TY - JOUR
T1 - The sensitivity of exome sequencing in identifying pathogenic mutations for LGMD in the United States
AU - Reddy, Hemakumar M.
AU - Cho, Kyung Ah
AU - Lek, Monkol
AU - Estrella, Elicia
AU - Valkanas, Elise
AU - Jones, Michael D.
AU - Mitsuhashi, Satomi
AU - Darras, Basil T.
AU - Amato, Anthony A.
AU - Lidov, Hart Gw
AU - Brownstein, Catherine A.
AU - Margulies, David M.
AU - Yu, Timothy W.
AU - Salih, Mustafa A.
AU - Kunkel, Louis M.
AU - Macarthur, Daniel G.
AU - Kang, Peter B.
N1 - Publisher Copyright:
© 2017 The Japan Society of Human Genetics All rights reserved.
PY - 2017/2/1
Y1 - 2017/2/1
N2 - 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.
AB - 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.
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U2 - 10.1038/jhg.2016.116
DO - 10.1038/jhg.2016.116
M3 - Article
C2 - 27708273
AN - SCOPUS:85010886965
SN - 1434-5161
VL - 62
SP - 243
EP - 252
JO - Journal of Human Genetics
JF - Journal of Human Genetics
IS - 2
ER -