Exome sequencing unveils novel disease-causing variation in Charcot-Marie-Tooth disease and suggests genetic burden contributes to phenotypic variability and complex neuropathy. C. Gonzaga-Jauregui1,2, T. Harel1, T. Gambin1, M. Kousi2, L. B. Griffin3,4, M. N. Bainbridge5, K. S. Lawson6, D. Pehlivan1, Y. Okamoto1, M. Withers1, P. Mancias7, A. Slavotinek8, P. J. Reitnauer9, M. Shy10, T. O. Crawford11, M. Koenig12,13, M. T. Goksungur14, S. Jhangiani5, J. Willer2, B. N. Flores3, W. Wiszniewski1, A. Antonellis3,15,16, N. Katsanis2, D. M. Muzny5, E. Boerwinkle5,6, R. A. Gibbs1,5, J. R. Lupski1,17,18, Baylor-Hopkins Center for Mendelian Genomics 1) Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA; 2) Center for Human Disease Modeling, Duke University, Durham, NC, 27710, USA; 3) Cellular and Molecular Biology Program, University of Michigan Medical School, Ann Arbor, MI, 48109, USA; 4) Medical Scientist Training Program, University of Michigan Medical School, Ann Arbor, MI, 48109, USA; 5) Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA; 6) Human Genetics Center and Institute of Molecular Medicine, University of Texas-Houston Health Science Center, Houston, TX, 77030, USA; 7) Department of Neurology and Pediatrics, Division of Child & Adolescent Neurology, University of Texas Medical School at Houston, Houston, TX, 77030, USA; 8) Division of Genetics, Department of Pediatrics, University of California, San Francisco, CA, 94158, USA; 9) Pediatric Teaching Program, Cone Health System and UNC-Chapel Hill, Greensboro NC 27401, USA; 10) Department of Neurology, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA; 11) Departments of Neurology and Pediatrics, Johns Hopkins University, Baltimore, Maryland, USA; 12) Institut de Genetique et de Biologie Moleculaire et Cellulaire (IGBMC), CNRS-INSERM-Universite de Strasbourg, Illkirch, 67404, France; 13) INSERM UMR_S 827, Institut Universitaire de Recherche Clinique, and Laboratoire de Génétique Moléculaire, Centre Hospitalier Universitaire de Montpellier, Montpellier, France; 14) Department of Neurology, Istanbul University, Istanbul Medical Faculty, Istanbul, Turkey; 15) Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI, 48109, USA; 16) Department of Neurology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA; 17) Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030, USA; 18) Texas Childrens Hospital, Houston, TX, 77030, USA.

   Charcot-Marie-Tooth (CMT) disease is the most common hereditary neuropathy affecting approximately 1/2500 individuals. It is a clinically heterogeneous distal symmetric polyneuropathy (DSP) with two major groups distinguished electrophysiologically and pathologically into demyelinating CMT1 and axonal CMT2. CMT shows extensive underlying genetic heterogeneity, with ~50 loci identified or linked to date to different subtypes of the disease. Exome sequencing (ES) allows assessment of most of the coding variation in the human diploid genome, but the interpretation can be complicated by the presence of extensive allelic and genetic heterogeneity and oligogenic inheritance with rare variants in more than one causative gene. We performed ES at high coverage in a cohort of 40 patients from 37 unrelated families with CMT-like peripheral neuropathy, in whom the genetic cause had not been previously identified using a multitude of molecular genetic analyses. We identified the apparent disease-causative variants in 47.5% of patients, accounting for 18 of 37 of the families; and potentially disease causing variants in novel genes in three additional families. We also show that affected individuals can have an enrichment of rare variants in multiple CMT genes as compared to unaffected control individuals, and we propose that this mutation burden likely contributes to phenotypic variability of the disease in the population. These findings are consistent with the proposed Clan Genomics hypothesis which posits that new mutations in patients or those that arose in recent ancestors, and novel combinations from the probands parents, rather than common/ancient alleles in populations, can have a more pronounced effect on the probands phenotypic presentation and account for medically actionable variants. We performed functional studies in yeast and zebrafish to elucidate the functional impact of the novel identified variants and the genetic interactions and modifier effects of different genes in the neuropathy disease network. We observed that a fraction of non-neuropathy affected control individuals can carry an excess of rare carrier variants in recessive neuropathy associated genes which perhaps in the presence of further genetic or environmental factors can contribute to the presentation of complex neuropathy disease. Our findings suggest that rare variants can contribute susceptibility to DSP and other common neuropathies beyond the known Mendelian forms.

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