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.

在几乎一半的受影响个体中，智力障碍的遗传病因仍然难以捉摸。在 Solve-RD 联盟内，对未解决的（综合征）智力障碍病例（n  = 1,472 个先证者）的全外显子组测序 (WES) 数据进行了系统的重新分析。该重新分析包括线粒体 DNA (mtDNA) 变体的变体调用，尽管 mtDNA 不是 WES 中的特定目标。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)，在 23 年的研究中，全血异质性水平为 22%患有严重智力障碍、癫痫、阵发性头痛伴呕吐、痉挛性四肢轻瘫、大脑异常和喂养困难的老年男性。血液和尿液的针对性验证支持致病性，指数异质性水平分别为 23% 和 58%，母亲异质性水平分别为 4% 和 17%。有趣的是，并非索引中观察到的所有表型特征之前都与该MT-TL1变体相关，这表明 m.3291T > C 相关表型的扩大，或存在同时发生的疾病。因此，我们的案例强调了从 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及其母系亲属的病例。