg, nonsense variants, frameshifts, consensus splice site disruption or initiator codon variants). No clinically diagnosed attenuated patients were homozygous or compound heterozygous for such variants. Of the remaining 123 severe patients, 76 comprised 19 recurrent genotypes (Table 3) with the remaining 47 patients (12.6%) having unique genotypes (listed in Table S1). Thirty‐seven of the 84 unique genotypes identified in severe patients were compound heterozygous with two severe variants (as defined above) and were comprised of 34 separate severe variants (listed in Table S1). There were nine missense recurrent variants and one intronic recurrent variant that were exclusively seen in severe patients (Table 5A).

      Case#: Severe MPS1 patients

      DiseaseAssertion: Severe MPS I

      FamilyInfo: n/a, "neither the laboratory method used to determine the sequence variants nor whether parental testing confirmed the inheritance or phase of the variants is captured by the Registry"

      CasePresentingHPOs:

      CaseHPOFreeText: "All patients enrolled in the Registry have confirmation of MPS I diagnosis by either mutation analysis or measurement of IDUA levels."

      CaseNotHPOs:

      CaseNotHPOFreeText:

      CasePreviousTesting: n/a

      GenotypingMethod: n/a

      PreviouslyPublished: possible since this is a multinational registry

      Variant: c.1403-1G>T/c.1728-1G>C

      ClinVar: 556064

      CAID: CA355965306

      SupplementalData: Table S1 has the genotypes listed

    2. 3.3.1. Severe patients There were 115 individual genotypes represented in the 380 patients with a severe phenotype and two reported alleles; 31 genotypes were recurrent and 84 genotypes unique (Table 3). The most common genotypes in severe patients were W402X/W402X (109/380; 28.7%), W402X/Q70X (61/380; 16.1%) and Q70X/Q70X (24/380; 6.3%). In total, these two nonsense variants defined the genotypes of 51% (194/380) of severe patients. Of severe patients, 67.6% (257/380) were either homozygous or compound heterozygous for two variants predicted to severely disrupt gene transcription or translation (eg, nonsense variants, frameshifts, consensus splice site disruption or initiator codon variants). No clinically diagnosed attenuated patients were homozygous or compound heterozygous for such variants. Of the remaining 123 severe patients, 76 comprised 19 recurrent genotypes (Table 3) with the remaining 47 patients (12.6%) having unique genotypes (listed in Table S1). Thirty‐seven of the 84 unique genotypes identified in severe patients were compound heterozygous with two severe variants (as defined above) and were comprised of 34 separate severe variants (listed in Table S1). There were nine missense recurrent variants and one intronic recurrent variant that were exclusively seen in severe patients (Table 5A).

      Case#: Severe MPS1 patients

      DiseaseAssertion: Severe MPS I

      FamilyInfo: n/a, "neither the laboratory method used to determine the sequence variants nor whether parental testing confirmed the inheritance or phase of the variants is captured by the Registry"

      CasePresentingHPOs:

      CaseHPOFreeText: "All patients enrolled in the Registry have confirmation of MPS I diagnosis by either mutation analysis or measurement of IDUA levels."

      CaseNotHPOs:

      CaseNotHPOFreeText:

      CasePreviousTesting: n/a

      GenotypingMethod: n/a

      PreviouslyPublished: possible since this is a multinational registry

      Variant: c.1728-1G>C/W402X

      ClinVar: 556064

      CAID: CA355965306

      SupplementalData: Table S1 has the genotypes listed

    3. 3.3.1. Severe patients There were 115 individual genotypes represented in the 380 patients with a severe phenotype and two reported alleles; 31 genotypes were recurrent and 84 genotypes unique (Table 3). The most common genotypes in severe patients were W402X/W402X (109/380; 28.7%), W402X/Q70X (61/380; 16.1%) and Q70X/Q70X (24/380; 6.3%). In total, these two nonsense variants defined the genotypes of 51% (194/380) of severe patients. Of severe patients, 67.6% (257/380) were either homozygous or compound heterozygous for two variants predicted to severely disrupt gene transcription or translation (eg, nonsense variants, frameshifts, consensus splice site disruption or initiator codon variants). No clinically diagnosed attenuated patients were homozygous or compound heterozygous for such variants. Of the remaining 123 severe patients, 76 comprised 19 recurrent genotypes (Table 3) with the remaining 47 patients (12.6%) having unique genotypes (listed in Table S1). Thirty‐seven of the 84 unique genotypes identified in severe patients were compound heterozygous with two severe variants (as defined above) and were comprised of 34 separate severe variants (listed in Table S1). There were nine missense recurrent variants and one intronic recurrent variant that were exclusively seen in severe patients (Table 5A).

      Case#: Severe MPS1 patients

      DiseaseAssertion: Severe MPS I

      FamilyInfo: n/a, "neither the laboratory method used to determine the sequence variants nor whether parental testing confirmed the inheritance or phase of the variants is captured by the Registry"

      CasePresentingHPOs:

      CaseHPOFreeText: "All patients enrolled in the Registry have confirmation of MPS I diagnosis by either mutation analysis or measurement of IDUA levels."

      CaseNotHPOs:

      CaseNotHPOFreeText:

      CasePreviousTesting: n/a

      GenotypingMethod: n/a

      PreviouslyPublished: possible since this is a multinational registry

      Variant: Q70X/Y343X

      ClinVar: 222997

      CAID: CA356984

      SupplementalData: Table S1 has the genotypes listed

    1. 263

      Case#: Patient 26 (see Table 2), 40 weeks (Gestational age)

      DiseaseAssertion: MPS1-S

      FamilyInfo: Sibling of Patient 25 (see Table 2)

      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.1148G>A (p.R383H)

      Variant2ClinVarID: 558189

      Variant2CAID: CA:2802205

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished N/A

    2. 17

      Case#: Patient 17 (see Table 2), 40 weeks (Gestational age)

      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.1205G>A (p.W402X)

      Variant1ClinVarID: 11908

      Variant1CAID: CA220498

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

      Variant2ClinVarID: 11908

      Variant2CAID: CA220498

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished N/A

    1. 6

      Case#: Patient 6 was biochemically diagnosed with MPS I because they showed an increase in urinary GAGs and a reduction in IDUA activity in leukocytes. Patient 6 was diagnosed at 1 year.

      DiseaseAssertion: MPSI-H/S

      FamilyInfo: N/A

      CasePresentingHPOs: Coarse facies, corneal clouding, hernias, intellectual disability, skeletal abnormalities, cardiac abnormalities, and hepatosplenomegaly (HP:0000256, HP:0007957, HP:0100790, HP:0001249, HP:0002360, HP:0001627, HP:0001433)

      CaseHPOFreeText: N/A

      CaseNotHPOs: Growth delay (HP:0001510)

      CaseNotHPOFreeText: N/A

      CaseEnzymeAssay: IDUA activity of 1.78 nmol/mg/protein/hr. No reference range provided.

      CaseUrineGAGs: 2517.8 CPC unit/g creatinine. No reference range provided.

      CaseERT: N/A

      CaseBMT: N/A

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

      Variant1ClinVarID: 496861

      Variant1CAID: CA2802275

      Variant2: c.1854C>A (p.Y618X)

      Variant2ClinVarID: 554826

      Variant2CAID: CA355965929

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished N/A

    1. 4F41.23.3

      Case#:Patient Sample unique ID 2

      DiseaseAssertion:MPS type I-Hurler children

      FamilyInfo:None

      CasePresentingHPOs:None

      CaseHPOFreeText:None

      CaseNotHPOs:Obstructive sleep apnea, HP:0002870

      CaseNotHPOFreeText:None

      CaseEnzymeAssay:None

      CaseUrineGAGs: Tested but amounts not reported

      CaseERT:No

      CaseBMT:Hematopoietic stem cell transplantation

      Variant1:c.208C>T

      Variant1ClinVarID:11909

      Variant1CAID:CA204563

      Variant2:c.1413C>G

      Variant2ClinVarID:1094781

      Variant2CAID:CA417702021

      AdditionalVariants:None

      ParentalGenotype:None provided

      PreviouslyPublished:N/A

    1. Table 2.

      Case#:Not assigned

      DiseaseAssertion:MPS type I with evidence of cognitive impairment defined as a score of at least 1 SD below mean on IQ testing or in one domain of neuropsychological function; attenuated MPS I

      FamilyInfo:No information

      CasePresentingHPOs:HP:0100543

      CaseHPOFreeText:

      CaseNotHPOs:HP:0032557

      CaseNotHPOFreeText:Subjects were excluded if they had undergone hematopoietic stem cell transplantation, were unable to comply with study procedures, had significant lumbar pathology precluding access to the intrathecal space via lumbar puncture, or significantly impaired spinal CSF flow as detected on a nuclear medicine flow study as part of screening.

      CaseEnzymeAssay:No information

      CaseUrineGAGs:No information

      CaseERT:Yes

      CaseBMT:No (exclusion criterion)

      Variant1:Q70X

      Variant1ClinVarID:

      Variant1CAID:

      Variant2:Q380R

      Variant2ClinVarID:550799

      Variant2CAID:

      AdditionalVariants:N/A

      ParentalGenotype:Not specified

      PreviouslyPublished

    1. T141S in exon 4, and IVS2+6c>t

      Case#: Patient 3, Egyptian, female, 3 years old

      DiseaseAssertion: MPS1-H

      FamilyInfo: Parents were nonconsanguineous

      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.421A>T (p.T141S)

      Variant1ClinVarID: N/A

      Variant1CAID: CA355961378

      Variant2: c.299+6C>T (in the paper the variant is labeled as c.IVS2+6C>T which is old nomenclature)

      Variant2ClinVarID: 92640

      Variant2CAID: CA145880

      AdditionalVariants: A8A, A20A, N297N, IVS11 (3318)C>A, IVS10 (3122)T>C - these are not the current nomenclatures for these variants but they are identified as polymorphisms in the article

      ParentalGenotype: All mutations were confirmed in the parental DNA

      PreviouslyPublished N/A

    1. P10

      Case#: P10, Female, 11.4 years (diagnosed), 15.8 (report), 31 kg (weight), 131 cm (height), Algerian

      DiseaseAssertion: Hurler-Scheie Syndrome

      FamilyInfo: Parents are consanguineous

      CasePresentingHPOs: HP:0001249, HP:0001999, HP:0000943, HP:0001387, HP:0001433, HP:0001387, HP:0000365, HP:0007957, HP:0000238 (Mental Retardation, Facial Dysmorphic Features, Multiple Dysostosis, Joint Stiffness, Hepatosplenomegaly, Hernia(Ombelical), Deafness(perceptive), Corneal Opacity, Hydrocephalus)

      CaseHPOFreeText: Chronic Rhinorrhea, Cardiac Manifestations(Mitral Stenosis)

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

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

      CaseUrineGAGs: GAG quantitation 46 (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

    2. P13

      Case#: P13, Female, 2.7 years (diagnosed), 5.1 (report), 18 kg (weight), 96 cm (height), Algerian

      DiseaseAssertion: Hurler Syndrome

      FamilyInfo: Parents are not consanguineous

      CasePresentingHPOs: HP:0001249, HP:0001999, HP:0000943, HP:0001387, HP:0002240, HP:0001387, HP:0007957, HP:0000238 (Mental Retardation, Facial Dysmorphic Features, Multiple Dysostosis, Joint Stiffness, Hepatomegaly, Hernia(Ombelical), Corneal Opacity, Hydrocephalus)

      CaseHPOFreeText: Chronic Rhinorrhea

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: Cardiac Manifestations

      CaseEnzymeAssay: IDUA Enzyme activity 2 (% to the reference range mean)

      CaseUrineGAGs: GAG quantitation 19.6 (fold change to the reference range mean according to age)

      CaseERT: N/A

      CaseBMT: N/A

      GenotypingMethod: Direct DNA Fragments Sequencing

      Variant1: c.501C>G (p.Tyr167*)

      Variant1ClinVarID: 92644

      Variant1CAID: CA220511

      Variant2: c.501C>G (p.Tyr167*)

      Variant2ClinVarID: 92644

      Variant2CAID: CA220511

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished N/A

    1. Patients of family B

      Case#: Family B proband, male, 1 year and 4 months old (age of onset), 3 years old (age at report), Tunisia.

      DiseaseAssertion: MPS1-H

      FamilyInfo: Three affected maternal cousins (one of them, 13 years old, was followed for convulsing encephalopathy and infirmity matrix, the other cousin, 3 years old, was followed in the same Pediatric Unit for encephalopathy). Parents were 2nd degree relatives (second cousins) (See Table 1).

      CasePresentingHPOs: HP:0000256, HP:0001433, HP:0001263, HP:0002463, HP:0000470, HP:0000687, HP:0030812, HP:0000158, HP:0012471, HP:0001513 (Macrocephaly, hepatosplenomegaly, global developmental delay, language impairment, short neck, widely spaced teeth, enlarged tonsils, macroglossia, thick lips, obesity)

      CaseHPOFreeText: Short trunk

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CaseEnzymeAssay: IDUA activity (0.08 nmol/h/mg) (usual values: 1-5).

      CaseUrineGAGs: Glycosaminoglycans (120 mg/g of creatinine) (usual values: 9-46), abnormal electrophoresis profile with dermatan sulfate and heparan sulfate.

      CaseERT: No

      CaseBMT: No

      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

    1. 730.248 (3.0)9.6DS 3.3heterozygous VUS: c.1744G>A; p.E582KNormal examinationHS 4.9heterozygous PD: c.235G>A; p.A79Theterozygous PD: c.296C>T; p.T99I

      Case#:Patient Sample unique ID 73, Infant screened positive at birth (specimens with activity ≤15% of the DMA for enzyme activity and a CLIR screening algorithm result of indeterminate or MPS I)

      DiseaseAssertion:None

      FamilyInfo:None

      CasePresentingHPOs:None

      CaseHPOFreeText:None

      CaseNotHPOs:None

      CaseNotHPOFreeText: Normal examination at follow up after screening positive at birth (specimens with activity ≤15% of the DMA for enzyme activity and a CLIR screening algorithm result of indeterminate or MPS I)

      CaseEnzymeAssay: IDUA activity 0.248 (3.0) umol/L/h (%DMA) during new born screening through dried blood spot (plasma) and 9.6 pmol/punch/h Confirmatory IDUA enzyme

      CaseUrineGAGs: DS 3.3 g/mol creatinine and HS 4.9 g/mol creatinine (Normal)

      CaseERT:No

      CaseBMT:No

      Variant1:heterozygous VUS: c.1744G>A; p.E582K (Normal examination)

      Variant1ClinVarID:538474

      Variant1CAID:CA1944440

      Variant2:heterozygous PD: c.235G>A; p.A79T

      Variant2ClinVarID:41682

      Variant2CAID:CA000358

      AdditionalVariants:heterozygous PD: c.296C>T; p.T99I (ClinVarID:53610, CAID:CA326991)

      ParentalGenotype:None provided

      PreviouslyPublished:N/A

    2. 530.351 (4.2)6.9DS 4.6heterozygous PD: c.235G>A; p.A79TNormal examinationHS 3.3heterozygous PD: c.667G>A; p.D223N

      Case#:Patient Sample unique ID 53, Infant screened positive at birth (specimens with activity ≤15% of the DMA for enzyme activity and a CLIR screening algorithm result of indeterminate or MPS I)

      DiseaseAssertion:None

      FamilyInfo:None

      CasePresentingHPOs:None

      CaseHPOFreeText:None

      CaseNotHPOs:None

      CaseNotHPOFreeText: Normal examination at follow up after screening positive at birth (specimens with activity ≤15% of the DMA for enzyme activity and a CLIR screening algorithm result of indeterminate or MPS I)

      CaseEnzymeAssay: IDUA activity 0.351 (4.2) umol/L/h (%DMA) during new born screening through dried blood spot (plasma) and 6.9 pmol/punch/h Confirmatory IDUA enzyme

      CaseUrineGAGs: DS 4.6 g/mol creatinine and HS 3.3 g/mol creatinine (Normal)

      CaseERT:No

      CaseBMT:No

      Variant1:heterozygous PD: c.235G>A; p.A79T (Normal examination)

      Variant1ClinVarID:41682

      Variant1CAID:CA000358

      Variant2:heterozygous PD: c.667G>A; p.D223N

      Variant2ClinVarID:2220838

      Variant2CAID:CA363422841

      AdditionalVariants: None

      ParentalGenotype:None provided

      PreviouslyPublished:N/A

    1. patient

      Case#: 20 months old, Male, 78 cm of height (-3 S.D.), 10 kg of weight (-3 S.D.), head circumference of 50.5 cm (>90th percentile).

      DiseaseAssertion: Severe MPS-I

      FamilyInfo: First son of healthy non-consanguineous parents with an unremarkable family history.

      CasePresentingHPOs: Snoring, noisy breathing (since 3 months old), sleep apnea, upper airway obstruction, breathing cessation, cyanosis, facial dysmorphic features, short stature (since 8 months old), coarse facial features, scaphocephaly, mild corneal clouding, depressed nasal bridge, wide nose, anteverted nares, nasal congestion, long philtrum, thick lips, small and spaced teeth, low set ears, short neck, gibbus deformity, umbilical hernia, claw hands, global developmental delay, frontal bossing, Mongolia spots, dysostosis multiplex, scoliosis, broad ribs bilaterally (HP:0025267, HP:0010307, HP:0010535, HP:0002781, HP:0005943, HP:0000961, HP:0001999, HP:0004322, HP:0000256, HP:0030799, HP:0007957, HP:0005280, HP:0000445, HP:0000463, HP:0001742, HP:0000343, HP:0000219, HP:0000687, HP:0000369, HP:0000470, HP:0002808, HP:0001537, HP:0034337, HP:0001263, HP:0002007, HP:0011369, HP:0000943, HP:0002650, HP:0000885)

      CaseHPOFreeText: Had neonatal complications such as being late in crying and breathing. Hyporeactive Apgar 5/8 Silverman-Anderson 3/2. Upper airway infections, bulging frontal bone, enlarged tongue, short trunk, protruding abdomen. The liver edge was palpated 2 cm below the right costal margin and had blue cutaneous pigmentation with dorsal distribution. Limited extension of the arms and small joints. No ability to walk or speak at the age of 20 months. Lumbar gibbus with vertebral hypoplasia. Hand bullet-shaped phalanges and widened metacarpals pointed proximally. Widened diaphysis and cortical thinning of long bones. Pelvis with rounded or flared iliac wings.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CaseEnzymeAssay: IDUA activity of 0.24 μmol/L/h, enzymatic IDUA activity was 10 times less than the reference minimum level of this enzyme (2.02–16.10 μmol/L/h).

      CaseUrineGAGs: N/A

      CaseERT: Yes - at 2 years of age

      CaseBMT: N/A

      Variant1: c.1898C>G (p.S633W)

      Variant1ClinVarID: 286242

      Variant1CAID: CA10605410

      Variant2: c.1898C>G (p.S633W)

      Variant2ClinVarID: 286242

      Variant2CAID: CA10605410

      AdditionalVariants: N/A

      ParentalGenotype: Sequence analysis of parental genomic DNA showed that both parents are heterozygous for c.1898C>G variant, with no clinical phenotype of MPS I. Enzymatic IDUA activity was 1.29 μmol/L/h and 3.25 μmol/L/h for the father and the mother, respectively. These levels were 5.4 and 13.5 higher than the ones observed in the patient, respectively. The low enzyme activity observed in the father, which would be expected to be greater because he is a heterozygous with a normal allele, could be explained by a condition known as pseudodeficiency, in which clinically normal individuals shows levels of enzyme activity below the normal levels.

      PreviouslyPublished N/A

    1. 1

      Case#: Patient 1: Enrolled in study at 18 years, male, onset at 3 years, diagnosed at 14.8 years, ERT started 16.7 years DiseaseAssertion:MPS1 H-S FamilyInfo:Consanguinity Yes CasePresentingHPOs:Corneal opacity (HP:0007957), Joint stiffness (HP:0001387), CaseHPOFreeText: CaseNotHPOs: Hepatosplenomegaly (HP:0001433), Macrocephaly (HP:0000256) CaseNotHPOFreeText: CaseEnzymeAssay: CaseUrineGAGs: 1.07(min)-3.08(max) mg GAG/mmol creatinine while on ERT CaseERT: Laronidase dose-optimization trial : standard regimen – 0.58 mg/kg/week; biweekly regimen – 1.2 mg/kg every two weeks CaseBMT:Nil Variant1:P533R Variant1ClinVarID:11910 Variant1CAID:CA256112 Variant2:P533R Variant2ClinVarID:11910 Variant2CAID:CA256112 AdditionalVariants:Nil ParentalGenotype:NA PreviouslyPublishedNA

    1. Patient 1

      Case#:2.2 year female, diagnosed at 0.9 years DiseaseAssertion:MPS1H FamilyInfo:NA CasePresentingHPOs:NA CaseHPOFreeText:NA CaseNotHPOs:NA CaseNotHPOFreeText:NA CaseEnzymeAssay:Undetectable CaseUrineGAGs:NA CaseERT:NA CaseBMT:Yes, Unrelated cord blood, Post HSCT <br /> 29.3 nmol/h/mg of protein ( α-l-Iduronidase Levels) Variant1:IDUA : c.457A>T Variant1ClinVarID:917689 Variant1CAID: Variant2:IDUA: c.1205G>A Variant2ClinVarID: 11908 Variant2CAID:CA220498 AdditionalVariants: ParentalGenotype: PreviouslyPublished

    1. 12 base pairs

      Case#: One patient from Norway

      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.134del12 (p.Arg45ProfsTer?)

      Variant1ClinVarID: N/A

      Variant1CAID: CA3064219537

      Variant2: c.134del12 (p.Arg45ProfsTer?)

      Variant2ClinVarID: N/A

      Variant2CAID: CA3064219537

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished N/A

    2. 1 nonsense mutation

      Case#: One patient whose country of origin is not identifiable.

      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.1861C>T (p.R621X)

      Variant1ClinVarID: 11917

      Variant1CAID: CA256118

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

      Variant2ClinVarID: 11908

      Variant2CAID: CA220498

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished N/A

    1. 6

      Case#: Patient 6 (see Table 2), male, 16.7 years old (age at report), 10.4 years (duration of treatment), 4 surgeries

      DiseaseAssertion: MPS1-HS

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0002360 (Sleep abnormality)

      CaseHPOFreeText: Psychiatric problems

      CaseNotHPOs: HP:0000238, HP:0002176 (Hydrocephalus, spinal cord compression)

      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: (Int3-2a>g) Current HGVS nomenclature is c.386-2A>G.

      Variant2ClinVarID: 222994

      Variant2CAID: CA356991

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished N/A

    1. 10 MPS I patients

      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.1918_1927del p.E640Cfs

      Variant2ClinVarID: N/A

      Variant2CAID: CA2586965997

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished N/A

    1. Two other IDUA mutations occurred in CpG dinucleotides (678 G→A and Y202X) and were found in the same patient, along with M133I. The analysis of parental DNA showed that the mutation M133I was linked to the Y202X mutation in the father whereas the other mutation (678 G→A) was maternally inherited. The 678 G→A mutation, a transition in the first base of intron 6, is also a splice site mutation that would cause the change of a glycine to an aspartic acid in position 196 of the protein. However, since skin fibroblasts from this patient were not available, it was not known whether mutant mRNA coding for the G197D α-l-iduronidase was produced. Therefore, this IDUA change was considered only as a splice mutation and was not expressed in CHO-K1 cells.

      Case#: Patient #19, Brazilian

      DiseaseAssertion: MPS1, severe(Hurler)

      FamilyInfo: n/a

      CasePresentingHPOs:

      CaseHPOFreeText: underwent bone marrow transplant

      CaseNotHPOs:

      CaseNotHPOFreeText:

      Genotyping Method: Patients were screened for 10 known mutations using PCR and restriction enzymes and all 14 exons of the IDUA gene were amplified and analyzed by single strand conformational polymorphism (SSCP) analysis. PCRs were performed and sequenced using the big dye terminator kit and an ABI 373 automated sequencer (Applied Biosystems). Mutations were confirmed by sequencing the reverse strand using the same method.

      PreviouslyPublished: n/a

      Variant: allele 1: M133I/ Y202X (father); allele 2: 678 G→A (mother)

      other changes: A8, A20, Q33H, L118

      ClinVar: CA355961907

    1. 7

      Case#: Patient 7 (see Table 1), 13 years old (age at report), 5 years old (age at onset), female, height of 110 cm, weight of 15 kg, location at Djerba: Land

      DiseaseAssertion: MPS1 - intermediate

      FamilyInfo: One affected siblings (Patient 6), parents were 1st cousins (see Table 2), parents have the same grandfather but with a different wife (see Table 4), aged 40 yrs (M) and 49 yrs (F).

      CasePresentingHPOs: HP:0004322, HP:0001999 (Short stature, moderate facial dysmorphia)

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CaseEnzymeAssay: N/A

      CaseUrineGAGs: N/A

      CaseERT: N/A

      CaseBMT: N/A

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

      Variant1ClinVarID: 11910

      Variant1CAID: CA:256112

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

      Variant2ClinVarID: 11910

      Variant2CAID: CA:256112

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished N/A

    1. 4/f

      Case#: Patient 4, female, 10.9 months (age at diagnosis), 16.5 months (age at HSCT), 8.3 - 17.3 months (age at ERT), 7 MRI + neuropsychological observations over the course of 11 years.

      DiseaseAssertion: MPS-1H

      FamilyInfo: N/A

      CasePresentingHPOs: N/A

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CaseEnzymeAssay: 67.7 nmol/h/mg (Normal values: 11-43 nmol/h/mg)

      CaseUrineGAGs: N/A

      CaseERT: Yes

      CaseBMT: Yes

      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

    1. case 2

      Case#: Case 2, male, 5 years old (age at diagnosis).

      DiseaseAssertion: MPS1

      FamilyInfo: Proband's mother was pregnant and her genomic DNA was extracted from cultured amniocytes, her fetus acquired the same pathogenic gene as the proband and was affected.

      CasePresentingHPOs: N/A

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CaseEnzymeAssay: Proband was diagnosed using enzymatic detection. IDUA enzyme activity in the mother's amniotic fluid cells in the 2nd pregnancy was 0.5 nmol/(h·mg protein).

      CaseUrineGAGs: N/A

      CaseERT: N/A

      CaseBMT: N/A

      Variant1: c.530dupT, in the article this is written as c.531insT (old nomenclature). Various variants from Wang articles have nomenclature errors that are 1 base pair off from the described variant.

      Variant1ClinVarID: N/A

      Variant1CAID: CA2586973520

      Variant2: c.1037T>G (p.Leu346Arg)

      Variant2ClinVarID: 11927

      Variant2CAID: CA256128

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished N/A

    1. Case#: Patient 10, 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.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

    1. 3/F

      Case#: Patient 3, female, Russian

      DiseaseAssertion: MPS1-H

      FamilyInfo: N/A

      CasePresentingHPOs: Severe intellectual disability, corneal clouding, skeletal deformities, hepatosplenomegaly (HP:0010864, HP:0007957, HP:0000924, HP:0001433)

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CaseEnzymeAssay: 0.05 nmol/mg/h (reference range 135 ± 57 nmol/mg/h)

      CaseUrineGAGs: 265.24 mg GAG/mmol/creatinine (reference range 6.17 ± 3.79 mg GAG/mmol creatinine)

      CaseERT: No

      CaseBMT: No

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

      Variant1ClinVarID: 11909

      Variant1CAID: CA204563

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

      Variant2ClinVarID: 11909

      Variant2CAID: CA204563

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished N/A

    1. 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

    1. 1

      Case#: Subject 1, female, in her 30s (age at enrollment), died during extension study from pneumonia and respiratory failure sixty-five days after her first dose in the extension study.

      DiseaseAssertion: MPS1-HS

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0002093, HP:0002540, HP:0002090, HP:0002176 (Chronic respiratory insufficiency, inability to walk, pneumonia, spinal cord compression)

      CaseHPOFreeText: Hemidiaphragmatic paralysis, improved strength and range of motion

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CaseEnzymeAssay: N/A

      CaseUrineGAGs: N/A

      CaseERT: Yes - Enzyme replacement therapy with laronidase

      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

    1. the patient (II‐2)

      Case#: II-2, Female, 2 years (onset), Chinese

      DiseaseAssertion: MPS 1

      FamilyInfo: I-1 and I-2 are the parents, II-4 is a full sibling of II-2 and a full child of I-1 and I-2. II-4 also carries the disease. (pedigree is figure # 1).

      CasePresentingHPOs: HP:0001367, HP:0000622, HP:0007663, HP:0001718, HP:0001643, HP:0001698, HP:0000238, (Abnormal joints, Blurred vision, Decreased vision, Mitral stenosis (severe), Patent ductus arteriosus (tubular), Pericardial effusion (moderate), Hydrocephalus)

      CaseHPOFreeText: Abnormal mitral valve development, Anterior mitral valve prolapses and insufficiency (moderate), Pulmonary hypertension (moderate), Bilateral temporal arachnoid cyst, Congenital spinal stenosis, Congenital glaucoma, Corneal gray degeneration, Corneal staphyloma

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CaseEnzymeAssay: N/A

      CaseUrineGAGs: N/A

      CaseERT: N/A

      CaseBMT: N/A

      GenotypingMethod: Sanger Sequencing

      Variant1: c.1037T>G

      Variant1ClinVarID: 11927

      Variant1CAID: CA256128

      Variant2: c.18115dupT

      Variant2ClinVarID: 1454082

      Variant2CAID: CA2573137507

      AdditionalVariants: N/A

      ParentalGenotype: N/A

      PreviouslyPublished: N/A