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 Owen 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

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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Exome
Sequence Analysis
Genes
Mutation
Charcot-Marie-Tooth Disease
Polyneuropathies
Peripheral Nervous System Diseases
Zebrafish
Refractory materials
Assays
Tooth
Phenotype

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., ... 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

Exome Sequence Analysis Suggests that Genetic Burden Contributes to Phenotypic Variability and Complex Neuropathy. / Gonzaga-Jauregui, Claudia; Harel, Tamar; Gambin, Tomasz; Kousi, Maria; Griffin, Laurie B.; Francescatto, Ludmila; Ozes, Burcak; Karaca, Ender; Jhangiani, Shalini N.; Bainbridge, Matthew N.; Lawson, Kim S.; Pehlivan, Davut; Okamoto, Yuji; Withers, Marjorie; Mancias, Pedro; Slavotinek, Anne; Reitnauer, Pamela J.; Goksungur, Meryem T.; Shy, Michael; Crawford, Thomas Owen; Koenig, Michel; Willer, Jason; Flores, Brittany N.; Pediaditrakis, Igor; Us, Onder; Wiszniewski, Wojciech; Parman, Yesim; Antonellis, Anthony; Muzny, Donna M.; Katsanis, Nicholas; Battaloglu, Esra; Boerwinkle, Eric; Gibbs, Richard A.; Lupski, James R.

In: Cell Reports, Vol. 12, No. 7, 18.08.2015, p. 1169-1183.

Research output: Contribution to journalArticle

Gonzaga-Jauregui, C, Harel, T, Gambin, T, Kousi, M, Griffin, LB, Francescatto, L, Ozes, B, Karaca, E, Jhangiani, SN, Bainbridge, MN, Lawson, KS, Pehlivan, D, Okamoto, Y, Withers, M, Mancias, P, Slavotinek, A, Reitnauer, PJ, Goksungur, MT, Shy, M, Crawford, TO, Koenig, M, Willer, J, Flores, BN, Pediaditrakis, I, Us, O, Wiszniewski, W, Parman, Y, Antonellis, A, Muzny, DM, Katsanis, N, Battaloglu, E, Boerwinkle, E, Gibbs, RA & Lupski, JR 2015, 'Exome Sequence Analysis Suggests that Genetic Burden Contributes to Phenotypic Variability and Complex Neuropathy', Cell Reports, vol. 12, no. 7, pp. 1169-1183. https://doi.org/10.1016/j.celrep.2015.07.023
Gonzaga-Jauregui C, Harel T, Gambin T, Kousi M, Griffin LB, Francescatto L et al. Exome Sequence Analysis Suggests that Genetic Burden Contributes to Phenotypic Variability and Complex Neuropathy. Cell Reports. 2015 Aug 18;12(7):1169-1183. https://doi.org/10.1016/j.celrep.2015.07.023
Gonzaga-Jauregui, Claudia ; Harel, Tamar ; Gambin, Tomasz ; Kousi, Maria ; Griffin, Laurie B. ; Francescatto, Ludmila ; Ozes, Burcak ; Karaca, Ender ; Jhangiani, Shalini N. ; Bainbridge, Matthew N. ; Lawson, Kim S. ; Pehlivan, Davut ; Okamoto, Yuji ; Withers, Marjorie ; Mancias, Pedro ; Slavotinek, Anne ; Reitnauer, Pamela J. ; Goksungur, Meryem T. ; Shy, Michael ; Crawford, Thomas Owen ; Koenig, Michel ; Willer, Jason ; Flores, Brittany N. ; Pediaditrakis, Igor ; Us, Onder ; Wiszniewski, Wojciech ; Parman, Yesim ; Antonellis, Anthony ; Muzny, Donna M. ; Katsanis, Nicholas ; Battaloglu, Esra ; Boerwinkle, Eric ; Gibbs, Richard A. ; Lupski, James R. / Exome Sequence Analysis Suggests that Genetic Burden Contributes to Phenotypic Variability and Complex Neuropathy. In: Cell Reports. 2015 ; Vol. 12, No. 7. pp. 1169-1183.
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AU - Gonzaga-Jauregui, Claudia

AU - Harel, Tamar

AU - Gambin, Tomasz

AU - Kousi, Maria

AU - Griffin, Laurie B.

AU - Francescatto, Ludmila

AU - Ozes, Burcak

AU - Karaca, Ender

AU - Jhangiani, Shalini N.

AU - Bainbridge, Matthew N.

AU - Lawson, Kim S.

AU - Pehlivan, Davut

AU - Okamoto, Yuji

AU - Withers, Marjorie

AU - Mancias, Pedro

AU - Slavotinek, Anne

AU - Reitnauer, Pamela J.

AU - Goksungur, Meryem T.

AU - Shy, Michael

AU - Crawford, Thomas Owen

AU - Koenig, Michel

AU - Willer, Jason

AU - Flores, Brittany N.

AU - Pediaditrakis, Igor

AU - Us, Onder

AU - Wiszniewski, Wojciech

AU - Parman, Yesim

AU - Antonellis, Anthony

AU - Muzny, Donna M.

AU - Katsanis, Nicholas

AU - Battaloglu, Esra

AU - Boerwinkle, Eric

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AU - Lupski, James R.

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N2 - 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.

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