Biallelic mutations in SUPV3L1 cause an inherited neurodevelopmental disorder with variable leukodystrophy due to aberrant mitochondrial double stranded RNA processing

Abstract We describe eighteen individuals from twelve families with an autosomal recessive neurodevelopmental disorder and variable leukodystrophy harbouring biallelic variants in SUPV3L1. SUPV3L1 encodes the RNA helicase SUV3 (also known as SUPV3L1), with previous studies demonstrating a role for the protein as part of the mitochondrial degradosome. Patient mutations result in an accumulation of mitochondrial double stranded RNAs in human cells. An assessment of supv3l1 knock-out zebrafish confirmed the role of supv3l1 in neurodevelopment, with gross defects identified in mitochondrial biogenesis and microglial function. Zebrafish displayed a significant activation of the type 1 interferon pathway, which was supported by qPCR of blood RNA from four patients with biallelic SUV3 mutations. Altogether, we describe a clinico-radiological spectrum associated with biallelic SUPV3L1 mutations, demonstrating that loss of SUV3 function results in altered mitochondrial biogenesis, increased mitochondrial double stranded RNA, dysplastic microglia and activation of the type 1 interferon innate immune pathway.