Targeted Next Generation Sequencing Approach Towards Improving Genetic Diagnosis of Limb Girdle Muscular Dystrophy

Abstract

Limb-girdle muscular dystrophies (LGMDs) are a heterogeneous group of rare muscle disorders in which progressive skeletal muscle weakness and wasting affect primarily the shoulders, hips and proximal limbs. More than 30 genes are causally linked to LGMDs; many more are implicated in metabolic, congenital, and other myopathies that present with LGMD-like patterns of muscle weakness. For patients affected by myopathies characterized by limb-girdle weakness, receiving a genetic diagnosis can impact their prognosis, therapeutic options and reproductive choices. We hypothesize that using whole exome sequencing as a first-pass diagnostic approach effectively prioritizes causal variants of LGMDs and clinically similar myopathies. Targeted whole exome sequencing was applied to 1,001 undiagnosed patients of mixed ancestry with suspected genetic muscle disease. We analyzed exome data for pathogenic variants in 169 muscle disease-associated genes. Likely causal variants were identified in 468 families (47%), involving 72 genes. LGMD2A, due to mutations in CAPN3, was the most common disease in our cohort. Variants in CAPN3, DYSF, ANO5, DMD, RYR1, TTN, COL6A2 and SGCA collectively accounted for more than half of the solved cases. Over 150 patients were diagnosed with conditions for which effective therapies or tailored management were available, all of which are currently being applied. We assembled one of the largest genetically characterized muscle disease cohort. Our results demonstrate that WES represents a powerful approach for diagnosis in a clinically and genetically heterogeneous disease, and in a subset of patients can identify diagnoses that alter clinical outcomes.