A MT-TL1 variant identified by whole exome sequencing in an individual with intellectual disability, epilepsy, and spastic tetraparesis.
A MT-TL1 variant identified by whole exome sequencing in an individual with intellectual disability, epilepsy, and spastic tetraparesis.
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DOI：
10.1038/s41431-021-00900-2
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发表时间：
2021-09
期刊：
影响因子：
--
通讯作者：
Vissers LELM
中科院分区：
文献类型：
--
作者：
de Boer E;Ockeloen CW;Matalonga L;Horvath R;Solve-RD SNV-indel working group;Rodenburg RJ;Coenen MJH;Janssen M;Henssen D;Gilissen C;Steyaert W;Paramonov I;Solve-RD-DITF-ITHACA;Trimouille A;Kleefstra T;Verloes A;Vissers LELM
智力残疾的遗传病因在几乎一半的受影响个体中仍然难以捉摸。在Solve-RD联盟中，对未解决的（综合征型）智力残疾病例（n = 1,472先证）的全外显子组测序（WES）数据进行了系统的重新分析。这项重新分析包括线粒体DNA （mtDNA）变异的召唤，尽管mtDNA不是WES的特异性目标。我们在MT-TL1中发现了一个功能相关的mtDNA变异（NC_012920.1:m.3291T > C; NC_012920.1:n）。62T > C)，全血异质性水平为22%，患者为23岁男性，患有严重智力残疾、癫痫、发作性头痛伴呕吐、痉挛性四肢麻痹、脑异常和进食困难。血液和尿液的靶向验证支持致病性，指数异质性水平分别为23%和58%，母体异质性水平分别为4%和17%。有趣的是，并非该指数中观察到的所有表型特征先前都与MT-TL1变异有关，这表明m.3291T > c相关表型的扩大，或存在共同发生的疾病。因此，我们的病例强调了从WES数据中可识别的未被充分认识的mtDNA变异的重要性，特别是对于具有非典型线粒体表型的病例及其母系亲属。
The genetic etiology of intellectual disability remains elusive in almost half of all affected individuals. Within the Solve-RD consortium, systematic re-analysis of whole exome sequencing (WES) data from unresolved cases with (syndromic) intellectual disability (n = 1,472 probands) was performed. This re-analysis included variant calling of mitochondrial DNA (mtDNA) variants, although mtDNA is not specifically targeted in WES. We identified a functionally relevant mtDNA variant in MT-TL1 (NC_012920.1:m.3291T > C; NC_012920.1:n.62T > C), at a heteroplasmy level of 22% in whole blood, in a 23-year-old male with severe intellectual disability, epilepsy, episodic headaches with emesis, spastic tetraparesis, brain abnormalities, and feeding difficulties. Targeted validation in blood and urine supported pathogenicity, with heteroplasmy levels of 23% and 58% in index, and 4% and 17% in mother, respectively. Interestingly, not all phenotypic features observed in the index have been previously linked to this MT-TL1 variant, suggesting either broadening of the m.3291T > C-associated phenotype, or presence of a co-occurring disorder. Hence, our case highlights the importance of underappreciated mtDNA variants identifiable from WES data, especially for cases with atypical mitochondrial phenotypes and their relatives in the maternal line.
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