Cell Reports (Aug 2015)
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,
- Nicholas Katsanis,
- Esra Battaloglu,
- Eric Boerwinkle,
- Richard A. Gibbs,
- James R. Lupski
Affiliations
- Claudia Gonzaga-Jauregui
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
- Tamar Harel
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
- Tomasz Gambin
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
- Maria Kousi
- Center for Human Disease Modeling, Duke University, Durham, NC 27701, USA
- Laurie B. Griffin
- Cellular and Molecular Biology Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA
- Ludmila Francescatto
- Center for Human Disease Modeling, Duke University, Durham, NC 27701, USA
- Burcak Ozes
- Department of Molecular Biology and Genetics, Bogazici University, Istanbul 34342, Turkey
- Ender Karaca
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
- Shalini N. Jhangiani
- Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA
- Matthew N. Bainbridge
- Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA
- Kim S. Lawson
- Human Genetics Center and Institute of Molecular Medicine, University of Texas-Houston Health Science Center, Houston, TX 77030, USA
- Davut Pehlivan
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
- Yuji Okamoto
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
- Marjorie Withers
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
- Pedro Mancias
- Division of Child & Adolescent Neurology, Department of Neurology and Pediatrics, University of Texas Medical School at Houston, Houston, TX 77030, USA
- Anne Slavotinek
- Division of Genetics, Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94158, USA
- Pamela J. Reitnauer
- Pediatric Teaching Program, Cone Health System and UNC-Chapel Hill, Greensboro, NC 27401, USA
- Meryem T. Goksungur
- Department of Neurology, Istanbul University, Istanbul Medical Faculty, Istanbul 34093, Turkey
- Michael Shy
- Department of Neurology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
- Thomas O. Crawford
- Departments of Neurology and Pediatrics, Johns Hopkins University, Baltimore, MD 21218, USA
- Michel Koenig
- Institut de Genetique et de Biologie Moleculaire et Cellulaire (IGBMC), CNRS-INSERM-Universite de Strasbourg, Illkirch 67404, France
- Jason Willer
- Center for Human Disease Modeling, Duke University, Durham, NC 27701, USA
- Brittany N. Flores
- Cellular and Molecular Biology Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA
- Igor Pediaditrakis
- Center for Human Disease Modeling, Duke University, Durham, NC 27701, USA
- Onder Us
- Department of Neurology, Acibadem Kozyatagı Hospital, Istanbul 34742, Turkey
- Wojciech Wiszniewski
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
- Yesim Parman
- Department of Neurology, Istanbul University, Istanbul Medical Faculty, Istanbul 34093, Turkey
- Anthony Antonellis
- Cellular and Molecular Biology Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA
- Donna M. Muzny
- Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA
- Nicholas Katsanis
- Center for Human Disease Modeling, Duke University, Durham, NC 27701, USA
- Esra Battaloglu
- Department of Molecular Biology and Genetics, Bogazici University, Istanbul 34342, Turkey
- Eric Boerwinkle
- Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA
- Richard A. Gibbs
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
- James R. Lupski
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
- DOI
- https://doi.org/10.1016/j.celrep.2015.07.023
- Journal volume & issue
-
Vol. 12,
no. 7
pp. 1169 – 1183
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.
