Exome Sequencing Reveals a Rare Autosomal Dominant Variant in MSTO1 Gene as a Novel Leber's Hereditary Optic Neuropathy (LHON) Modifier in a Thai Family with High Penetrance of G11778A Mutation

Background: Leber's hereditary optic neuropathy (LHON) is a prevalent mitochondrial disease that is predominantly caused by mitochondrial (mtDNA) mutations. However, not all siblings with identical LHON mutations develop visual impairment, suggesting the influence of nuclear genetic variants. This study explores the role of these variants in LHON expression among siblings and relatives with the same maternal LHON mutations. Methods: A family with a homoplasmic G11778A mutation displaying significant LHON penetrance (50 % in female carriers) was examined. Exome sequencing was performed on four members (two affected, two unaffected). Detected variations were predicted using a Variant Effect Predictor (VEP) with a dbNSFP (database for nonsynonymous single nucleotide polymorphisms' functional predictions) plugin. Candidate variants were chosen based on their scores and LHON-related gene variations. Sanger sequencing was used for validation of 15 family members. Results: Exome analysis identified nine potential variations across eight genes. However, only the MSTO1 c.692 693delCC mutation showed a significant linkage to LHON expression in both additive (adj. p -value = 0.04) and dominant models (adj. p -value = 0.0112). This rare variant, located at the cleavage and polyadenylation site of the MSTO1 gene, could disrupt transcriptional termination, and thus alter MSTO1 gene expression. Conclusions: Given the role of the MSTO1 gene in controlling mitochondrial morphology, the MSTO1 c.692 693delCC mutation might instigate mitochondrial dysfunction. Thus, the MSTO1 gene is potentially a novel nuclear modifier for LHON. These findings pave the way for further research into the underlying mechanisms of LHON.