ZFIN ID: ZDB-PUB-150811-4
Exome Sequence Analysis Suggests that Genetic Burden Contributes to Phenotypic Variability and Complex Neuropathy
Gonzaga-Jauregui, C., Harel, T., Gambin, T., Kousi, M., Griffin, L.B., Francescatto, L., Ozes, B., Karaca, E., Jhangiani, S.N., Bainbridge, M.N., Lawson, K.S., Pehlivan, D., Okamoto, Y., Withers, M., Mancias, P., Slavotinek, A., Reitnauer, P.J., Goksungur, M.T., Shy, M., Crawford, T.O., Koenig, M., Willer, J., Flores, B.N., Pediaditrakis, I., Us, O., Wiszniewski, W., Parman, Y., Antonellis, A., Muzny, D.M., Baylor-Hopkins Center for Mendelian Genomics, Katsanis, N., Battaloglu, E., Boerwinkle, E., Gibbs, R.A., Lupski, J.R.
Date: 2015
Source: Cell Reports   12(7): 1169-83 (Journal)
Registered Authors: Francescatto, Ludmila, Katsanis, Nicholas, Slavotinek, Anne, Willer, Jason
Keywords: none
MeSH Terms:
  • Animals
  • Charcot-Marie-Tooth Disease/genetics*
  • Exome*
  • Female
  • Genetic Load*
  • Genetic Variation
  • HSP40 Heat-Shock Proteins/genetics
  • Humans
  • Male
  • Mutation
  • Myelin P2 Protein/genetics
  • Pedigree
  • Penetrance
  • Peripheral Nervous System Diseases/genetics*
  • Phenotype*
  • Serine C-Palmitoyltransferase/genetics
  • Suppression, Genetic
  • Zebrafish
PubMed: 26257172 Full text @ Cell Rep.
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┬ávivo 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.