Complex I deficiency is the most common pediatric mitochondrial disease. It can cause a wide range of clinical disorders, including Leigh syndrome. TIMMDC1 encodes an assembly protein of complex I and has been recently associated with early onset mitochondrial disease in three unrelated families. In all three families the same homozygous deep intronic variant was identified leading to inclusion of a new exon resulting in a frameshift and premature stop codon (c.596 + 2146A > G, p.Gly199_Thr200ins5*). Herein, we describe two brothers of Dutch descent, presenting in infancy with hypotonia and respiratory insufficiency and a rapidly progressive and fatal disease course. Laboratory findings and metabolic investigations revealed no specific abnormalities, notably no raised plasma lactate. MRI showed transient lesions in the basal ganglia of brother 1. A muscle biopsy demonstrated complex I deficiency in brother 2. Exome sequencing yielded a novel heterozygous TIMMDC1 variant: c.385C > T, p.(Arg129*). Targeted sequencing revealed the previously published deep intronic variant c.596 + 2146A > G, p.(Gly199_Thr200ins5*) on the second allele which is not detected by exome sequencing. In summary, we present the fourth family with TIMMDC1-related disease, with a novel nonsense variant. This report illustrates the importance of considering mitochondrial disease even when laboratory findings are normal, and the added value of targeted sequencing of introns.

复合物I缺乏症是最常见的小儿线粒体疾病。它可以引起多种临床疾病，包括利氏综合征。TIMMDC1编码复合物I的装配蛋白，最近在三个无关家族中与线粒体疾病的早期发病有关。在所有三个家族中，鉴定出相同的纯合深度内含子变异体，导致包含新的外显子，从而导致移码和过早的终止密码子（c.596 + 2146A> G，p.Gly199_Thr200ins5 *）。在这里，我们描述了荷兰裔的两个兄弟，他们在婴儿期出现肌张力低下和呼吸功能不全，并迅速发展为致命疾病。实验室检查和代谢检查均未发现特异性异常，尤其是血浆乳酸水平未升高。MRI显示兄弟1的基底神经节有短暂性病变。肌肉活检显示兄弟2出现复杂的I缺陷。外显子组测序产生了新型的杂合体TIMMDC1变体：c.385C> T，第（Arg129 *）。靶向测序揭示了先前发布的第二等位基因上的深度内含子变体c.596 + 2146A> G，p。（Gly199_Thr200ins5 *），而外显子组测序未检测到。总而言之，我们介绍了与TIMMDC1相关疾病的第四家族，具有新的无意义变异。该报告说明了即使实验室检查结果正常也要考虑线粒体疾病的重要性，以及内含子靶向测序的附加价值。