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

Cell Rep. 2015 Aug 18;12(7):1169-83. Epub 2015 Aug 06

Claudia Gonzaga-Jauregui ¹ , Tamar Harel ² , Tomasz Gambin ² , Maria Kousi ³ , Laurie B Griffin ⁴ ,

Claudia Gonzaga-Jauregui ¹ , Tamar Harel ² , Tomasz Gambin ² , Maria Kousi ³ , Laurie B Griffin ⁴ , Ludmila Francescatto ³ , Burcak Ozes ⁵ , Ender Karaca ² , Shalini N Jhangiani ⁶ , Matthew N Bainbridge ⁶ , Kim S Lawson ⁷ , Davut Pehlivan ² , Yuji Okamoto ² , Marjorie Withers ² , Pedro Mancias ⁸ , Anne Slavotinek ⁹ , Pamela J Reitnauer ¹⁰ , Meryem T Goksungur ¹¹ , Michael Shy ¹² , Thomas O Crawford ¹³ , Michel Koenig ¹⁴ , Jason Willer ³ , Brittany N Flores ¹⁵ , Igor Pediaditrakis ³ , Onder Us ¹⁶ , Wojciech Wiszniewski ² , Yesim Parman ¹¹ , Anthony Antonellis ¹⁷ , Donna M Muzny ⁶ , Baylor-Hopkins Center for Mendelian Genomics , Nicholas Katsanis ³ , Esra Battaloglu ⁵ , Eric Boerwinkle ¹⁸ , Richard A Gibbs ¹⁹ , James R Lupski ²⁰

+ et al

Author information

¹ 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.
² Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
³ Center for Human Disease Modeling, Duke University, Durham, NC 27701, USA.
⁴ 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.
⁵ Department of Molecular Biology and Genetics, Bogazici University, Istanbul 34342, Turkey.
⁶ Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
⁷ Human Genetics Center and Institute of Molecular Medicine, University of Texas-Houston Health Science Center, Houston, TX 77030, USA.
⁸ Division of Child & Adolescent Neurology, Department of Neurology and Pediatrics, University of Texas Medical School at Houston, Houston, TX 77030, USA.
⁹ Division of Genetics, Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94158, USA.
¹⁰ Pediatric Teaching Program, Cone Health System and UNC-Chapel Hill, Greensboro, NC 27401, USA.
¹¹ Department of Neurology, Istanbul University, Istanbul Medical Faculty, Istanbul 34093, Turkey.
¹² Department of Neurology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
¹³ Departments of Neurology and Pediatrics, Johns Hopkins University, Baltimore, MD 21218, USA.
¹⁴ 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.
¹⁵ Cellular and Molecular Biology Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
¹⁶ Department of Neurology, Acibadem Kozyatagı Hospital, Istanbul 34742, Turkey.
¹⁷ 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.
¹⁸ 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.
¹⁹ 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.
²⁰ 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.

摘要

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 â¼ 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.

基因

rp1l1a, ankrd6b, med25, fabp11a, gdap1, wnk1b, dnajb5, abhd12

原始数据

保存测序数据

Sample name	Organism	Experiment title	Sample type	Library instrument	Attributes
Sample name	Organism	Experiment title	Sample type	Library instrument