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.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Center for Human Disease Modeling, Duke University, Durham, NC 27701, USA.
authors.forename: Claudia
authors.initials: C
authors.lastname: Gonzaga-Jauregui
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Tamar
authors.initials: T
authors.lastname: Harel
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Gambin
authors.affiliation: Center for Human Disease Modeling, Duke University, Durham, NC 27701, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Kousi
authors.affiliation: 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, USA.
authors.forename: Laurie B
authors.initials: LB
authors.lastname: Griffin
authors.affiliation: Center for Human Disease Modeling, Duke University, Durham, NC 27701, USA.
authors.forename: Ludmila
authors.initials: L
authors.lastname: Francescatto
authors.affiliation: Department of Molecular Biology and Genetics, Bogazici University, Istanbul 34342, Turkey.
authors.forename: Burcak
authors.initials: B
authors.lastname: Ozes
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Ender
authors.initials: E
authors.lastname: Karaca
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Shalini N
authors.initials: SN
authors.lastname: Jhangiani
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Matthew N
authors.initials: MN
authors.lastname: Bainbridge
authors.affiliation: Human Genetics Center and Institute of Molecular Medicine, University of Texas-Houston Health Science Center, Houston, TX 77030, USA.
authors.forename: Kim S
authors.initials: KS
authors.lastname: Lawson
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Davut
authors.initials: D
authors.lastname: Pehlivan
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Okamoto
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Marjorie
authors.initials: M
authors.lastname: Withers
authors.affiliation: Division of Child & Adolescent Neurology, Department of Neurology and Pediatrics, University of Texas Medical School at Houston, Houston, TX 77030, USA.
authors.forename: Pedro
authors.initials: P
authors.lastname: Mancias
authors.affiliation: Division of Genetics, Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Anne
authors.initials: A
authors.lastname: Slavotinek
authors.affiliation: Pediatric Teaching Program, Cone Health System and UNC-Chapel Hill, Greensboro, NC 27401, USA.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Reitnauer
authors.affiliation: Department of Neurology, Istanbul University, Istanbul Medical Faculty, Istanbul 34093, Turkey.
authors.forename: Meryem T
authors.initials: MT
authors.lastname: Goksungur
authors.affiliation: Department of Neurology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Shy
authors.affiliation: Departments of Neurology and Pediatrics, Johns Hopkins University, Baltimore, MD 21218, USA.
authors.forename: Thomas O
authors.initials: TO
authors.lastname: Crawford
authors.affiliation: 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, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Koenig
authors.affiliation: Center for Human Disease Modeling, Duke University, Durham, NC 27701, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Willer
authors.affiliation: Cellular and Molecular Biology Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Brittany N
authors.initials: BN
authors.lastname: Flores
authors.affiliation: Center for Human Disease Modeling, Duke University, Durham, NC 27701, USA.
authors.forename: Igor
authors.initials: I
authors.lastname: Pediaditrakis
authors.affiliation: Department of Neurology, Acibadem Kozyatagı Hospital, Istanbul 34742, Turkey.
authors.forename: Onder
authors.initials: O
authors.lastname: Us
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Wiszniewski
authors.affiliation: Department of Neurology, Istanbul University, Istanbul Medical Faculty, Istanbul 34093, Turkey.
authors.forename: Yesim
authors.initials: Y
authors.lastname: Parman
authors.affiliation: 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, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Antonellis
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Muzny
authors.affiliation: Center for Human Disease Modeling, Duke University, Durham, NC 27701, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Katsanis
authors.affiliation: Department of Molecular Biology and Genetics, Bogazici University, Istanbul 34342, Turkey.
authors.forename: Esra
authors.initials: E
authors.lastname: Battaloglu
authors.affiliation: 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, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
authors.affiliation: 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.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
authors.affiliation: 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.
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
mesh_terms: D000818:Animals; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics*; D059472:Exome; D005260:Female; D040741:Genetic Load; D014644:Genetic Variation; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics; D006801:Humans; D008297:Male; D009154:Mutation; D018996:Myelin P2 Protein / Q000235:genetics; D010375:Pedigree; D019683:Penetrance; D010523:Peripheral Nervous System Diseases / Q000235:genetics*; D010641:Phenotype; D051102:Serine C-Palmitoyltransferase / Q000235:genetics; D013489:Suppression, Genetic; D015027:Zebrafish
chemical_list: C485714:DNAJB5 protein, human; D050956:HSP40 Heat-Shock Proteins; D018996:Myelin P2 Protein; C560555:PMP2 protein, human; C521151:SPTLC3 protein, human; D051102:Serine C-Palmitoyltransferase