RESUMO
BACKGROUND: Fifty random genetically unstudied families (limb-girdle muscular dystrophy (LGMD)/myopathy) were screened with a gene panel incorporating 759 OMIM genes associated with neurological disorders. Average coverage of the CDS and 10 bp flanking regions of genes was 99 %. All families were referred to the Neurosciences Clinic of King Faisal Specialist Hospital and Research Centre, Saudi Arabia. Patients presented with muscle weakness affecting the pelvic and shoulder girdle. Muscle biopsy in all cases showed dystrophic or myopathic changes. Our main objective was to evaluate a neurological gene panel as a first-line diagnostic test for LGMD/myopathies. RESULTS: Our panel identified the mutation in 76 % of families (38/50; 11 novel). Thirty-four families had mutations in LGMD-related genes with four others having variants not typically associated with LGMD. The majority of cases had recessive inheritance with homoallelic pathogenic variants (97.4 %, 37/38), as expected considering the high rate of consanguinity in the study population. In one case, we detected a heterozygous mutation in DNAJB responsible for LGMD-1E. Our cohort included seven different subtypes of LGMD2. Mutations of DYSF were the most commonly identified cause of disease followed by that in CAPN3 and FKRP. Non-LGMD myopathies were due to mutations in genes associated with congenital disorder of glycosylation (ALG2), rigid spine muscular dystrophy 1 (SEPN1), inclusion body myopathy2/Nonaka myopathy (GNE), and neuropathy (WNK1). Whole exome sequencing (WES) of patients who remained undiagnosed with the neurological panel did not improve our diagnostic yield. CONCLUSIONS: Our neurological panel achieved a high clinical sensitivity (76 %) and is an effective first-line laboratory test in patients with LGMD and other myopathies. This sensitive, cost-effective, and rapid assay significantly assists clinical practice especially in these phenotypically and genetically heterogeneous disorders. Moreover, the application of the American College of Medical Genetics (ACMG) and Association for Molecular Pathology (AMP) guidelines applied in the classification of variant pathogenecity provides a clear interpretation for physicians on the relevance of such findings.
RESUMO
OBJECTIVE: Characterization of the phenotypic, pathological, radiological, and genetic findings in 2 Saudi Arabian families with anoctaminopathies, and limb girdle muscular dystrophy type 2L (LGMD2L). METHODS: Over a 2-year period from December 2010 to January 2013, the clinical presentations were analyzed and all genes responsible for limb girdle muscular dystrophy (LGMD) were screened in families seen at King Faisal Specialist Hospital and Research Centre, a tertiary care hospital in Riyadh, Saudi Arabia. Out of 66 families with LGMD, we identified 2 families (3.1%) with anoctaminopathy, ANO5 muscular dystrophy. RESULTS: In the first case, a man presented with asymmetrical calves` muscles weakness and atrophy, which was first noted at age 39. The creatinine kinase (CK) level was >20x normal, muscle biopsy showed necrotizing myopathic changes, and an MRI of the legs showed fatty-tissue replacement to muscle tissue with volume loss involving the gastrocnemius and soleus muscles in an asymmetrical fashion. Minimal disease progression was noted over 18 years of follow up. Exercise induced recurrent rhabdomyolysis was noted over the last 2 years. A novel ANO5 gene mutation (Arg58Trp) was found. In the second family, a male presented at the age of 41 with asymptomatic hyperCkemia and intermittent dyspnea. Over 10 years follow up, he became disabled with muscle cramps, rhabdomyolysis, my oglobinurea, and difficulty ambulating. Muscle biopsy showed necrotizing myopathy and perivascular and interstitial amyloid deposit in skeletal muscle. A homozygous deletion of 11.9 Kb encompassing exon 13 to exon 17 was found in the ANO5 gene. Full cardiac investigations were normal in both patients. CONCLUSION: The prevalence of LGMD2L is approximately 3.1% in a Saudi Arabian native LGMD cohort. Slowly progressive, late onset, and asymmetrical weakness was the salient features in these 2 families. The genetic findings were novel and will add to the spectrum of ANO5 known mutations.
