RT Journal Article SR Electronic T1 Whole genome and exome sequencing identify NDUFV2 mutations as a new cause of progressive cavitating leukoencephalopathy JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP jmedgenet-2020-107383 DO 10.1136/jmedgenet-2020-107383 A1 Zhimei Liu A1 Li Zhang A1 Changhong Ren A1 Manting Xu A1 Shufang Li A1 Rui Ban A1 Ye Wu A1 Ling Chen A1 Suzhen Sun A1 Matthias Elstner A1 Masaru Shimura A1 Minako Ogawa-Tominaga A1 Kei Murayama A1 Tieliu Shi A1 Holger Prokisch A1 Fang Fang YR 2021 UL http://jmg.bmj.com/content/early/2021/04/01/jmedgenet-2020-107383.abstract AB Background Progressive cavitating leukoencephalopathy (PCL) is thought to result from mutations in nuclear genes affecting mitochondrial function and energy metabolism. To date, mutations in two subunits of complex I, NDUFS1 and NDUFV1, have been reported to be related to PCL.Methods Patients underwent clinical examinations, brain MRI, skin biopsy and muscle biopsy. Whole-genome or whole-exome sequencing was performed on the index patients from two unrelated families with PCL. The effects of the mutations were examined through complementation of the NDUFV2 mutation by cDNA expression.Results The common clinical features of the patients in this study were recurring episodes of acute or subacute developmental regression that appeared in the first years of life, followed by gradual remissions and prolonged periods of stability. MRI showed leukoencephalopathy with multiple cavities. Three novel NDUFV2 missense mutations were identified in these families. Complex I deficiency was confirmed in affected individuals’ fibroblasts and a muscle biopsy. Functional and structural analyses revealed that these mutations affect the structural stability and function of the NDUFV2 protein, indicating that defective NDUFV2 function is responsible for the phenotypes in these individuals.Conclusions Here, we report the clinical presentations, neuroimaging and molecular and functional analyses of novel mutations in NDUFV2 in two sibling pairs of two Chinese families presenting with PCL. We hereby expand the knowledge on the clinical phenotypes associated with mutations in NDUFV2 and the genotypes causative for PCL.Data are available on reasonable request. The data that support the findings of this study are available from the corresponding author on reasonable request.