BCS1L-Associated Disease: 5'-UTR Variant Shifts the Phenotype Towards Axonal Neuropathy.

objectivesTo investigate the consequences of a pathogenic missense variant (c.838C>T; p.L280F) and a 5'-UTR regulatory variant (c.-122G>T) in BCS1L on disease pathogenesis and to understand how regulatory variants influence disease severity and clinical presentation.

methodsDeep phenotyping, research-based whole genome sequencing, biochemical characterization of identified variants, and studies in patient-derived fibroblast cultures were applied to uncover the underlying genetic cause and molecular defects in siblings with a genetically uncharacterized complex neurologic condition.

resultsGenome sequencing identified a paternally inherited missense variant (c.838C>T; p.L280F) and a maternally inherited 5'-UTR variant (c.-122G>T) in BCS1L in two affected siblings. Although the missense variant disrupts complex III assembly, the 5'-UTR variant allows residual wild-type BCS1L expression, likely mitigating disease severity. Biochemical studies in patient-derived fibroblasts confirmed the pathogenicity of both variants and demonstrated a moderate in vitro response to a coenzyme Q10 analog.

interpretationThis study expands the clinical spectrum of BCS1L-related disorders to include a comparatively milder phenotype with central and peripheral nervous system involvement. Our findings demonstrate that the 5'-UTR variant modulates disease severity by enabling residual wild-type BCS1L expression, partially mitigating the pathogenic effects of the missense variant. These insights underscore the importance of evaluating both protein coding and regulatory variants in mitochondrial disease diagnostics and pathogenesis.