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

Hemakumar M. Reddy, Kyung Ah Cho, Monkol Lek, Elicia Estrella, Elise Valkanas, Michael D. Jones, Satomi Mitsuhashi, Basil T. Darras, Anthony A. Amato, Hart Gw Lidov, Catherine A. Brownstein, David M. Margulies, Timothy W. Yu, Mustafa A. Salih, Louis M. Kunkel, Daniel G. Macarthur, Peter B. Kang

Research output: Contribution to journalArticlepeer-review

69 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)243-252
Number of pages10
JournalJournal of Human Genetics
Issue number2
StatePublished - Feb 1 2017
Externally publishedYes

Bibliographical note

Funding Information:
We thank all the study participants for their valuable contributions to this study. The work was supported by NIH R01 NS080929 (HMR, KAC, EE and PBK), NIH R01 GM104371 (DGM), Department of Pediatrics at the University of Florida College of Medicine (KAC and PBK), Muscular Dystrophy Association Research Grant 186796 (PBK) and the Bernard F and Alva B Gimbel Foundation (LMK). Exome sequencing was supported by Medical Sequencing Program Grant U54HG003067 from the National Human Genome Research Institute. MAS was supported by the Deanship of Scientific Research, King Saud University, Riyadh, Saudi Arabia via research group project number RGP-VPP-301.

Publisher Copyright:
© 2017 The Japan Society of Human Genetics All rights reserved.


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