Improved inherited peripheral neuropathy genetic diagnosis by whole-exome sequencing
Improved inherited peripheral neuropathy genetic diagnosis by whole-exome sequencing
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DOI：
10.1002/mgg3.126
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发表时间：
2015-03-01
影响因子：
2
通讯作者：
Kennerson, Marina L.
中科院分区：
文献类型：
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作者：
Drew, Alexander P.;Zhu, Danqing;Kennerson, Marina L.
遗传性周围神经病(IPN)是一组主要影响周围运动神经元和感觉神经元的相关疾病。它们包括遗传性感觉神经病(HSN)、遗传性运动神经病(HMN)和Charcot-Marie-Tooth病(CMT)。使用全外显子组测序(WES)来实现遗传诊断特别适合于IPNS，其中超过80个基因涉及除了最常见的基因之外的弱的基因型-表型相关性。我们对110名IPN指标性患者进行了WES，这些患者的遗传原因在先前对根据表型和遗传模式选择的常见基因突变进行筛查后尚未确定。我们在110名指数患者的队列中发现了已知IPN基因中的41个错义序列变体。在基因Mfn2、GJB1、BSCL2和SETX中发现的9个突变(8%)是先前报道的突变，被认为是这些家族中的致病基因。基因NEFL、TRPV4、KIF1B、BICD2和SETX中的12个新变种(11%)与该病有关，但需要进一步的致病性证据。剩下的20个变异被确认为多态(不会导致疾病)，在这里详细介绍，以帮助解释其他家族研究中发现的序列变异。使用分离、正常对照和生物信息学工具进行验证是支持序列变异与疾病有关的有价值的证据。此外，我们还鉴定了一个SETX序列变异体(c.7640T>；C)，这是先前报道的一种可能的突变，我们已经确认这是一种非致病的罕见多态。这项研究强调了在IPNS等高度异质性疾病中使用WES进行基因诊断的优势，并在由于以前不明显的表型和遗传模式而无法实现基因诊断的这一队列中尤其强大。然而，在临床明确的病例中对共同基因进行一级检测仍然很重要，并将解释大多数阳性结果。
Inherited peripheral neuropathies (IPNs) are a group of related diseases primarily affecting the peripheral motor and sensory neurons. They include the hereditary sensory neuropathies (HSN), hereditary motor neuropathies (HMN), and Charcot-Marie-Tooth disease (CMT). Using whole-exome sequencing (WES) to achieve a genetic diagnosis is particularly suited to IPNs, where over 80 genes are involved with weak genotype-phenotype correlations beyond the most common genes. We performed WES for 110 index patients with IPN where the genetic cause was undetermined after previous screening for mutations in common genes selected by phenotype and mode of inheritance. We identified 41 missense sequence variants in the known IPN genes in our cohort of 110 index patients. Nine variants (8%), identified in the genes MFN2, GJB1, BSCL2, and SETX, are previously reported mutations and considered to be pathogenic in these families. Twelve novel variants (11%) in the genes NEFL, TRPV4, KIF1B, BICD2, and SETX are implicated in the disease but require further evidence of pathogenicity. The remaining 20 variants were confirmed as polymorphisms (not causing the disease) and are detailed here to help interpret sequence variants identified in other family studies. Validation using segregation, normal controls, and bioinformatics tools was valuable as supporting evidence for sequence variants implicated in disease. In addition, we identified one SETX sequence variant (c. 7640T> C), previously reported as a putative mutation, which we have confirmed as a nonpathogenic rare polymorphism. This study highlights the advantage of using WES for genetic diagnosis in highly heterogeneous diseases such as IPNs and has been particularly powerful in this cohort where genetic diagnosis could not be achieved due to phenotype and mode of inheritance not being previously obvious. However, first tier testing for common genes in clinically well-defined cases remains important and will account for most positive results.