Exome Sequence Analysis Suggests that Genetic Burden Contributes to Phenotypic Variability and Complex Neuropathy.


Journal Article

Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous distal symmetric polyneuropathy. Whole-exome sequencing (WES) of 40 individuals from 37 unrelated families with CMT-like peripheral neuropathy refractory to molecular diagnosis identified apparent causal mutations in ∼ 45% (17/37) of families. Three candidate disease genes are proposed, supported by a combination of genetic and in vivo studies. Aggregate analysis of mutation data revealed a significantly increased number of rare variants across 58 neuropathy-associated genes in subjects versus controls, confirmed in a second ethnically discrete neuropathy cohort, suggesting that mutation burden potentially contributes to phenotypic variability. Neuropathy genes shown to have highly penetrant Mendelizing variants (HPMVs) and implicated by burden in families were shown to interact genetically in a zebrafish assay exacerbating the phenotype established by the suppression of single genes. Our findings suggest that the combinatorial effect of rare variants contributes to disease burden and variable expressivity.

Full Text

Cited Authors

  • Gonzaga-Jauregui, C; Harel, T; Gambin, T; Kousi, M; Griffin, LB; Francescatto, L; Ozes, B; Karaca, E; Jhangiani, SN; Bainbridge, MN; Lawson, KS; Pehlivan, D; Okamoto, Y; Withers, M; Mancias, P; Slavotinek, A; Reitnauer, PJ; Goksungur, MT; Shy, M; Crawford, TO; Koenig, M; Willer, J; Flores, BN; Pediaditrakis, I; Us, O; Wiszniewski, W; Parman, Y; Antonellis, A; Muzny, DM; Baylor-Hopkins Center for Mendelian Genomics, ; Katsanis, N; Battaloglu, E; Boerwinkle, E; Gibbs, RA; Lupski, JR

Published Date

  • August 18, 2015

Published In

Volume / Issue

  • 12 / 7

Start / End Page

  • 1169 - 1183

PubMed ID

  • 26257172

Pubmed Central ID

  • 26257172

Electronic International Standard Serial Number (EISSN)

  • 2211-1247

Digital Object Identifier (DOI)

  • 10.1016/j.celrep.2015.07.023


  • eng

Conference Location

  • United States