Uniparental disomy (UPD) is an underestimated cause of autosomal recessive disorders. In this study, we aim to raise awareness about the possibility of UPD in mitochondrial disorders - where it is a hardly described event -, by functionally characterizing a novel variant in a structural subunit of complex I (CI) of the mitochondrial oxidative phosphorylation system.

Using next-generation sequencing, we identified a new intronic homozygous c.350 + 5G > A variant in the NDUFS4 gene in a one-year-old girl (being alive at the age of 7) belonging to a non-consanguineous family presenting with encephalopathy, psychomotor delay, lactic acidosis and a single CI deficiency, a less severe phenotype than those previously reported in most NDUFS4 patients. One parent lacked the variant, and microsatellite genotyping showed complete paternal uniparental isodisomy of the non-imprinted chromosome 5.

We demonstrated in patient's skeletal muscle and fibroblasts splicing abnormalities, low expression of NDUFS4, undetectable NDUFS4 protein, defects in cellular respiration (decreased oxygen consumption and ATP production), and impaired assembly or stability of mitochondrial supercomplexes containing CI.

Our findings support that c.350 + 5G > A variant is pathogenic, and reinforce that UPD, although rare, should be considered as a possible cause of mitochondrial diseases in order to provide accurate genetic counselling.

单亲二体性（UPD）是常染色体隐性遗传疾病的低估原因。在这项研究中，我们旨在通过功能性地表征线粒体氧化磷酸化系统的复合物I（CI）的结构亚基中的新型变体，来提高人们对线粒体疾病中UPD可能性的认识-在UPD中这是很难描述的事件。

使用下一代测序，我们鉴定了一个新的内含子纯合子c.350 + 5G> NDUFS4基因的一个变体，该变体来自一个非血缘家族的一岁女孩（7岁时活着），该女孩与脑病，精神运动迟缓，乳酸性酸中毒和单一CI缺乏症，其表型不如大多数NDUFS4患者先前报道的严重。一位父母没有该变异，微卫星基因分型显示未受印记的第5号染色体的完全父亲单亲等位基因。

我们在患者的骨骼肌和成纤维细胞中发现了剪接异常，NDUFS4的低表达，NDUFS4的蛋白检测不到，细胞呼吸缺陷（耗氧量和ATP产生减少）以及含CI的线粒体超复合物的组装或稳定性受损。

我们的发现支持c.350 + 5G>变体具有致病性，并强化了UPD（尽管罕见）应被认为是线粒体疾病的可能原因，以便提供准确的遗传咨询。