Case5: Female, 50 yrs report

CasePresentingHPOs: HP:0002355, HP:0100753, HP:0003089, HP:0003798, HP:0031237, HP:0031318 (Difficulty walking, Schizophrenia, Hamstring contracture, Nemaline bodies, Internally nucleated skeletal muscle fibers, Myofiber disarray)

HPOsFreeText: Jaw contractures, Pectoral contractures, Ankle dorsiflexor contractures, Quad contractures, Increased oxidative staining

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Daughter of Case 4, Sibling of Case 6

CasePreviousTesting: N/A

CaseGenotypingMethod: The TPM2 gene was sequenced and variants identified. No other information is provided.

Variant: NM_003289.3:c.14_16delAGA (p.Lys7del)

ClinVar: 140486 https://www.ncbi.nlm.nih.gov/clinvar/variation/140486/

gnomAD: Not in gnomAD

Case8: Female, 65 yrs report

CasePresentingHPOs: HP:0001263, HP:0030051, HP:0003326, HP:0003731, HP:0002540, HP:0003236, HP:0006466, HP:0005830, HP:0012785, HP:0009600, HP:0003798, HP:0031237, HP:0003555, HP:0001761 (Delayed milestones, Tip-toe gait, Myalgia, Quadriceps weakness, Non-ambulatory, Elevated serum creatine phosphokinase, Ankle contracture, Toe contractures, Flexion contracture of finger, Contracture of thumb, Nemaline bodies, Internally nucleated skeletal muscle fibers, Muscle fiber splitting, Pes cavus)

HPOsFreeText: Tendo-achilles release performed, NCPAP from 54 yrs, Jaw contractures, Nuclei clumps, Fiber type grouping, Required non-invasive nocturnal ventilatory support at age 54 years

CaseNotHPOs: HP:0001627 (Cardiac abnormality)

NotHPOsFreeText: N/A

CaseAddInfo: Parental testing not performed

CasePreviousTesting: ACTA1 was sequenced and returned negative.

CaseGenotypingMethod: The TPM2 gene was sequenced and variants identified. No other information is provided.

Variant: NM_003289.3:c.14_16delAGA (p.Lys7del)

ClinVar: 140486 https://www.ncbi.nlm.nih.gov/clinvar/variation/140486/

gnomAD: Not in gnomAD

Case1: Female, 45 yrs report

CasePresentingHPOs: HP:0008994, HP:0002015, HP:0003236, HP:0003273, HP:0031237, HP:0003555, HP:0100295, HP:0012548 (Proximal muscle weakness in lower limbs, Dysphagia, Elevated serum creatine phosphokinase, Hip contracture, Internally nucleated skeletal muscle fibers, Fiber splitting, Muscle fiber atrophy, Skeletal muscle fatty infiltration)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Proband of Family 1, Mother of Case 2, Variant is de novo

CasePreviousTesting: N/A

CaseGenotypingMethod: The TPM2 gene was sequenced and variants identified. No other information is provided.

Variant: NM_003289.3:c.14_16delAGA (p.Lys7del)

ClinVar: 140486 https://www.ncbi.nlm.nih.gov/clinvar/variation/140486/

gnomAD: Not in gnomAD

CaseVII-3: Male, 4 years report, Turkey

CasePresentingHPOs: HP:0004912, HP:0002540, HP:0002970 (Hypophosphatemic rickets, Inability to walk, Genu varum)

HPOsFreeText: -3.44 standard deviation score

CaseNotHPOs: HP:0000083, HP:0002024, HP:0001947 (Renal failure, Malabsorption, Renal tubular acidosis)

NotHPOsFreeText: Other tubulopathies that cause secondary hypophosphatemia, Vitamin D-dependent rickets type 1 and 2

CaseAddInfo: Variant is asserted de novo and confirmed by parental testing, Proband is hemizygous for this mutation, Mutation is at splice donor site at Intron 2

CasePreviousTesting: Calcium levels (9.0 mg/dL), Decreased serum phosphate levels (3.1 mg/dL; reference 3.8-6.5), Elevated serum ALP (393 IU/L; reference 90-325), 25OHD3 levels (4.9 ng/ml), 1,25(OH)2D3 levels (N/A pg/mL), PTH levels (154.7 ng/L), TPR levels (58.7), Decreased TmP/GFR levels (1.82; reference 2.9-6.1)

CaseGenotypingMethod: Genomic DNA was isolated from peripheral blood leukocytes, amplified, and directly sequenced in all the coding exons and intron-exon boundaries of PHEX. If no mutations were found, FGF23 followed by consecutive analysis of DMP1, ENPP1, CLCN5, SLC34A3 and SLC34A1 was performed. Significance of found mutations was predicted by computational programs and sorted.

Variant: NM_000444.5(PHEX):c.187+1G>T

CinVar: 438537 https://www.ncbi.nlm.nih.gov/clinvar/variation/438537/

gnomAD: Not in gnomAD

CaseII:II-2: Female, 37 years, Turkey

CasePresentingHPOs: HP:0004912, HP:0004322, HP:0002970, (Hypophosphatemic rickets, Short stature, Genu varum)

HPOsFreeText: -3.95 standard deviation score

CaseNotHPOs: HP:0000083, HP:0002024, HP:0001947 (Renal failure, Malabsorption, Renal tubular acidosis)

NotHPOsFreeText: Other tubulopathies that cause secondary hypophosphatemia, Vitamin D-dependent rickets type 1 and 2

CaseAddInfo: Variant is asserted novel, Mother of II:II-3

CasePreviousTesting: Calcium levels (9.8 mg/dL), Decreased serum phosphate levels (2.1 mg/dL; reference 2.7-4.5), Normal serum ALP (111 IU/L; reference 41-120), 25OHD3 levels (10.5 ng/ml), 1,25(OH)2D3 levels (N/A pg/mL), PTH levels (73 ng/L), TPR levels (87), Decreased TmP/GFR levels (1.70; reference 2.2-3.6)

CaseGenotypingMethod: Genomic DNA was isolated from peripheral blood leukocytes, amplified, and directly sequenced in all the coding exons and intron-exon boundaries of PHEX. If no mutations were found, FGF23 followed by consecutive analysis of DMP1, ENPP1, CLCN5, SLC34A3 and SLC34A1 was performed. Significance of found mutations was predicted by computational programs and sorted.

Variant: NM_000444.5:c.979_983dup (p.His329Thrfs*4)

CAID: CA913187410 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA913187410

gnomAD: Not in gnomAD

CA3281798

Variant 1: CA8401572 Variant 2: ClinVar ID: 66035

p.W31X in trans with p.P1380L

Case7: Female, 8 yrs onset

CasePresentingHPOs: HP:0006785, HP:0003236, HP:0040083, HP:0003701, HP:0003323, HP:0008981, HP:0003458, HP:0030951 (Limb-girdle muscular dystrophy, Elevated serum creatine kinase, Toe walking, Proximal muscle weakness, Progressive muscle weakness, Calf muscle hypertrophy, EMG: myopathic abnormalities, Skeletal muscle fibrosis)

HPOsFreeText: N/A

CaseNotHPOs: HP:0100543 (Cognitive impairment)

NotHPOsFreeText: N/A

CaseAddInfo: Proband is homozygous for this deletion, Mother is confirmed heterozygous

CasePreviousTesting: Peak CPK at 17,000 IU/l, Partially absent α- and β-sarcoglycan staining, Normal dystrophin content, Totally absent γ-sarcoglycan staining

CaseGenotypingMethod: Total mRNA was isolated from muscle biopsies and cDNA was synthesized from it via reverse transcriptase. PCR and SSCP analysis was performed and excised, amplified, and sequenced. After finding the mutations, DNA from peripheral blood leukocytes or muscle biposies was isolated, PCR amplified, and sequenced to confirm the results.

Variant: SGCG, 2-BP DEL, 793TG

ClinVar: 2007 https://www.ncbi.nlm.nih.gov/clinvar/variation/2007/

Also Reported As

Variant: NM_000231.2(SGCG):c.794_795GT[3] (p.Cys267fs)

ClinVar: 552513 https://www.ncbi.nlm.nih.gov/clinvar/variation/552513/

gnomAD: 0.00009923, https://gnomad.broadinstitute.org/variant/13-23898596-CTG-C

Case19: Male, 4 yrs onset

CasePresentingHPOs: HP:0006785, HP:0003236, HP:0003458, HP:0008981, HP:0031322, HP:0032019, HP:0003701 (Limb-girdle muscular dystrophy, Elevated serum creatine kinase, EMG: myopathic abnormalities, Calf muscle hypertrophy, Myocardial lymphocytic infiltration, Muscle eosinophilia, Proximal muscle weakness)

HPOsFreeText: N/A

CaseNotHPOs: HP:0100543 (Cognitive impairment)

NotHPOsFreeText: N/A

CaseAddInfo: Proband is homozygous for this deletion, Parents are confirmed heterozygous and consangeuinous

CasePreviousTesting: Peak CPK at 25,000 IU/l, Partially absent α- and β-sarcoglycan staining, Normal dystrophin content, Totally absent γ-sarcoglycan staining

CaseGenotypingMethod: Total mRNA was isolated from muscle biopsies and cDNA was synthesized from it via reverse transcriptase. PCR and SSCP analysis was performed and excised, amplified, and sequenced. After finding the mutations, DNA from peripheral blood leukocytes or muscle biposies was isolated, PCR amplified, and sequenced to confirm the results.

ClinVar: 2004 https://www.ncbi.nlm.nih.gov/clinvar/variation/2004/

Also Reported As

Variant: NM_000231.2(SGCG):c.525del (p.Phe175fs)

ClinVar: 189243 https://www.ncbi.nlm.nih.gov/clinvar/variation/189243/

gnomAD: 0.00009671, https://gnomad.broadinstitute.org/variant/13-23869568-CT-C

Case44: Female, 7 yrs onset

CasePresentingHPOs: HP:0006785, HP:0003236, HP:0040083, HP:0003307, HP:0002527, HP:0003701, HP:0003323, HP:0009042, HP:0003458, HP:0100305, HP:0031542 (Limb-girdle muscular dystrophy, Elevated serum creatine kinase, Toe walking, Hyperlordosis, Falls, Proximal muscle weakness, Progressive muscle weakness, Marked muscular hypertrophy, EMG: myopathic abnormalities, Ring fibers, Myelin-like whorls in vacuolated fibers)

HPOsFreeText: Wheelchair at 14 yrs

CaseNotHPOs: HP:0003115, HP:0100543 (Abnormal EKG, Cognitive impairment)

NotHPOsFreeText: N/A

CaseAddInfo: Proband is homozygous for this duplication, Parents are confirmed heterozygous

CasePreviousTesting: Peak CPK at 20,000 IU/l, Partially absent α- and β-sarcoglycan staining, Normal dystrophin content, Totally absent γ-sarcoglycan staining

CaseGenotypingMethod: Total mRNA was isolated from muscle biopsies and cDNA was synthesized from it via reverse transcriptase. PCR and SSCP analysis was performed and excised, amplified, and sequenced. After finding the mutations, DNA from peripheral blood leukocytes or muscle biposies was isolated, PCR amplified, and sequenced to confirm the results.

Variant: NM_000231.2(SGCG):c.87dup (p.Gly30fs)

ClinVar: 2008 https://www.ncbi.nlm.nih.gov/clinvar/variation/2008/

gnomAD: 0.000008805, https://gnomad.broadinstitute.org/variant/13-23777919-A-AT

Case 2: male, diagnosed at 24 yrs, 38mm septal wall thickness, no mutations in HCM associated genes, no family history

HP:0002094, HP:0001681, HP:0001962, (dyspnea, angina pectoris, palpitations)

Variant: NM_020433.4(JPH2):c.421T>C (p.Tyr141His)

Clinvar ID: 30456

https://www.ncbi.nlm.nih.gov/clinvar/variation/30456/

ExAC Freq: 1.772e-05

Case 3: Female, diagnosed at 30 yrs, 18mm septal wall thickness, no mutations in HCM associated genes, no family history

HP:0002094, HP:0006689, (dyspnea, bacterial endocarditis)

Variant: NM_020433.4(JPH2):c.494C>T (p.Ser165Phe),

ClinVar ID: 30457

https://www.ncbi.nlm.nih.gov/clinvar/variation/30457/

not in ExAC

Case: Bolino Proband 3, reported at 14yo, symptom onset at 4yo

CasePresentingHPOs: HP:0009053, HP:0008959, HP:0007181, HP:0009049, HP:0001284, HP:0010871, HP:0001337, HP:0001761, HP:0001765, HP:0012447, HP:0003383 (distal lower limb muscle weakness, distal upper limb muscle weakness, interosseous muscle atrophy, peroneal muscle atrophy, absent tendon reflexes, sensory ataxia, tremor, pes cavus, hammertoe, abnormal myelination, onion bulb formation)

HPOsFreeText: interosseous muscle weakness, normal psychomotor development, sensory ataxia noted with tremor, normal autonomic function and superficial sensations, unremarkable general examination, routine laboratory tests normal, CSF exam normal, CMAPS absent from peroneal and median nerves, SNAPs absent from sural nerves. Light microscopy showed irregularities and outfoldings of myelin sheath

CountryOrigin: Italy

FamilyInfo: non-consanguineous parents

PreviouslyPublished: 10673338, 8195799

GenotypingMethod: PCR of genomic DNA, establishment of MTMR2 genomic structure, cDNA sequence aligned with partial genomic sequence from PAC clone CMB9-9116, available family members analyzed and segregation of variant with disease confirmed in pedigree

Variant: NM_016156.5(MTMR2):c.1444C>T (p.Gln482Ter), homozygous

ClinVar: 6234, https://www.ncbi.nlm.nih.gov/clinvar/variation/6234/

gnomAD: 0.000003988, https://gnomad.broadinstitute.org/variant/11-95574816-G-A

This family has been added to the VCI and assessed separately.

PreviouslyPublished: PMID:18065439

CaseP550: Male, 8 yrs onset,

CasePresentingHPOs: HP:0002078, HP:0000639, HP:0007340, HP:0007210, HP:0002495, HP:0001760 (Truncal ataxia, Nystagmus, Lower limb muscle weakness, Lower limb amyotrophy, Impaired vibratory sensation, Abnormal foot morphology)

HPOsFreeText: N/A

CaseNotHPOs: HP:0000648, HP:0001639, HP:0002015, HP:0001260 (Optic atrophy, Hypertrophic cardiomyopathy, Dysphagia, Dysarthria)

NotHPOsFreeText: Not wheelchair-bound

CaseAddInfo: N/A

CasePreviousTesting: 30.9% fratraxin protein levels

CaseGenotypingMethod: See Group

Variant1: FXN, (GAA)n REPEAT EXPANSION, IVS1

ClinVar: 561195, https://www.ncbi.nlm.nih.gov/clinvar/variation/561195/

gnomAD: Not in gnomAD

Variant2: NM_000144.5(FXN):c.157del (p.Arg53fs)

CAID: 3985, https://www.ncbi.nlm.nih.gov/clinvar/variation/3985/

gnomAD: 0.000 MAF

CaseP840: Female, 11 yrs onset,

CasePresentingHPOs: HP:0002078, HP:0002015, HP:0001152, HP:0000639, HP:0007340, HP:0007210, HP:0002495 (Truncal ataxia, Dysphagia, Saccadic smooth pursuit, Nystagmus, Lower limb muscle weakness, Lower limb amyotrophy, Impaired vibratory sensation)

HPOsFreeText: Wheelchair-bound 25 yrs

CaseNotHPOs: HP:0000648, HP:0000365, HP:0001760, HP:0001639 (Optic atrophy, Hearing impairment, Abnormal foot morphology, Hypertrophic cardiomyopathy)

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CasePreviousTesting: 19.9% fratraxin protein levels

CaseGenotypingMethod: See Group

Variant1: FXN, (GAA)n REPEAT EXPANSION, IVS1

ClinVar: 561195, https://www.ncbi.nlm.nih.gov/clinvar/variation/561195/

gnomAD: Not in gnomAD

Variant2: NM_000144.5:c.101del (p.Pro35HisfsTer?)

CAID: CA193369020, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA193369020

gnomAD: Not in gnomAD

CaseJO: Female, 56 yrs onset

CasePresentingHPOs: HP:0002326, HP:0003236, HP:0001712, HP:0003458, HP:0012548, HP:0030197, HP:0003557, HP:0031237 (Transient ischemic attack, Elevated serum creatine kinase, Left ventricular hypertrophy, EMG: myopathic abnormalities, Fatty replacement of skeletal muscle, Fatigable weakness of skeletal muscles, Increased variability in muscle fiber diameter, Internally nucleated skeletal muscle fibers)

HPOsFreeText: N/A

CaseNotHPOs: HP:0030972, HP:0030177 (Abnormal systemic blood pressure, Abnormal nerve conduction study)

NotHPOsFreeText: N/A

CaseAddInfo: Proband is homozygous for this variant

CasePreviousTesting: No family history suggestive of neuromuscular or cardiac disorders

CaseGenotypingMethod: Leukocyte-derived DNA was examined via NGS sequencing with 265 genes and shown to carry a homozygous nonsense mutation in TRIM63. TRIM54 was examined and no variants were found.

Variant: NM_032588.3(TRIM63):c.739C>T (p.Gln247Ter)

ClinVar: 222849, https://www.ncbi.nlm.nih.gov/clinvar/variation/222849/

gnomAD: 0.008100, https://gnomad.broadinstitute.org/variant/1-26384973-G-A

Case3: Female, Birth onset

CasePresentingHPOs: HP:0001558, HP:0008947, HP:0002643, HP:0011470, HP:0001270, HP:0001349, HP:0001488, HP:0007941, HP:0010628, HP:0003327, HP:0003722, HP:0003391, HP:0030051, HP:0002938, HP:0002943, HP:0008081, HP:0003273, HP:0012785, HP:0012432, HP:0010300, HP:0001611, HP:0002792, HP:0003458, HP:0003557, HP:0003803, HP:0003715 (Reduced fetal movements, Infantile hypotonia, Neonatal respiratory distress, Nasogastric tube feeding in infancy, Motor delay, Facial diplegia, Bilateral ptosis, Limited extraocular movement, Facial muscle weakness, Axial muscle weakness, Neck flexor weakness, Gowers sign, Tip-toe gait, Lumbar hyperlordosis, Thoracic scoliosis, Pes valgus, Hip contracture, Flexion contracture of finger, Chronic fatigue, Abnormally low-pitched voice, Nasal voice, Reduced vital capacity, EMG: myopathy, Increased fiber size variation, Type 1 muscle fiber predominance, Myofibrillar myopathy)

HPOsFreeText: Nocturnal ventilation started at 2 yrs, Tracheostomy performed, Hypermobility of the upper extremities, Spinal contracture, Intermyofibrillar network was coarse and irregular, Cap structures, Jagged z-lines

CaseNotHPOs: HP:0001627, HP:0040081, HP:0040129 (Cardiac abnormality, Abnormal levels of creatine kinase in blood, Abnormal nerve conduction)

NotHPOsFreeText: 24-hour Holter-EKG recording and cardiac ultrasound were normal

CaseAddInfo: Healthy parents and 3 healthy siblings, Mutation is de novo

CasePreviousTesting: N/A

CaseGenotypingMethod: PCR and sequencing analysis were performed on genomic DNA, specifically the entire coding sequence of TPM2. TPM2 was sequenced in both parents and all siblings with negative results.

Variant: NM_003289.3:c.606C>G (p.Asn202Lys)

ClinVar: 12467 https://www.ncbi.nlm.nih.gov/clinvar/variation/12467/

gnomAD: Not in gnomAD

Case1118: 11 yrs onset, United States, Hispanic

CasePresentingHPOs: HP:0006785, HP:0003236, HP:0001644, HP:0002540 (Limb-girdle muscular dystrophy, Elevated serum creatine kinase, Dilated cardiomyopathy, Inability to walk)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Parental testing not performed

CasePreviousTesting: Serum CK levels 3,000 - 4,000 UI/l; Genetic testing also included DSG

CaseGenotypingMethod: DNA was collected from peripheral blood or saliva samples. WES was performed and processed though a pipeline before aligning the reads and analyzing the candidate gene list for any variants using the various inheritance patterns. Screening was performed based on in silico predictors with a liberal threshold to filter variants before PCR amplification and Sanger sequencing confirmed the pathogenic mutations.

Variant: NM_000231.2(SGCG):c.787G>A (p.Glu263Lys)

ClinVar: 2009 https://www.ncbi.nlm.nih.gov/clinvar/variation/2009/

gnomAD: 0.00006193, https://gnomad.broadinstitute.org/variant/13-23898591-G-A

Note: Variant-level evidence found in PMID: 16832103. Immunohistochemistry showed absent γ-sarcoglycan in this proband.

CURATE AS FAMILY

Case2: Male, Birth onset, Bosnia

CasePresentingHPOs: HP:0008872, HP:0006829, HP:0001270, HP:0010628, HP:0006466, HP:0000486, HP:0012630, HP:0012240 (Feeding difficulties in infancy, Severe muscular hypotonia, Motor delay, Facial muscle weakness, Ankle contracture, Squint, Abnormality of the trabecular meshwork, Increased muscle lipid droplets)

HPOsFreeText: Predominance of Type 1 muscle fibres, Broad z-band

CaseNotHPOs: HP:0002795, HP:0002540, HP:0003798 (Abnormal respiration, Inability to walk, Nemaline bodies)

NotHPOsFreeText: N/A

CaseAddInfo: Affected Mother had myopathic facies and high-arched palate, weak neck flexors, and asymmetric limb involvement, Healthy grandparents and the father did not have any mutations present

CasePreviousTesting: N/A

CaseGenotypingMethod: Genomic DNA and RNA was extracted from blood or lymphoblastoid cell lines. SSCP was used to analyze all 10 exons of TPM2. After locating the mutations, RT-PCR was used to confirm the mutated allele expression and haplotype analysis was performed on the probands and their family.

Variant: NM_003289.3:c.349G>A (p.Glu117Lys)

ClinVar: 12462 https://www.ncbi.nlm.nih.gov/clinvar/variation/12462/

gnomAD: Not in gnomAD

Case 2: male, dx at 16 yrs, no family history of HCM, both parents genotype neg

HP:0001639, HP:0002094, HP:0100749, HP:0002321

HCM, dyspnea, chest pain

Variant: NM_020433.4(JPH2):c.1213G>T (p.Ala405Ser)

ClinVar ID: 372724, https://www.ncbi.nlm.nih.gov/clinvar/variation/372724/

ExAC Frequency: 1.45e-5, http://gnomad.broadinstitute.org/variant/20-42747220-C-A

Expression of the Ser600Arg variant in OPA1-null mouse embryonic fibroblasts showed complete fragmentation of the mitochondrial network and a slight, non-significant reduction of mtDNA amount indicating that this variant impacts protein function (PMID: 30293569)(PS3_Supporting).

Case1: Female, Austria, 18 yrs report

CasePresentingHPOs: HP:0010628, HP:0001558, HP:0002643, HP:0002015, HP:0040288, HP:0001260, HP:0003690, HP:0009046, HP:0003551, HP:0003798 (Facial weakness, Reduced fetal movement, Neonatal respiratory distress, Swallowing difficulties, Nasogastric tube feeding, Dysarthric speech, Limb weakness, Difficulty running, Difficulty climbing stairs, Nemaline bodies)

HPOsFreeText: 4/5/7 Apgar score

CaseNotHPOs: HP:0002015, HP:0002540, HP:0002650, HP:0002098 (Swallowing difficulties, Non-ambulatory, Scoliosis, Respiratory distress)

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CasePreviousTesting: N/A

CaseGenotypingMethod: Whole exome sequencing of the proband revealed this homozygous LMOD3 mutation.

Variant: NM_198271.4:c.1648C>T (p.Leu550Phe)

ClinVar: 374498 https://www.ncbi.nlm.nih.gov/clinvar/variation/374498/

gnomAD: Not in gnomAD

Case1: Male, Spain, Birth onset

CasePresentingHPOs: HP:0003722, HP:0001324, HP:0000297, HP:0003701, HP:0001252, HP:0001284, HP:0001283, HP:0002540, HP:0002307, HP:0000218, HP:0011471 (Nemaline bodies, Muscle weakness, Facial hypotonia, Proximal muscle weakness, Muscular hypotonia, Areflexia, Bulbar palsy, Inability to walk, Drooling, High palate, PEG-fed in infancy)

HPOsFreeText: Bimodal communication, Wheelchair dependence, Cephalic support, Sedestation

CaseNotHPOs: HP:0002460, HP:0000602, HP:0001249, HP:0001627, HP:0002093, HP:0002650, HP:0006466, HP:0001382, HP:0003798 (Neck flexor weakness, Distal muscle weakness, Ophthalmoplegia, Intellectual disability, cardiac abnormality, Respiratory insufficiency, Scoliosis, Ankle contracture, Joint hypermobility)

NotHPOsFreeText: Mechanic ventilation

CaseAddInfo: Intermediate variant, Paternity/ maternity was confirmed

CasePreviousTesting: N/A

CaseGenotypingMethod: A research panel with 751 genes relating to neurological disorders, including the coding and intronic flanking regions of ACTA1, CFL2, KBTBD13, NEB, TNNT1, TNNT3, TPM2 and TPM3, was used to locate any variants in the proband. These variants were then prioritized and confirmed by Sanger sequencing in the probands and their relatives.

Variant1: NM_001164507.1:c.17779_17780del (p.Tyr5927Hisfs*17)

CAID: CA913203561 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA913203561

gnomAD: Not in gnomAD

Variant2: NM_001164507.1:c.11086A>C (p.Thr3696Pro)

CAID: CA348785269 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_001271208.2%3Ac.11086A%3EC

gnomAD: Not in gnomAD

CaseB:III-2: Male, 2 years onset, China

CasePresentingHPOs: HP:0004912, HP:0003109, HP:0003155, HP:0006505, HP:0002753, HP:0002982, HP:0004349, HP:0000944, HP:0011849, HP:0002970, HP:0003170 (Hypophosphatemic rickets, Hyperphosphaturia, Elevated alkaline phosphatase, Abnormality of limb epiphysis morphology, Thin cortices, Tibial bowing, Reduced bone mineral density, Abnormality of the metaphysis, Abnormal bone ossification, Genu varum, Abnormality of the acetabulum)

HPOsFreeText: Fuzzy structures

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Proband is hemizygous for this mutation, Has a mother and grandmother with the same mutation/disease at 141.3 cm and 142.8 cm respectively

CasePreviousTesting: For all probands: Decreased serum phosphorus levels (0.64–0.9 mM; normal range, 1.29–1.94 mM), Increased 24-h urinary phosphorus levels (49.8–68.4 mmol/day; normal range, 12.9–42.0 mmol/day), Elevated blood alkaline phosphatase levels (350–668.7 U/L; normal range, 42–390 U/L), Lower limit of normal serum 1,25-dihydroxyvitamin D3 levels, Normal blood PTH, serum calcium levels and urine calcium/creatinine ratio, Elevated serum FGF23 (>1500 pg/mL; lower than 28 pg/mL in healthy family members)

CaseGenotypingMethod: Peripheral blood from the probands and affected family members was collected and genomic DNA extracted and quantified. Next-generation sequencing was performed on the probands following PCR amplification and the results were examined with the TruSight One Sequencing Panel, with such genes as PHEX, FGF23, SLC34A3, DMP1 and ENPP1. The mutations were then compared to a reference sequence and filtered for pathogenicity. Sanger sequencing was performed on the probands and family members to confirm the detected mutations.

Variant: NM_000444.5:c.433G>T (p.Glu145Ter)

CAID: CA412571205 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000444.5%3Ac.433G%3ET

gnomAD: Not in gnomAD

Case2: Female, Birth onset

CasePresentingHPOs: HP:0002093, HP:0002938, HP:0002015, HP:0003798, HP:0003200, HP:0003548 (Respiratory insufficiency, Lumbar hyperlordosis, Dysphagia, Nemaline bodies, Ragged-red fibers, Subsarcolemmal accumulations of abnormally shaped mitochondria)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Mother of proband

CasePreviousTesting: N/A

CaseGenotypingMethod: See Family

Variant: NM_003289.3:c.397C>T (p.Arg133Trp)

ClinVar: 12463 https://www.ncbi.nlm.nih.gov/clinvar/variation/12463/

gnomAD: Not in gnomAD

Case1: Female, Birth onset

CasePresentingHPOs: HP:0008947, HP:0008872, HP:0002033, HP:0030043, HP:0001349, HP:0001488, HP:0010804, HP:0002650 (Infantile hypotonia, Feeding difficulties in infancy, Poor suck, Hip subluxation, Facial diplegia, Bilateral ptosis, Tented mouth, Scoliosis)

HPOsFreeText:Disorganized myofibrils and thickened Z bands

CaseNotHPOs: HP:0003798 (Nemaline bodies)

NotHPOsFreeText: N/A

CaseAddInfo: Proband of Family 1

CasePreviousTesting: N/A

CaseGenotypingMethod: See Family

Variant: NM_003289.3:c.397C>T (p.Arg133Trp)

ClinVar: 12463 https://www.ncbi.nlm.nih.gov/clinvar/variation/12463/

gnomAD: Not in gnomAD

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: L396P

Variant1ClinVarID:

Variant1CAID: CA355963499

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: Variant not associated with a proband. Variant listed in supplementary materials in Supplementary Table 4

DiseaseAssertion: Mucopolysaccharidosis type I, MPS I

FamilyInfo: N/A

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: P496R

Variant1ClinVarID: 496861

Variant1CAID: CA2802275

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: Variant not associated with a proband. Variant listed in supplementary materials in Supplementary Table 4

DiseaseAssertion: Mucopolysaccharidosis type I, MPS I

FamilyInfo: N/A

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: A436P

Variant1ClinVarID:

Variant1CAID: CA355963897

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: Variant not associated with a proband. Variant listed in supplementary materials in Supplementary Table 4

DiseaseAssertion: Mucopolysaccharidosis type I, MPS I

FamilyInfo: N/A

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: G208D

Variant1ClinVarID: 554590

Variant1CAID: CA355961948

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: Variant not associated with a proband. Variant listed in supplementary materials in Supplementary Table 4

DiseaseAssertion: Mucopolysaccharidosis type I, MPS I

FamilyInfo: N/A

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: E276K

Variant1ClinVarID:

Variant1CAID: CA355962355

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: Variant not associated with a proband. Variant listed in supplementary materials in Supplementary Table 4

DiseaseAssertion: Mucopolysaccharidosis type I, MPS I

FamilyInfo: N/A

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: H449N

Variant1ClinVarID: 350230

Variant1CAID: CA2802233

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: Variant not associated with a proband. Variant listed in supplementary materials in Supplementary Table 4

DiseaseAssertion: Mucopolysaccharidosis type I, MPS I

FamilyInfo: N/A

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: H82P

Variant1ClinVarID: 195039

Variant1CAID: CA201510

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: Variant not associated with a proband. Variant listed in supplementary materials in Supplementary Table 4

DiseaseAssertion: Mucopolysaccharidosis type I, MPS I

FamilyInfo: N/A

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: E178K

Variant1ClinVarID: 2203495

Variant1CAID: CA355961709

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: Variant not associated with a proband. Variant listed in supplementary materials in Supplementary Table 4

DiseaseAssertion: Mucopolysaccharidosis type I, MPS I

FamilyInfo: N/A

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: P385R

Variant1ClinVarID: 556024

Variant1CAID: CA355963438

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: Variant not associated with a proband. Variant listed in supplementary materials in Supplementary Table 4

DiseaseAssertion: Mucopolysaccharidosis type I, MPS I

FamilyInfo: N/A

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: H240R

Variant1ClinVarID: 947028

Variant1CAID: CA355962127

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: Variant not associated with a proband. Variant listed in supplementary materials in Supplementary Table 4

DiseaseAssertion: Mucopolysaccharidosis type I, MPS I

FamilyInfo: N/A

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1:

Variant1ClinVarID:

Variant1CAID: CA355963739

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: Patient 2474, male, northern European origin, he was class valedictorian in high school and then a practicing attorney until his intellect deteriorated later in life.

DiseaseAssertion: MPS1-S, mild

FamilyInfo: Affected sister with MPS-1 who had a similar or slightly more severe clinical phenotype.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: Fibroblasts has enabled detection of 0.041 ± 0.008 (n = 6) ng of IDUA protein of total cellular protein/mg (0.13% of normal mean). This gives a calculated specific activity and VmX, of 88 and 102 pmol/min/ng of IDUA toward the fluorogenic and heparin-derived disaccharide substrates, respectively, both of which are in the normal range.

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.590-7G>A (678-7G>A)

Variant1ClinVarID: 222996

Variant1CAID: CA356990

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

Variant2ClinVarID: 11908

Variant2CAID: CA220498

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

PMID: 21734815

Gene: IDUA

Disease: MPS1

Inheritance: Autosomal recessive

Case#: 6, 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: Not identified

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: OS of sibship 1, female, 8 years old (age at diagnosis), 8.8 years old (age at ERT enrollment), 5.4 years (duration of ERT)

DiseaseAssertion: MPS1-HS

FamilyInfo: Affected male YS (YS of sibship 1)

CasePresentingHPOs: HP:0007957, HP:0000943, HP:0002828, HP:0000365, HP:0001263, HP:0001260, HP:0002751 (Corneal opacity, dysostosis, joint contractures, mild hearing impairment, psychomotor delay, speech difficulty, kyphoscoliosis)

CaseHPOFreeText: Cardiac disease, lung function tests 50% of normal, organomegaly

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: Yes - symptoms present at T1 were stabilized or improved (organomegaly and hearing) at T2, except for worsening of kyphoscoliosis.

CaseBMT: N/A

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

Variant1ClinVarID: 11910

Variant1CAID: CA256112

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

Variant2ClinVarID: 11910

Variant2CAID: CA256112

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: YS of sibship 4, male, 0.8 years old (age at diagnosis), 1.3 years old (age at ERT enrollment), 3.6 years (duration of ERT)

DiseaseAssertion: MPS1-HS

FamilyInfo: Affected male OS (OS of sibship 4)

CasePresentingHPOs: HP:0007957, HP:0000943, HP:0002828 (Corneal opacity, dysostosis, joint contractures)

CaseHPOFreeText: Cardiac disease, progression of respiratory symptoms

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: Yes - Had poor compliance (~60 %) with ERT, which may have impacted the symptom progression.

CaseBMT: N/A

Variant1: c.623G>A (p.G208D)

Variant1ClinVarID: 554590

Variant1CAID: CA355961948

Variant2: (p.P520R), Typo, no proline at this position

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: YS of sibship 8, male, 3.3 years old (age at diagnosis), 3.7 years old (age at ERT enrollment), 5.8 years (duration of ERT)

DiseaseAssertion: MPS1-HS

FamilyInfo: Affected OS (OS of sibship 8)

CasePresentingHPOs: HP:0007957, HP:0000943, HP:0002828 (Corneal opacity, dysostosis, joint contracture)

CaseHPOFreeText: Cardiac disease

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: Yes - Had progression of cardiac symptoms at T2, dysostosis multiplex stabilized, and remained milder. Joint contractures progressed into the moderate range.

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

Case#: YS of sibship 7, female, 3.3 years old (age at diagnosis), 3.4 years old (age at ERT enrollment), 5.6 years (duration of ERT)

DiseaseAssertion: MPS1-HS

FamilyInfo: Affected OS (OS of sibship 7)

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

CaseHPOFreeText: Cardiac disease, somatic impairment

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: Yes - After 5 years of ERT, cardiac symptoms progressed but remained mild. Corneal clouding progressed as well. At the age of 5, motor development remained normal, and cognitive skills and musculoskeletal disease improved.

CaseBMT: N/A

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

Variant1ClinVarID: 11910

Variant1CAID: CA256112

Variant2: (L564fsx) No CDNA change provided.

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: OS2 of sibship 6 (see Table 1), male, 8 years old (age at diagnosis), 11 years old (age at ERT enrollment), 6 years (duration of ERT)

DiseaseAssertion: MPS1-HS

FamilyInfo: Two affected siblings (OS1 and YS of sibship 6)

CasePresentingHPOs: HP:0007957, HP:0000943, HP:0002828 (Corneal opacity, dysostosis, joint contractures)

CaseHPOFreeText: Cardiac disease, musculoskeletal symptoms

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: Yes - Pulmonary function was 45–50 % of normal at T2. No restrictions in ADL.

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

PMID: 29240299

Gene: IDUA

Disease: MPS1

Inheritance: Autosomal recessive

Case#: Patient 13, born in 2010 (paper published in 2017), 16 months (age at first treatment)

DiseaseAssertion: MPSI-H

FamilyInfo: N/A

CasePresentingHPOs: Corneal clouding (HP:0007957)

CaseHPOFreeText: N/A

CaseNotHPOs: Retinopathy, cataract (HP:0000488, HP:0000518)

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 55 ng/mol (36 weight matched enzyme reference assay)

CaseUrineGAGs: 0.28 DS/CS

CaseERT: N/A

CaseBMT: Yes, MUD (GOS)

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

PMID: 34928474

Gene: IDUA

Disease: MPS1

Inheritance: Autosomal recessive

Case#: PKMPS1P6, 8 months old (age at presentation), 2 years old (age at report), female, Pakastani

DiseaseAssertion: MPS-I

FamilyInfo: Proband's parents were first cousins.

CasePresentingHPOs: Coarse facial features, recurrent respiratory tract infections, joint stiffness, upper airway obstructive symptoms, mild developmental delay, umbilical hernia (HP:0000256, HP:0002788, HP:0001387, HP:0002781, HP:0001263, HP:0001537)

CaseHPOFreeText: Widening of the wrist and a stunted, pectus carinatum

CaseNotHPOs: Visceromegaly (HP:0003271)

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1469T>C (p.L490P)

Variant1ClinVarID: 11919

Variant1CAID: CA220503

Variant2: c.1469T>C (p.L490P)

Variant2ClinVarID: 11919

Variant2CAID: CA220503

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: PKMPS1P8, 10 years old (age at presentation), male, Pakastani

DiseaseAssertion: MPS-I

FamilyInfo: Born to consanguineous parents

CasePresentingHPOs: Coarse facial features, mild developmental delay, short stature, pectus carinatum, genu valgum, corneal clouding (HP:0000256, HP:0001263, HP:0004322, HP:0000768, HP:0002857, HP:0007957)

CaseHPOFreeText: Difficulty walking since the age of 4 years. Widening of the wrist, underweight, soft abdomen.

CaseNotHPOs: Visceromegaly (HP:0003271)

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1469T>C (p.L490P)

Variant1ClinVarID:

Variant1CAID: 11919

Variant2: CA220503

Variant2ClinVarID: c.1469T>C (p.L490P)

Variant2CAID: 11919

AdditionalVariants: CA220503

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: PKMPS1P4, 16 months (age of presentation), male, Pakastani

DiseaseAssertion: MPS-I

FamilyInfo: Proband was born to a consanguineous family.

CasePresentingHPOs: Snoring, failure to thrive, developmental delay, coarse facial features, skeletal deformities, umbilical hernia (HP:0025267, HP:0001508, HP:0001263, HP:0000256, HP:0002652, HP:0001537)

CaseHPOFreeText: Copious nasal secretions, chest infections, underweight, and a liver span of 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

Case#: PKMPS1P5, 10 months old (age at presentation), 2 years old (age at report), female, Pakastani

DiseaseAssertion:MPS-I

FamilyInfo: Her parents were related

CasePresentingHPOs: Upper airway obstructive symptoms, stridor, developmental delay, coarse facial features, pneumonia, umbilical hernia, short neck, kyphosis (HP:0002781, HP:0010307, HP:0001263, HP:0000256, HP:0002090, HP:0001537, HP:0000470, HP:0002808)

CaseHPOFreeText: Copious nasal discharge, widening of the wrist, 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

Case#: Patient 17, 3 years old (age at report), male, Indian

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: Coarse facial features, hepatosplenomegaly, joint contractures, corneal clouding, recurrent infections, dysostosis multiplex, intellectual disability, hernia (HP:0000280, HP:0001433, HP:0002828, HP:0007957, HP:0002719, HP:0000943, HP:0001249, HP:0100790)

CaseHPOFreeText: Cardiac disease

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 3.6% (Range of residual enzyme activity: 0.0%-4.8%)

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.784delC (p.His262Thrfs*55)

Variant1ClinVarID: 956890

Variant1CAID: CA2802083

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

Variant2ClinVarID: 956890

Variant2CAID: CA2802083

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 6, 1 years old (age at report), male, Indian

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

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

CaseHPOFreeText: Cardiac disease

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 2.7% (Range of residual enzyme activity: 0.0%-4.8%)

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.362T>C (p.Leu121Pro)

Variant1ClinVarID: 1343382

Variant1CAID: CA355961174

Variant2: c.362T>C (p.Leu121Pro)

Variant2ClinVarID: 1343382

Variant2CAID: CA355961174

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 54, 8 years old (age at report), female, Indian

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

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

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 2.3% (Range of residual enzyme activity: 0.0%-4.8%)

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.568_581del (p.Asn190His)

Variant1ClinVarID: 3639714

Variant1CAID: CA2801994

Variant2: c.1469T>C (p.Leu490Pro)

Variant2ClinVarID: 11919

Variant2CAID: CA220503

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 31, 6 years old (age at report), male, Indian

DiseaseAssertion: MPS1-H

FamilyInfo: Sibling of Patient 32

CasePresentingHPOs: Coarse facial features, hepatosplenomegaly, joint contractures, corneal clouding, recurrent infections, dysostosis multiplex, hernia (HP:0000280, HP:0001433, HP:0002828, HP:0007957, HP:0002719, HP:0000943, HP:0100790)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 3.0% (Range of residual enzyme activity: 0.0%-4.8%)

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1373T>C (p.Leu458Pro)

Variant1ClinVarID: N/A

Variant1CAID: CA355964255

Variant2: c.1373T>C (p.Leu458Pro)

Variant2ClinVarID: N/A

Variant2CAID: CA355964255

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 12, 7 years old (age at report), female, Indian

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: Coarse facial features, hepatosplenomegaly, joint contractures, intellectual disability (HP:0000280, HP:0001433, HP:0002828, HP:0001249)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 2.7% (Range of residual enzyme activity: 0.0%-4.8%)

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.532G>A (p.Glu178Lys)

Variant1ClinVarID: 2203495

Variant1CAID: CA355961709

Variant2: c.532G>A (p.Glu178Lys)

Variant2ClinVarID: 2203495

Variant2CAID: CA355961709

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 23, 9 months old (age at report), female, Indian

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: Intellectual disability (HP:0001249)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1029C>A (p.Tyr353Ter)

Variant1ClinVarID: 222997

Variant1CAID: CA356984

Variant2: c.1029C>A (p.Tyr353Ter)

Variant2ClinVarID: 222997

Variant2CAID: CA356984

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 33 (Table 3)

DiseaseAssertion: Attenuated naïve MPS 1

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 3 nmol/h/mg per DBS (dried blood spots) determined during NBS. 13.2 DBS protein concentration determined by Immuno-SRM (pmol/L).

CaseUrineGAGs: N/A

CaseERT: Yes

CaseBMT: N/A

Variant1: c.1577T>C (p.L526P)

Variant1ClinVarID: 567566

Variant1CAID: CA2802300

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

Variant2ClinVarID: 567566

Variant2CAID: CA2802300

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 29 (Table 3)

DiseaseAssertion: Severe naïve MPS 1

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: <1 nmol/h/mg per DBS (dried blood spots) determined during NBS

CaseUrineGAGs: N/A

CaseERT: Yes

CaseBMT: N/A

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

Variant1ClinVarID: 11908

Variant1CAID: CA220498

Variant2: c.1524+1G>T

Variant2ClinVarID: 555169

Variant2CAID: CA355964830

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 32 (Table 3)

DiseaseAssertion: Moderate 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

Case#: Patient 41 (Table 3)

DiseaseAssertion: Moderate MPS 1

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 77.5 DBS protein concentration determined by Immuno-SRM (pmol/L).

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

Case#: P4, Male, 13 years (diagnosed), 16.1 (report), 38 kg (weight), 146 cm (height), Algerian

DiseaseAssertion: Scheie Syndrome

FamilyInfo: Parents are consanguineous

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

CaseHPOFreeText: Cardiac Manifestations(Mitral Stenosis & Aortic Insufficiency)

CaseNotHPOs: HP:0001249, HP:0000238 (Mental Retardation, Hydrocephalus)

CaseNotHPOFreeText: Chronic Rhinorrhea

CaseEnzymeAssay: IDUA Enzyme activity 7 (% to the reference range mean)

CaseUrineGAGs: GAG quantitation 18 (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

Case#: P12, Male, 2.6 years (diagnosed), 9.6 (report), Algerian

DiseaseAssertion: Hurler Syndrome

FamilyInfo: Parents are not consanguineous

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

CaseHPOFreeText: Chronic Rhinorrhea

CaseNotHPOs: HP:0007957 (Corneal Opacity)

CaseNotHPOFreeText: N/A

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

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

GenotypingMethod: Direct DNA Fragments Sequencing

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

Variant1ClinVarID: 11910

Variant1CAID: CA256112

Variant2:c.1743C>G (p.Tyr581*)

Variant2ClinVarID: 550883

Variant2CAID: CA2802392

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 9, 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.1598C>T (p.P533L)

Variant1ClinVarID: 429205

Variant1CAID: CA355965029

Variant2: c.1598C>T (p.P533L)

Variant2ClinVarID: 429205

Variant2CAID: CA355965029

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 6, 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.793-5C>A (homozygous)

Variant1ClinVarID: N/A

Variant1CAID: CA3250086379

Variant2: c.793-6C>G (homozygous)

Variant2ClinVarID: N/A

Variant2CAID: CA2739858898

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

PMID: 31298590

Gene: IDUA

Disease: MPS1

Inheritance: Autosomal recessive

PMID: 31298590

Gene: IDUA

Disease: MPS1

Inheritance: Autosomal recessive

Case#: Patient 6, Male, 1 year (diagnosed), 2 years (report), Djerba Island (Tunisian origin)

DiseaseAssertion: N/A

FamilyInfo: Parents are consanguineous between 2nd cousins

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: Leukocyte IDUA activity 0.3% (% normal) ; determined in sonicated leukocyte pellets using the artificial substrate 4-methylumbellifery IDUA

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

GenotypingMethod: Sequencing exons and intro-exon junctions; Phenol/chloroform procedure

Variant1: p.P533R

Variant1ClinVarID: 11910

Variant1CAID: CA256112

Variant2: p.P533R

Variant2ClinVarID: 11910

Variant2CAID: CA256112

AdditionalVariants: p.A8A (c.24 A > C, p.A20A (c.60G > A); p.Q433Q (c.99T > G), IVS2-44 (c.300 44C > T); p.R105Q (c.314G > A); p.N181N (c.543 T > C), IVS5-45 (c.590-45G > C); IVS5-8 (c.590- 8C > T); p.A314A (c.942G > C); IVS7+48 (c.972+48A > G), IVS7-45 (c.973-45 G > C; p.A361 (Tc.1081G > A); p.T388T (c.116G > C); p.V454I (c.1360G > A); IVS9+36 (c.1402+36T > C), p.R489R (c.1467C > T), IVS12+72 (c.1727T > G), 3'UTR+44 (c.1962+44G > C).

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 3, Male, 2 years (diagnosed), 12 years (report), Sfax (Tunisian origin)

DiseaseAssertion: N/A

FamilyInfo: Parents are consanguineous between 3rd cousins

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: Leukocyte IDUA activity 0.2% (% normal) ; determined in sonicated leukocyte pellets using the artificial substrate 4-methylumbellifery IDUA

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

GenotypingMethod: Sequencing exons and intro-exon junctions; Phenol/chloroform procedure

Variant1: p.P533R

Variant1ClinVarID: 11910

Variant1CAID: CA256112

Variant2: p.P533R

Variant2ClinVarID: 11910

Variant2CAID: CA256112

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: No additional case information provided

DiseaseAssertion: MPSI-H/S

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.523_534delTGGAACTTCGAG (p.Trp175_Glu178del)

Variant1ClinVarID: 2734635

Variant1CAID: CA645372297

Variant2: c.523_534delTGGAACTTCGAG (p.Trp175_Glu178del)

Variant2ClinVarID: 2734635

Variant2CAID: CA645372297

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

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: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.784_784delC (p.H262TfsTer55)

Variant1ClinVarID: 956890

Variant1CAID: CA2802083

Variant2: c.784_784delC (p.H262TfsTer55)

Variant2ClinVarID: 956890

Variant2CAID: CA2802083

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

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: 0.13 umol/g hr, reference range 10–50 umol/g hr.

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.158+1G>A

Variant1ClinVarID: 526835

Variant1CAID: CA355945713

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

Variant2ClinVarID: 11908

Variant2CAID: CA220498

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: No additional case information provided

DiseaseAssertion: MPSI-H/S

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 0.4 umol/g hr, reference range 10–50 umol/g hr.

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.17_24dupCCCGCGCC (p.Ala9ProfsTer102)

Variant1ClinVarID: N/A

Variant1CAID: CA645372294

Variant2: c.1871A>T (p.D624V)

Variant2ClinVarID: N/A

Variant2CAID: CA355965955

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

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: 0.05 umol/g hr, reference range 10–50 umol/g hr.

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.36_44delGCTCCTGGC (p.Leu13_Ala15del)

Variant1ClinVarID: 3720558

Variant1CAID: CA645372295

Variant2: c.1205G>A (W402X)

Variant2ClinVarID: 11908

Variant2CAID: CA220498

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Free, full-text NOT available. Text obtained through a University account and annotations added to the free PubMed abstract.

IDUA variants were pulled from various public databases and subjected to in silico analyses. No individual-level patient data (e.g., phenotypes) are provided.

PMID: 22280094

Gene: IDUA

Disease: MPS1

Inheritance: Autosomal recessive

PMID: 35073349 Gene: IDUA Disease: MPS1 Inheritance: Autosomal recessive

Case#: Patient 6 (see Table 2), 33 weeks, 6 days (Gestational age)

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 0.47 nmol x mg-1 × hr-1

CaseUrineGAGs: N/A

CaseERT:N/A

CaseBMT: N/A

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

Variant1ClinVarID: 11909

Variant1CAID: CA204563

Variant2: c.653T>C (p.L218P)

Variant2ClinVarID: 222995

Variant2CAID: CA356986

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 8 (see Table 2), 38 weeks (Gestational age)

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Upper respiratory tract involvement

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 0.58 nmol x mg-1 × hr-1

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

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

Variant1ClinVarID: 11909

Variant1CAID: CA204563

Variant2: c.653T>C (P.L218P)

Variant2ClinVarID: 222995

Variant2CAID: CA356986

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 19 (see Table 2), 38 weeks (Gestational age)

DiseaseAssertion: MPS1-H/S

FamilyInfo: Sibling of Patient 20 (see Table 2)

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: Inguinal hernia (HP:0000023)

CaseNotHPOFreeText: Upper respiratory tract involvement

CaseEnzymeAssay: 0.92 nmol x mg-1 × hr-1

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

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

Variant1ClinVarID: 11908

Variant1CAID: CA220498

Variant2: c.1044C>A (p.N348K)

Variant2ClinVarID: N/A

Variant2CAID: CA:355963142

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 3 (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.208C>T (p.Q70X)

Variant2ClinVarID: 11909

Variant2CAID: CA204563

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

PMID: 37516270

Gene: IDUA

Disease: MPS1

Inheritance: Autosomal recessive

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: Abnormal

CaseUrineGAGs: Abnormal

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: N/A

PreviouslyPublished N/A

Case#: No additional case information provided.

DiseaseAssertion: Not specified

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: Abnormal

CaseUrineGAGs: Normal

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1504C>T (p.R502W)

Variant1ClinVarID: 2070831

Variant1CAID: CA2802280

Variant2: c.1504C>T (p.R502W)

Variant2ClinVarID: 2070831

Variant2CAID: CA2802280

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: No additional case information provided.

DiseaseAssertion: Not specified

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: Abnormal

CaseUrineGAGs: Normal

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1163C>T (p.T388M)

Variant1ClinVarID: 558615

Variant1CAID: CA355963455

Variant2: c.1163C>T (p.T388M)

Variant2ClinVarID: 558615

Variant2CAID: CA355963455

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: No additional case information provided.

DiseaseAssertion: Not specified

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: Abnormal

CaseUrineGAGs: Normal

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1855C>T (p.R619X)

Variant1ClinVarID: 280976

Variant1CAID: CA2802455

Variant2: c.1169T>C (p.M390T)

Variant2ClinVarID: 1496867

Variant2CAID: CA355963466

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 1, Chinese descent, 7 years old (age at report), born via normal pregnancy and delivery, height of 96 cm (<3rd percentile), weight of 22.5 kg (25th-50th percentile).

DiseaseAssertion: MPS 1

FamilyInfo: The third child of non-consanguineous parents. Affected older sister (Patient 2).

CasePresentingHPOs: Short stature, skeletal dysplasia, joint stiffness, claw hand deformity, coarse facial features, prominent forehead, wide nose, flared nostrils, thick lips, inguinal hernia, visual impairment (HP:0004322, HP:0002652, HP:0001387, HP:0034337, HP:0000280, HP:0011220, HP:0000445, HP:0000454, HP:0000219, HP:0000023, HP:0000505)

CaseHPOFreeText: Corneal edema with diffuse granular opacity, central corneal thickness

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.2T>C (p.M1?)

Variant1ClinVarID: 639529

Variant1CAID: CA2801095

Variant2: c.911delT (p.V304fs)

Variant2ClinVarID: 1184991

Variant2CAID: CA2573052265

AdditionalVariants: N/A

ParentalGenotype: Paternal: c.2T>C, Maternal: c.911delT

PreviouslyPublished N/A

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.547C>T (p.P183S)

Variant1ClinVarID: 2432770

Variant1CAID: CA2801989

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

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

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.1225G>C (p.G409R)

Variant1ClinVarID: 92627

Variant1CAID: CA248659

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

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

DiseaseAssertion: MPS-I

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

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

Variant1ClinVarID: 556406

Variant1CAID: CA355966010

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: 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.218A>G (p.N73S)

Variant1ClinVarID: 2432733

Variant1CAID: CA355946346

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 9, male, Han origin, 8 years old (age at diagnosis)

DiseaseAssertion: MPS1-H/S

FamilyInfo: N/A

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

CaseHPOFreeText: N/A

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

CaseNotHPOFreeText: Cardiac disease

CaseEnzymeAssay: IDUA activity 0.2 nmol/h/mg protein. The normal range in Chinese controls was found to be 27.2–52 nmol/h/mg protein.

CaseUrineGAGs: Diagnosis was confirmed biochemically by the demonstration of an increased excretion of urinary dermatan sulfate and heparan sulfate.

CaseERT: N/A

CaseBMT: N/A

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

Variant1ClinVarID: 11927

Variant1CAID: CA256128

Variant2: c.156C>G (p.F52L)

Variant2ClinVarID: 554280

Variant2CAID: CA355945700

AdditionalVariants: N/A

ParentalGenotype: The transmission of sequence variations found in each patient was inferred by sequencing the corresponding exons of the patient's parents - confirmed in trans by parental testing.

PreviouslyPublished N/A

Case#: Patient 25, male, Han origin, 10 years old (age at diagnosis)

DiseaseAssertion: MPS1-H/S

FamilyInfo: N/A

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

CaseHPOFreeText: Cardiac disease

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

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: IDUA activity 1.2 nmol/h/mg protein. The normal range in Chinese controls was found to be 27.2–52 nmol/h/mg protein.

CaseUrineGAGs: Diagnosis was confirmed biochemically by the demonstration of an increased excretion of urinary dermatan sulfate and heparan sulfate.

CaseERT: N/A

CaseBMT: N/A

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

Variant1ClinVarID: 11927

Variant1CAID: CA256128

Variant2: c.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

Case#: Patient 56, male, Han origin, 3 years 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 0.8 nmol/h/mg protein. The normal range in Chinese controls was found to be 27.2–52 nmol/h/mg protein.

CaseUrineGAGs: Diagnosis was confirmed biochemically by the demonstration of an increased excretion of urinary dermatan sulfate and heparan sulfate.

CaseERT: N/A

CaseBMT: N/A

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

Variant1ClinVarID: 11927

Variant1CAID: CA256128

Variant2: c.1210G>T (p.E404X)

Variant2ClinVarID: 552095

Variant2CAID: N/A

AdditionalVariants: N/A