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. Crawford; Michel Koenig; Jason Willer; Brittany N. Flores; Igor Pediaditrakis; Onder Us; Wojciech Wiszniewski; Yesim Parman; Anthony Antonellis; Donna M. Muzny; Elias Nicholas Katsanis; Esra Battaloglu; Eric Boerwinkle; Richard A. Gibbs; James R. Lupski

doi:10.1016/j.celrep.2015.07.023

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, Elias Nicholas Katsanis, Esra Battaloglu, Eric Boerwinkle, Richard A. Gibbs, James R. Lupski^*

^*Corresponding author for this work

Pediatrics

Research output: Contribution to journal › Article › peer-review

200 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 language	English (US)
Pages (from-to)	1169-1183
Number of pages	15
Journal	Cell reports
Volume	12
Issue number	7
DOIs	https://doi.org/10.1016/j.celrep.2015.07.023
State	Published - Aug 18 2015

Funding

This work was supported in part by US National Institute of Neurological Disorders and Stroke (NINDS) grant R01NS058529 to J.R.L.; US National Human Genome Research Institute (NHGRI) grant National Heart, Lung, and Blood Institute (NHLBI) grant U54HG006542 to the Baylor-Hopkins Center for Mendelian Genomics and US National Human Genome Research Institute (NHGRI) grant U54HG003273 to R.A.G.; by seed funding from the Center for Human Disease Modeling, Duke University and by P50 MH094268 to N.K. A.A. is supported by a grant from the Muscular Dystrophy Association (MDA294479). W.W. is supported by the Career Development Award K23NS078056 from NINDS. T.H. is supported by the T32 GM07526-37 Medical Genetics Research Fellowship Program. L.B.G. was supported by the NIH Cellular and Molecular Biology Training Grant (GM007315), the NIH Medical Scientist Training Grant (GM07863), and an NIH F30 NRSA (NS092238). M.S. is supported by grants from MDA, CMTA, and NINDS/NCATS (U54NS065712) and from NINDS (R01NS075764).

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

Access to Document

10.1016/j.celrep.2015.07.023

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

@article{b1a16fa20997410c8c1d2fc432df4ecb,

title = "Exome Sequence Analysis Suggests that Genetic Burden Contributes to Phenotypic Variability and Complex Neuropathy",

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.",

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

note = "Publisher Copyright: {\textcopyright} 2015 The Authors.",

year = "2015",

month = aug,

day = "18",

doi = "10.1016/j.celrep.2015.07.023",

language = "English (US)",

volume = "12",

pages = "1169--1183",

journal = "Cell reports",

issn = "2211-1247",

publisher = "Cell Press",

number = "7",

}

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, EN, 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

TY - JOUR

T1 - Exome Sequence Analysis Suggests that Genetic Burden Contributes to Phenotypic Variability and Complex Neuropathy

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 O.

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, Elias Nicholas

AU - Battaloglu, Esra

AU - Boerwinkle, Eric

AU - Gibbs, Richard A.

AU - Lupski, James R.

PY - 2015/8/18

Y1 - 2015/8/18

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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84941023992&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84941023992&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2015.07.023

DO - 10.1016/j.celrep.2015.07.023

M3 - Article

C2 - 26257172

AN - SCOPUS:84941023992

SN - 2211-1247

VL - 12

SP - 1169

EP - 1183

JO - Cell reports

JF - Cell reports

IS - 7

ER -

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

Abstract

Funding

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this