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

Claudia Gonzaga-Jauregui , Tamar Harel , Tomasz Gambin , Maria Kousi , Laurie Griffin , Ludmila Francescatto , Burcak Ozes , Ender Karaca , Shalini Jhangiani , Matthew Bainbridge , Kim Lawson , Davut Pehlivan , Yuji Okamoto , Marjorie Withers , Pedro Mancias , Anne Slavotinek , Pamela J. Reitnauer (1) , Meryem Goksungur , Michael Shy (2) , Thomas Crawford , Michel Koenig (3, 4) , Jason Willer , Brittany Flores , Igor Pediaditrakis , Onder Us , Wojciech Wiszniewski , Yesim Parman , Anthony Antonellis , Donna Muzny (5) , Esra Battaloglu , Eric Boerwinkle (5) , Richard A. Gibbs (5) , James R Lupski (5)

1 Department of Pediatrics
2 University of Michigan [Ann Arbor]
3 LGMR - Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques
4 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]
5 BCM - Baylor College of Medicine

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.

Domaines: Biologie cellulaire

Claudia Gonzaga-Jauregui, Tamar Harel, Tomasz Gambin, Maria Kousi, Laurie Griffin, et al.. Exome Sequence Analysis Suggests that Genetic Burden Contributes to Phenotypic Variability and Complex Neuropathy. Cell Reports, 2015, 12 (7), pp.1169-1183. ⟨10.1016/j.celrep.2015.07.023⟩. ⟨hal-01958695⟩