Case#: 3 y.o, male, Palestinian-American

DiseaseAssertion: Limb Girdle muscular dystrophy

FamilyInfo: Parents are first cousins. Other two siblings had normal neurologic examination and normal creatine kinase values.

CasePresentingHPOs: HP:0003707, HP:0003701,HP:0003560, HP:0006785, HP:0003236,HP:0003325, HP:0008981, HP:0002515,

CaseHPOFreeText: Bulk was reduced in his shoulder and hip girdle. Bilateral pseudohypertrophy of the calves.

CaseNotHPOs:

CaseNotHPOFreeText:

MotorAchievement: Had a motor delay. Was able to walk well but cant run lifting his knees. Can jump but fell afterwards. Can not raise from without the use of a chair or another person. Walking gait is normal. When he does try to run there is a waddle.

CreatineKinase: 12,323 U/L

CasePreviousTesting:General examination and cranial nerve examination were normal

GenotypingMethod:

PreviouslyPublished:

Variant: NM_000231.2:c.525delT

ClinVar: 189243

PMID: 11261449

Gene: SGCG

HGNC: 10809

Case#: 10 y.o female, Palestinian-American

DiseaseAssertion: Limb Girdle muscular dystrophy

FamilyInfo: Parents are first cousins. Other two siblings had normal neurologic examination and normal creatine kinase values.

CasePresentingHPOs: HP:0003707, HP:0003701,HP:0003560, HP:0006785, HP:0003236,HP:0003325, HP:0008981, HP:0002515,

CaseHPOFreeText:During the physical examination the girl looked alert and aware. Calves were pseudohypertrophy

CaseNotHPOs:

CaseNotHPOFreeText:

MotorAchievement: Learned to walk at 15 months but if she fell couldnt get up. Not able to run by lifting her knees. She fatigued easier than her peers. Can’t stand on one foot. Waddling gait

CreatineKinase: 8,129 U/L

CasePreviousTesting: General examination and cranial nerve examination were normal.

GenotypingMethod: Muscle Biopsy of the quadricep. Immunostaining for sarcoglycan showed particle deficiency. Dystrophin and merson staining were normal

PreviouslyPublished:

Variant: NM_000231.2:c.525delT

ClinVar: 189243

Case#: 31 y.o Female European

DiseaseAssertion: Limb Girdle

FamilyInfo: Asymptomatic uncle who had persistent high serum CK levels

CasePresentingHPOs: HP:0003701,HP:0003560, HP:0006785, HP:0003236,HP:0003325, HP:0008981,

CaseHPOFreeText: Has seen a specialist for the last 25 years. High CADD scores. Exercise-induced myalgia and/or rhabdomyolysis

CaseNotHPOs:

CaseNotHPOFreeText:

MotorAchievement:

CreatineKinase: Ranging from 500 UI/L to 4500 UI/L

CasePreviousTesting: Latest neurological, cardiac and respiratory examinations were normal

GenotypingMethod: Muscle Biopsy using next generation sequencing and multiple gene panel. Minimal myopathic changes on histological assessment and normal immunofluorescence staining for muscle proteins including α-sarcoglycan.

PreviouslyPublished:

Variant: NM_000023.4(SGCA):c.850C>T (p.Arg284Cys) and NM_000023.4(SGCA):c.739G>A (p.Val247Met)

ClinVar: 9439 and 167677

CAID:

gnomAD: 0.0007716 and 0.0002411

Case#: 36 y.o male European

DiseaseAssertion: Limb Girdle

FamilyInfo: None

CasePresentingHPOs: HP:0003701,HP:0003560, HP:0006785, HP:0003236,HP:0003325, HP:0008981,

CaseHPOFreeText: Experienced two episodes of atrial fibrillation. High CADD scores. Exercise-induced myalgia and/or rhabdomyolysis

CaseNotHPOs:

CaseNotHPOFreeText:

MotorAchievement: Age 20 he developed exercise intolerance and sporadic myoglobinuria after intense exercise. Able to walk and cycle for long distances with little muscle pain.

CreatineKinase: Ranging from 1700 to 8000 UI/L), at the age of 10 years

CasePreviousTesting: Last neurological examination there was moderate calf hypertrophy.

GenotypingMethod: Muscle Biopsy using next generation sequencing and multiple gene panel. Minimal myopathic changes on histological assessment and normal immunofluorescence staining for muscle proteins including α-sarcoglycan

PreviouslyPublished:

Variant: NM_000023.4(SGCA):c.850C>T (p.Arg284Cys)

ClinVar: 9439

CAID:

gnomAD: 0.0007716

Case#: IV-1, male, 11 y.o, Pakistani

DiseaseAssertion: Limb-girdle muscular dystrophy (LGMD2F), sarcoglycanopathy

FamilyInfo: Consanguineous parents, both described as healthy and showing no abnormality. Three unaffected siblings were also reported: IV-2 (male, 10 y.o), IV-4 (male, 7 y.o), and IV-5 (female, 1.5 y.o). A deceased sister is included on the pedigree, but no details about this individual were reported. See Figure 1.

CasePresentingHPOs: HP:0001288, HP:0002650, HP:0003547, HP:0003749, HP:0001655

CaseHPOFreeText: Reduced weight gain noted at 3-4 y.o. Mild cardiac hypertrophy observed on cardiac review (additional echocardiography results reported in "Echocardiography" section). Additional phenotypic information reported in Supplementary Table 1.

CaseNotHPOs: HP:0009077, HP:0000703, HP:0001382, HP:0000365, HP:0001510, HP:0001249, HP:0000478, HP:0030148, HP:0011675

CaseNotHPOFreeText: Extensor muscles of the wrist, toes flexors, and hip abductors noted to be relatively normal. Additional phenotypic information reported in Supplementary Table 1.

MotorAchievement: Sat without assistance at 8 months of age, walked at 15 months of age, ran at 1.5 months of age. Never jumped or hopped. Frequent falls noted, as well as difficulty in walking and climbing stairs since 3 y.o.

CreatineKinase: 18SU (normal: 20SU for children, 10SU for adults) (see Supplementary Table 1). No assertion was made by the authors regarding whether this represents a normal or decreased CK level.

PreviousTesting: Thyroid stimulating hormone: 2.3mU/L (normal: <0.6mU/L); Serum VZV IgG: 286mlU/ml (normal: >150mlU/ml); IGF-1:186 ng/μl (normal: 102-520 ng/μl for males, 14 y.o); PRL: 202 ng/dl (normal: 42.5-414 ng/dl for males); Vitamin D: 47nmol/L (normal: 25-50 nmol/L); Free T4: 17.0 pmol/L (normal:10.8-19.0 pmol/L) (see Supplementary Table 1)

GenotypingMethod: (1) Targeted next generation sequencing of 31 genes associated with LGMD from proband genomic DNA extracted from peripheral blood sample; (2) Sanger sequencing of genomic DNA extracted from peripheral blood samples to confirm SGCD variant of interest in proband and three family members (III-3, III-4, IV-4). Variant was identified in homozygosity in the proband, in heterozygosity in each of the parents, and was not present in the unaffected sibling (IV-4).

Variant: NM_000337.5:c.289C>T (p.Arg97Ter)

CAID: CA3530549

gnomAD: Not reported