Journal article
Exome Sequence Analysis Suggests that Genetic Burden Contributes to Phenotypic Variability and Complex Neuropathy
Cell reports (Cambridge), Vol.12(7), pp.1169-1183
08/18/2015
DOI: 10.1016/j.celrep.2015.07.023
PMCID: PMC4545408
PMID: 26257172
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.
Details
- Title: Subtitle
- Exome Sequence Analysis Suggests that Genetic Burden Contributes to Phenotypic Variability and Complex Neuropathy
- Creators
- Claudia Gonzaga-Jauregui - Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Center for Human Disease Modeling, Duke University, Durham, NC 27701, USATamar Harel - Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USATomasz Gambin - Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USAMaria Kousi - Center for Human Disease Modeling, Duke University, Durham, NC 27701, USALaurie B Griffin - Cellular and Molecular Biology Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Medical Scientist Training Program, University of Michigan Medical School, Ann Arbor, MI 48109, USALudmila Francescatto - Center for Human Disease Modeling, Duke University, Durham, NC 27701, USABurcak Ozes - Department of Molecular Biology and Genetics, Bogazici University, Istanbul 34342, TurkeyEnder Karaca - Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USAShalini N Jhangiani - Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USAMatthew N Bainbridge - Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USAKim S Lawson - Human Genetics Center and Institute of Molecular Medicine, University of Texas-Houston Health Science Center, Houston, TX 77030, USADavut Pehlivan - Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USAYuji Okamoto - Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USAMarjorie Withers - Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USAPedro Mancias - Division of Child & Adolescent Neurology, Department of Neurology and Pediatrics, University of Texas Medical School at Houston, Houston, TX 77030, USAAnne Slavotinek - Division of Genetics, Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94158, USAPamela J Reitnauer - Pediatric Teaching Program, Cone Health System and UNC-Chapel Hill, Greensboro, NC 27401, USAMeryem T Goksungur - Department of Neurology, Istanbul University, Istanbul Medical Faculty, Istanbul 34093, TurkeyMichael Shy - Department of Neurology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USAThomas O Crawford - Departments of Neurology and Pediatrics, Johns Hopkins University, Baltimore, MD 21218, USAMichel Koenig - Institut de Genetique et de Biologie Moleculaire et Cellulaire (IGBMC), CNRS-INSERM-Universite de Strasbourg, Illkirch 67404, France; INSERM UMR_S 827, Institut Universitaire de Recherche Clinique and Laboratoire de Génétique Moléculaire, Centre Hospitalier Universitaire de Montpellier, Montpellier 34093, FranceJason Willer - Center for Human Disease Modeling, Duke University, Durham, NC 27701, USABrittany N Flores - Cellular and Molecular Biology Program, University of Michigan Medical School, Ann Arbor, MI 48109, USAIgor Pediaditrakis - Center for Human Disease Modeling, Duke University, Durham, NC 27701, USAOnder Us - Department of Neurology, Acibadem Kozyatagı Hospital, Istanbul 34742, TurkeyWojciech Wiszniewski - Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USAYesim Parman - Department of Neurology, Istanbul University, Istanbul Medical Faculty, Istanbul 34093, TurkeyAnthony Antonellis - Cellular and Molecular Biology Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Neurology, University of Michigan Medical School, Ann Arbor, MI 48109, USADonna M Muzny - Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USANicholas Katsanis - Center for Human Disease Modeling, Duke University, Durham, NC 27701, USAEsra Battaloglu - Department of Molecular Biology and Genetics, Bogazici University, Istanbul 34342, TurkeyEric Boerwinkle - Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Human Genetics Center and Institute of Molecular Medicine, University of Texas-Houston Health Science Center, Houston, TX 77030, USARichard A Gibbs - Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USAJames R Lupski - Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA. Electronic address: jlupski@bcm.edu
- Resource Type
- Journal article
- Publication Details
- Cell reports (Cambridge), Vol.12(7), pp.1169-1183
- Publisher
- United States
- DOI
- 10.1016/j.celrep.2015.07.023
- PMID
- 26257172
- PMCID
- PMC4545408
- ISSN
- 2211-1247
- eISSN
- 2211-1247
- Grant note
- U54HG003273 / NHGRI NIH HHS T32 GM007863 / NIGMS NIH HHS F30 NS092238 / NINDS NIH HHS P50 MH094268 / NIMH NIH HHS T32 GM07526-37 / NIGMS NIH HHS T32 GM007526 / NIGMS NIH HHS U54HG006542 / NHGRI NIH HHS R01 NS075764 / NINDS NIH HHS R01 NS058529 / NINDS NIH HHS U54 HG003273 / NHGRI NIH HHS U54NS065712 / NINDS NIH HHS T32 GM007315 / NIGMS NIH HHS R01NS075764 / NINDS NIH HHS U54 HG006542 / NHGRI NIH HHS K23NS078056 / NINDS NIH HHS R01NS058529 / NINDS NIH HHS NS092238 / NINDS NIH HHS K23 NS078056 / NINDS NIH HHS GM007315 / NIGMS NIH HHS U54 NS065712 / NINDS NIH HHS GM07863 / NIGMS NIH HHS
- Language
- English
- Date published
- 08/18/2015
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Stead Family Department of Pediatrics; Iowa Neuroscience Institute
- Record Identifier
- 9984020899602771
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