G.P.219: Diagnosing the limb-girdle muscular dystrophies using whole exome sequencing: An Australian cohort

Abstract

Limb-girdle muscular dystrophies (LGMDs) are a heterogeneous group of genetic disorders associated with proximal muscle weakness that begins after 2 years of age and dystrophic changes on muscle biopsy. The genetic cause of LGMD in Australia remains uncertain in approximately 40% of patients resulting in uncertainty about reproductive risks for patients and long term prognosis. We reviewed the clinical information in a large cohort of patients with LGMD who lacked a genetic diagnosis, usually after extensive previous investigations ( n = 50). We first screened patients for myotonic dystrophy type 2 and then performed whole exome sequencing (WES), analysing data using the ‘xBrowse’ web interface (Broad Institute). Testing for myotonic dystrophy type 2 (DM2) identified 2 families in our LGMD cohort. Using WES we identified likely pathogenic mutations in known myopathy genes in 20 families, often in genes not typically associated with LGMD. Two families were diagnosed with dominant LGMD, 9 families with recessive LGMD, 3 with mutations congenital muscular dystrophy genes, 3 with collagen myopathies, 2 with metabolic myopathies and 1 in ACTA1. In addition one family had a mutation CHD7, a gene usually associated with CHARGE syndrome. Our overall diagnostic success rate was 46% in our LGMD cohort of patients most of whom had been extensively investigated previously and who remained without a genetic diagnosis. The diversity of genetic causes that we identified supports the clinical observation of that LGMD is highly heterogeneous and shares clinical features with many other forms of myopathy. Our study emphasises the challenges that clinicians face making a genetic diagnosis in all families. Whole exome sequencing and similar next-generation sequencing are likely to be efficient and cost-effective methods for identifying the genetic basis of LGMD but clinicians must remember that some disorders in the differential diagnosis, such as DM2, are routinely missed by WES.