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

TitleThe sensitivity of exome sequencing in identifying pathogenic mutations for LGMD in the United States.
Publication TypeJournal Article
Year of Publication2017
AuthorsReddy, HM, Cho, K-A, Lek, M, Estrella, E, Valkanas, E, Jones, MD, Mitsuhashi, S, Darras, BT, Amato, AA, Lidov, HGw, Brownstein, CA, Margulies, DM, Yu, TW, Salih, MA, Kunkel, LM, MacArthur, DG, Kang, PB
JournalJ Hum Genet
Date Published2017 Feb
KeywordsBase Sequence, Distal Myopathies, Exome, Female, Genetic Testing, Glycogen Storage Disease Type II, Humans, Male, Muscular Dystrophies, Limb-Girdle, Muscular Dystrophy, Duchenne, Muscular Dystrophy, Facioscapulohumeral, Mutation, Myopathies, Structural, Congenital, Sequence Analysis, DNA, 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 cosegregation patterns were confirmed by Sanger sequencing. Twenty-two families (40%) had novel and previously reported pathogenic mutations, primarily in LGMD genes, and 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 because of the phenotypic overlap of many neuromuscular conditions. The confirmation of a benign DMD variant illustrates the potential of exome sequencing to help determine pathogenicity.

Alternate JournalJ Hum Genet
PubMed ID27708273
PubMed Central IDPMC5266644
Grant ListUM1 HG008900 / HG / NHGRI NIH HHS / United States
U54 HG003067 / HG / NHGRI NIH HHS / United States
R01 AR064300 / AR / NIAMS NIH HHS / United States
U54 HD090255 / HD / NICHD NIH HHS / United States
R01 GM104371 / GM / NIGMS NIH HHS / United States
R01 NS080929 / NS / NINDS NIH HHS / United States