Intragenic DOK7 deletion detected by whole-genome sequencing in congenital myasthenic syndromes.
Intragenic DOK7 deletion detected by whole-genome sequencing in congenital myasthenic syndromes.
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DOI：
10.1212/nxg.0000000000000152
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发表时间：
2017-06
期刊：
影响因子：
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通讯作者：
Lochmüller H
中科院分区：
文献类型：
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作者：
Azuma Y;Töpf A;Evangelista T;Lorenzoni PJ;Roos A;Viana P;Inagaki H;Kurahashi H;Lochmüller H
通过全基因组测序（WGS）确定1例上睑下垂和运动性肌无力患者的遗传病因，并诊断为先天性肌无力综合征（CMS）。对该病例进行候选基因筛选和WGS分析。随后进行等位基因特异性PCR以确认从WGS结果怀疑的拷贝数变异（CNV）。除了先前报道的移码突变c.1124_1127dup之外，WGS还在CMS患者中鉴定了DOK7基因5′非翻译区至内含子2的基因内6，261 bp缺失。基于WGS上的覆盖率降低怀疑杂合缺失，并通过等位基因特异性PCR证实。断裂点具有微同源性和反向重复，这可能导致DNA复制过程中缺失的发展。我们报告了一个CMS的情况下，使用WGS分析鉴定的基因内DOK7缺失的断点。该病例说明，通过桑格测序未检测到的CNV可以通过WGS鉴定，并突出了它们在可治疗的神经系统疾病如CMS的分子诊断中的相关性。
To identify the genetic cause in a patient affected by ptosis and exercise-induced muscle weakness and diagnosed with congenital myasthenic syndromes (CMS) using whole-genome sequencing (WGS). Candidate gene screening and WGS analysis were performed in the case. Allele-specific PCR was subsequently performed to confirm the copy number variation (CNV) that was suspected from the WGS results. In addition to the previously reported frameshift mutation c.1124_1127dup, an intragenic 6,261 bp deletion spanning from the 5′ untranslated region to intron 2 of the DOK7 gene was identified by WGS in the patient with CMS. The heterozygous deletion was suspected based on reduced coverage on WGS and confirmed by allele-specific PCR. The breakpoints had microhomology and an inverted repeat, which may have led to the development of the deletion during DNA replication. We report a CMS case with identification of the breakpoints of the intragenic DOK7 deletion using WGS analysis. This case illustrates that CNVs undetected by Sanger sequencing may be identified by WGS and highlights their relevance in the molecular diagnosis of a treatable neurologic condition such as CMS.