Whole-exome sequencing for variant discovery in blepharospasm
Whole-exome sequencing for variant discovery in blepharospasm
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DOI：
10.1002/mgg3.411
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发表时间：
2018-07-01
影响因子：
2
通讯作者：
LeDoux, Mark S.
中科院分区：
文献类型：
--
作者：
Tian, Jun;Vemula, Satya R.;LeDoux, Mark S.
背景眼睑痉挛（Blepharosystem，BSP）是一种以不自主眼轮匝肌痉挛为特征的局灶性肌张力障碍，通常为双侧、同步、对称性。尽管有强有力的证据表明遗传因素对BSP有贡献，但该领域的进展受到小队列、不完全遗传和发病年龄晚的限制。虽然几个遗传病因肌张力障碍已被确定通过全外显子组测序（WES），没有这些特征与BSP作为一个单一的或主要的manifestation.MethodsWe进行了WES从21个独立的家系与BSP的31名受试者。通过双向桑格测序确认来自计算机分析的最强候选序列变体，并进行共分离分析。CACNA 1A中的（GRCH 37/hg 19）（：c.7261_7262delinsGT，p.Pro2421Val），REEP4在4个独立的多代家系中鉴定出TOR 2A（：c.109C> T，p.Arg37Trp）、TOR 2A（：c.568C>T，p.Arg190Cys）和ATP 2A 3（：c.1966C>T，p.Arg656Cys）。HS 1BP 3（：c.94C>A，p.Gly32Cys）和GNA 14（：c.989_990del，p.Thr330ArgfsTer67）的有害变体在患有节段性头颈肌张力障碍的父亲和儿子中被鉴定，该节段性头颈肌张力障碍首先表现为BSP。DNAH 17、TRPV 4、CAPN 11、VPS 13 C、UNC 13 B、SPTBN 4、MYOD 1和MRPL 15的有害变异在两个或多个独立的家系中被发现。据我们所知，这些基因以前都没有与孤立的BSP，虽然其他CACNA 1A突变已与积极和消极的运动障碍，包括共济失调，发作性共济失调，偏瘫偏头痛，肌张力障碍。和寡基因遗传模式。
BackgroundBlepharospasm (BSP) is a type of focal dystonia characterized by involuntary orbicularis oculi spasms that are usually bilateral, synchronous, and symmetrical. Despite strong evidence for genetic contributions to BSP, progress in the field has been constrained by small cohorts, incomplete penetrance, and late age of onset. Although several genetic etiologies for dystonia have been identified through whole-exome sequencing (WES), none of these are characteristically associated with BSP as a singular or predominant manifestation.MethodsWe performed WES on 31 subjects from 21 independent pedigrees with BSP. The strongest candidate sequence variants derived from in silico analyses were confirmed with bidirectional Sanger sequencing and subjected to cosegregation analysis.ResultsCosegregating deleterious variants (GRCH37/hg19) in CACNA1A (: c.7261_7262delinsGT, p.Pro2421Val), REEP4 (: c.109C>T, p.Arg37Trp), TOR2A (: c.568C>T, p.Arg190Cys), and ATP2A3 (: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees. Deleterious variants in HS1BP3 (: c.94C>A, p.Gly32Cys) and GNA14 (: c.989_990del, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17, TRPV4, CAPN11, VPS13C, UNC13B, SPTBN4, MYOD1, and MRPL15 were found in two or more independent pedigrees. To our knowledge, none of these genes have previously been associated with isolated BSP, although other CACNA1A mutations have been associated with both positive and negative motor disorders including ataxia, episodic ataxia, hemiplegic migraine, and dystonia.ConclusionsOur WES datasets provide a platform for future studies of BSP genetics which will demand careful consideration of incomplete penetrance, pleiotropy, population stratification, and oligogenic inheritance patterns.