Gonzaga-Jauregui Claudia, Harel Tamar, Gambin Tomasz, Kousi Maria, Griffin Laurie B, Francescatto Ludmila, Ozes Burcak, Karaca Ender, Jhangiani Shalini N, Bainbridge Matthew N, Lawson Kim S, Pehlivan Davut, Okamoto Yuji, Withers Marjorie, Mancias Pedro, Slavotinek Anne, Reitnauer Pamela J, Goksungur Meryem T, Shy Michael, Crawford Thomas O, Koenig Michel, Willer Jason, Flores Brittany N, Pediaditrakis Igor, Us Onder, Wiszniewski Wojciech, Parman Yesim, Antonellis Anthony, Muzny Donna M, Katsanis Nicholas, Battaloglu Esra, Boerwinkle Eric, Gibbs Richard A, Lupski James R
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.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Cell Rep. 2015 Aug 18;12(7):1169-83. doi: 10.1016/j.celrep.2015.07.023. Epub 2015 Aug 6.
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.
夏科-马里-图斯（CMT）病是一种临床和遗传异质性的远端对称性多发性神经病。对37个无亲缘关系的患有类似CMT的周围神经病且分子诊断难治的家庭中的40名个体进行全外显子组测序（WES），在约45%（17/37）的家庭中鉴定出明显的致病突变。结合遗传和体内研究，提出了三个候选疾病基因。突变数据的汇总分析显示，与对照相比，受试者中58个神经病相关基因的罕见变异数量显著增加，这在第二个种族离散的神经病队列中得到证实，表明突变负荷可能导致表型变异性。在斑马鱼实验中，显示具有高外显率孟德尔化变异（HPMV）且在家族中因负荷而受累的神经病基因在遗传上相互作用，加剧了通过单个基因抑制所确立的表型。我们的研究结果表明，罕见变异的组合效应导致疾病负担和可变表达。
