Journal
CELL REPORTS
Volume 12, Issue 7, Pages 1169-1183Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2015.07.023
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Funding
- US National Institute of Neurological Disorders and Stroke (NINDS) [R01NS058529]
- US National Human Genome Research Institute (NHGRI) grant National Heart, Lung, and Blood Institute (NHLBI) grant [U54HG006542]
- US National Human Genome Research Institute (NHGRI) [U54HG003273]
- Center for Human Disease Modeling, Duke University
- Muscular Dystrophy Association [P50 MH094268, MDA294479]
- NINDS [K23NS078056, R01NS075764]
- Medical Genetics Research Fellowship Program [T32 GM07526-37]
- NIH [GM007315]
- NIH Medical Scientist Training Grant [GM07863]
- NIH F30 NRSA [NS092238]
- MDA
- CMTA
- NINDS/NCATS [U54NS065712]
- Regeneron Pharmaceuticals
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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 similar to 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.
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