Exome Sequence Analysis Suggests that Genetic Burden Contributes to Phenotypic Variability and Complex Neuropathy.
Exome Sequence Analysis Suggests that Genetic Burden Contributes to Phenotypic Variability and Complex Neuropathy.
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DOI：
10.1016/j.celrep.2015.07.023
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发表时间：
2015-08-18
期刊：
影响因子：
8.8
通讯作者：
Lupski JR
中科院分区：
文献类型：
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作者：
Gonzaga-Jauregui C;Harel T;Gambin T;Kousi M;Griffin LB;Francescatto L;Ozes B;Karaca E;Jhangiani SN;Bainbridge MN;Lawson KS;Pehlivan D;Okamoto Y;Withers M;Mancias P;Slavotinek A;Reitnauer PJ;Goksungur MT;Shy M;Crawford TO;Koenig M;Willer J;Flores BN;Pediaditrakis I;Us O;Wiszniewski W;Parman Y;Antonellis A;Muzny DM;Baylor-Hopkins Center for Mendelian Genomics;Katsanis N;Battaloglu E;Boerwinkle E;Gibbs RA;Lupski JR
腓骨肌萎缩症（CMT）是一种临床和遗传异质性远端对称性多发性神经病。对来自37个不相关的难治性CMT样周围神经病变家族的40名个体进行全外显子组测序（WES），在约45%（17/37）的家族中发现了明显的因果突变。提出了三个候选疾病基因，遗传和体内研究相结合的支持。突变数据的综合分析显示，与对照组相比，受试者中58个神经病相关基因的罕见变异数量显著增加;在第二个种族离散神经病队列中得到证实，表明突变负荷可能导致表型变异。显示具有高度外显孟德尔变异体（HMPV）并与家族负担有关的神经病基因在斑马鱼试验中显示出遗传相互作用，加剧了通过抑制单个基因建立的表型。我们的研究结果表明，罕见变异的组合效应有助于疾病负担和可变表达。
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 mutation burden potentially contributes to phenotypic variability. Neuropathy genes shown to have highly penetrant Mendelizing variants (HMPVs) 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.