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

Claudia Gonzaga-Jauregui, Tamar Harel, Tomasz Gambin, Maria Kousi, Laurie B. Griffin, Ludmila Francescatto, Burcak Ozes, Ender Karaca, Shalini N. Jhangiani, Matthew N. Bainbridge, Kim S. Lawson, Davut Pehlivan, Yuji Okamoto, Marjorie Withers, Pedro Mancias, Anne Slavotinek, Pamela J. Reitnauer, Meryem T. Goksungur, Michael Shy, Thomas O. CrawfordMichel Koenig, Jason Willer, Brittany N. Flores, Igor Pediaditrakis, Onder Us, Wojciech Wiszniewski, Yesim Parman, Anthony Antonellis, Donna M. Muzny, Nicholas Katsanis, Esra Battaloglu, Eric Boerwinkle, Richard A. Gibbs, James R. Lupski

Research output: Contribution to journalArticle

112 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1169-1183
Number of pages15
JournalCell Reports
Volume12
Issue number7
DOIs
StatePublished - Aug 18 2015

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

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., ... Lupski, J. R. (2015). Exome Sequence Analysis Suggests that Genetic Burden Contributes to Phenotypic Variability and Complex Neuropathy. Cell Reports, 12(7), 1169-1183. https://doi.org/10.1016/j.celrep.2015.07.023