Title | The sensitivity of exome sequencing in identifying pathogenic mutations for LGMD in the United States. |
Publication Type | Journal Article |
Year of Publication | 2017 |
Authors | Reddy, 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 |
Journal | J Hum Genet |
Volume | 62 |
Issue | 2 |
Pagination | 243-252 |
Date Published | 2017 Feb |
ISSN | 1435-232X |
Keywords | Base 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 |
Abstract | 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. |
DOI | 10.1038/jhg.2016.116 |
Alternate Journal | J Hum Genet |
PubMed ID | 27708273 |
PubMed Central ID | PMC5266644 |
Grant List | UM1 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 |