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

TitleExome Sequence Analysis Suggests that Genetic Burden Contributes to Phenotypic Variability and Complex Neuropathy.
Publication TypeJournal Article
Year of Publication2015
AuthorsGonzaga-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, Katsanis, N, Battaloglu, E, Boerwinkle, E, Gibbs, RA, Lupski, JR
Corporate Authors
JournalCell Rep
Volume12
Issue7
Pagination1169-83
Date Published2015 Aug 18
ISSN2211-1247
KeywordsAnimals, Charcot-Marie-Tooth Disease, Exome, Female, Genetic Load, Genetic Variation, HSP40 Heat-Shock Proteins, Humans, Male, Mutation, Myelin P2 Protein, Pedigree, Penetrance, Peripheral Nervous System Diseases, Phenotype, Serine C-Palmitoyltransferase, Suppression, Genetic, Zebrafish
Abstract

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.

DOI10.1016/j.celrep.2015.07.023
Alternate JournalCell Rep
PubMed ID26257172
PubMed Central IDPMC4545408
Grant ListP50 MH094268 / MH / NIMH NIH HHS / United States
U54HG003273 / HG / NHGRI NIH HHS / United States
U54 HG006542 / HG / NHGRI NIH HHS / United States
T32 GM007526 / GM / NIGMS NIH HHS / United States
U54 NS065712 / NS / NINDS NIH HHS / United States
R01NS058529 / NS / NINDS NIH HHS / United States
U54HG006542 / HG / NHGRI NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States
GM07863 / GM / NIGMS NIH HHS / United States
T32 GM007863 / GM / NIGMS NIH HHS / United States
K23 NS078056 / NS / NINDS NIH HHS / United States
T32 GM07526-37 / GM / NIGMS NIH HHS / United States
F30 NS092238 / NS / NINDS NIH HHS / United States
U54NS065712 / NS / NINDS NIH HHS / United States
R01 NS058529 / NS / NINDS NIH HHS / United States
GM007315 / GM / NIGMS NIH HHS / United States
K23NS078056 / NS / NINDS NIH HHS / United States
R01NS075764 / NS / NINDS NIH HHS / United States
R01 NS075764 / NS / NINDS NIH HHS / United States
NS092238 / NS / NINDS NIH HHS / United States
T32 GM007315 / GM / NIGMS NIH HHS / United States