Case#: Patient F, female, 25 years old (age at report), 61 kg of weight (50th percentile), height of 154 cm (10th percentile). She is now working as an office secretary and also practices aerobic activity three times a week. She drives a car autonomously with her driving license which is renewed every 2 years. Her quality of life was measured with EQ-5D-Y and resulted good (100/100). Overall cognitive abilities are in the lower average expected for age (IQ:80), with difficulties in executive functioning, working memory, and arithmetic reasoning.

DiseaseAssertion: attenuated form of MPS-1

FamilyInfo: Affected younger sibling (Patient M), born to non-consanguineous Italian parents.

CasePresentingHPOs: Moderate facial coarseness, moderately severe dysostosis multiplex, scoliosis, hyperlordosis, genua valga, corneal clouding, hyperopia, astigmatism, otitis media (completely corrected by eyeglasses), hearing impairment, mild obstructive sleep apnea (since 16 years old), mild thickened skin (HP:0000280, HP:0000943, HP:0002650, HP:0003307, HP:0002857, HP:0007957, HP:0000540, HP:0000483, HP:0000388, HP:0000365, HP:0010535, HP:0001072)

CaseHPOFreeText: Liver and spleen volumes were normalized within the first year of ERT and remained within normal limits at clinical examination, claw feet, stiffness of the tibio-tarsal joint, ROM of hip and knees were within the normal ranges, improved stiffness of the trunk, movements of shoulders, elbows and wrists were within the normal range, limited flexion of fingers due to mild rigidity, normal cerebral MRI, a mild–moderate tricuspid insufficiency with pulmonary artery pressure (PAP) within the upper normal range (25 mmHG) was reported (at 16 years old), cardiac involvement.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: Total urinary GAG excretion was slightly above the upper limit of the normal range (47 μg/mg creatinine with normal values < 26) with the qualitative assay showing a band of DS.

CaseERT: Yes - Began ERT and 5 years old. Laronidase infusions were started delivering weekly (at the dose of 0.5 mg/kg) using implanted venous access devices. Laronidase infusion generally lasted approximately 4 h, without the need for any premedication.

CaseBMT: N/A

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

Variant1ClinVarID: 11908

Variant1CAID: CA220498

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

Variant2ClinVarID: 638076

Variant2CAID: CA355865038

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished Yes (PMID: 20026495) and (PMID:26965916)

Case#: Patient M, male, 19 years of age (age at report), 71 kg of weight (50th percentile), height of 171 cm (25th percentile). He attended the last year of high school Institute of Art and practices aerobic activity three times a week. He is intellectually normal (IQ: 108) with a good quality of life (100/100 assessed by EQ-5D-Y).

DiseaseAssertion: attenuated form of MPS 1

FamilyInfo: Affected older sibling (Patient F), born to non-consanguineous Italian parents.

CasePresentingHPOs: Mild facial coarseness, temporomandibular joint dislocation, hypoplasia of the odontoid process, severe worsening of corneal clouding (noted at 12 months), mild hyperopia (noted at 7 years), astigmatism (noted at 7 years but completely corrected by eyeglasses), minimal multiplex dysostosis, mild joint stiffness, kyphosis, initial signs of carpal tunnel syndrome (HP:0000280, HP:6000814, HP:0003311, HP:0007957, HP:0000540, HP:0000483, HP:0000943, HP:0001387, HP:0002808, HP:0012185)

CaseHPOFreeText: Mild shoulder stiffness was present with limited forward elevation up to 120° and in abduction up to 100°, mild scoliosis with Cobb angle of 17°, triangular shape of cervical and thoracic vertebres (C4, C5, C6, D6, and D7), several dorsal herniated discs, normal brain MRI, mild heart involvement, stabilization of the cardiac valvulopathy, normal hearing.

CaseNotHPOs: Hepatosplenomegaly (HP:0001433)

CaseNotHPOFreeText: Respiratory or sleep disturbances, no recurrent infections.

CaseEnzymeAssay: N/A

CaseUrineGAGs: Total urinary glycosaminoglycans (GAG) determination on samples collected just before infusion remained within normal ranges (20,8 μg/mg creatinine with normal values < 42) but at the qualitative assay was present a band of DS.

CaseERT: Yes - Began ERT at 5 months old (pre symptomatically). Laronidase infusions were started delivering weekly (at the dose of 0.5 mg/kg) using implanted venous access devices. Laronidase infusion generally lasted approximately 4 h, without the need for any premedication.

CaseBMT: N/A

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

Variant1ClinVarID: 11908

Variant1CAID: CA220498

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

Variant2ClinVarID: 638076

Variant2CAID: CA355865038

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished Yes (PMID: 20026495) and (PMID:26965916)

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: L535F

Variant1ClinVarID: 638076

Variant1CAID: CA355965038

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: Patient M (male) is an Italian boy who was diagnosed with MPS I by enzyme assay at 3 days of age. His weight was 7.5 kg (75th percentile), length was 67.0 cm (90th percentile), and head circumference was 43.0 cm (75th percentile).

DiseaseAssertion: MPS1-H/S

FamilyInfo: The patient is a younger asymptomatic sibling who was diagnosed with the disease because of his older affected sister. Two months before patient M birth, his 4.5-year-old sister, patient F, had been diagnosed with the Hurler-Scheie form of MPS I on the basis of clinical findings, an elevated urinary glycosaminoglycan level, and low α-l-iduronidase activity in leukocytes.

CasePresentingHPOs: Corneal clouding (HP:0007957)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: He did not develop coarse facial features, joint disease, or organomegaly, and he has shown no evidence of cardiac disease or skeletal abnormalities. He has shown no signs of dysostosis multiplex on radiographs, and his heart valves functioned normally and were not thickened or dysplastic.

CaseEnzymeAssay: N/A

CaseUrineGAGs: 651.7 μg/mg creatinine (normal value for age: 30–200 μg/mg); predominance of heparan sulfate and dermatan sulfate. Urinary glycosaminoglycan excretion decreased to normal levels for age within 4 months of therapy, with complete disappearance of dermatan and heparan sulfate bands on electrophoresis.

CaseERT: Yes - started laronidase at the age of 5 months. Weekly intravenous infusions of laronidase, at the standard dose of 100 U/kg of body weight. Over the following 5 years, treatment was administered regularly (only 3 infusions were missed), and it was well tolerated without any significant adverse effects.

CaseBMT: N/A

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

Variant1ClinVarID: 11908

Variant1CAID: CA220498

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

Variant2ClinVarID: 638076

Variant2CAID: CA355965038

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

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

DiseaseAssertion: MPS1-H/S

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

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

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: Low α-l-iduronidase activity in leukocytes

CaseUrineGAGs: Elevated urinary glycosaminoglycan levels

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

CaseBMT: N/A

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

Variant1ClinVarID: 11908

Variant1CAID: CA220498

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

Variant2ClinVarID: 638076

Variant2CAID: CA355965038

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Sibling 2, Patient F, female, 17 years old (age at report)

DiseaseAssertion: MPS1

FamilyInfo: Affected younger sibling (Sibling 1)

CasePresentingHPOs: HP:0000280, HP:0034337, HP:0001376, HP:0007957, HP:0000540, HP:0000483, HP:0000388, HP:0008513, HP:0000943, HP:0006536 (Coarse facial features, claw hand deformity, limitation of joint mobility, corneal clouding (unchanged since ERT), hyperopia (age 11), astigmatism (age 11), otitis media, mild bilateral conductive hearing (age 16), multiplex dysostosis, airway obstruction)

CaseHPOFreeText: Joint disease with limitation of range of motion of both proximal and distal joints, straight spine, cannot raise arms above head, median nerve compression, bilateral elongation of the Achilles tendon.

CaseNotHPOs: N/A

CaseNotHPOFreeText: Respiratory or sleep disturbances, no significant progression of previously reported moderate mitral insufficiency with thickened valve leaflets, anterior edge prolapse and mild left atrium thickening, no improvement of her moderately severe dysostosis multiplex with evidence of slight worsening of thoracic vertebral changes but stable cervical and hand findings, no white matter alterations

CaseEnzymeAssay: N/A

CaseUrineGAGs: At the age of 5 years, before ERT, were 18.2 μg/ml (nv: 5.27 μg/ml ± 3.01) with a CS/DS ratio of 25/75 (nv: 100/0); after 6, 9 and 10 year of ERT, plasma GAGs have remained within the normal range for age.

CaseERT: Yes

CaseBMT: N/A

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

Variant1ClinVarID: 11908

Variant1CAID: CA220498

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

Variant2ClinVarID: 638076

Variant2CAID: CA355965038

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 10, Italy

DiseaseAssertion: MPS1-H/S

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

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

Variant1ClinVarID: 11908

Variant1CAID: CA220498

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

Variant2ClinVarID: 638076

Variant2CAID: CA355865038

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A