The sensitivity of exome sequencing in identifying pathogenic mutations for LGMD in the United States

The current study characterizes a cohort of limb-girdle muscular dystrophy (LGMD) in the United States using whole exome sequencing. Fifty-five families affected by LGMD were recruited using an institutionally-approved protocol. Exome sequencing was performed on probands and selected parental samples. Pathogenic mutations and co-segregation patterns were confirmed by Sanger sequencing. Twenty-two families (40%) had novel and previously reported pathogenic mutations, primarily in LGMD genes, but also in genes for Duchenne muscular dystrophy, facioscapulohumeral muscular dystrophy, congenital myopathy, myofibrillar myopathy, inclusion body myopathy, and Pompe disease. One family was diagnosed via clinical testing. Dominant mutations were identified in COL6A1, COL6A3, FLNC, LMNA, RYR1, SMCHD1, and VCP, recessive mutations in ANO5, CAPN3, GAA, LAMA2, SGCA, and SGCG, and X-linked mutations in DMD. A previously reported variant in DMD was confirmed to be benign. Exome sequencing is a powerful diagnostic tool for LGMD. Despite careful phenotypic screening, pathogenic mutations were found in other muscle disease genes, largely accounting for the increased sensitivity of exome sequencing. Our experience suggests that broad sequencing panels are useful for these analyses due to the phenotypic overlap of many neuromuscular conditions. The confirmation of a benign DMD variant illustrates the potential of exome sequencing to help determine pathogenicity.