PUBLICATION
Exome Sequence Analysis Suggests that Genetic Burden Contributes to Phenotypic Variability and Complex Neuropathy
- Authors
- 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.
- ID
- ZDB-PUB-150811-4
- 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.
Citation
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. (2015) Exome Sequence Analysis Suggests that Genetic Burden Contributes to Phenotypic Variability and Complex Neuropathy. Cell Reports. 12(7):1169-83.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping