Genetic architecture and inheritance patterns of Leber hereditary optic neuropathy among 419 Chinese pedigrees carrying the ND4 11778G>A mutation.

Leber's hereditary optic neuropathy (LHON) is a mitochondrial disease mainly driven by the m.11778G>A mutation, and its incomplete penetrance and diverse inheritance patterns remain unclear. This study integrates clinical and genetic analyses of 419 Han Chinese pedigrees carrying this mutation, covering 5262 matrilineal relatives. Distinct phenotypic heterogeneity emerges, including sporadic, maternal and complex transmission patterns; 209 pedigrees contain only single affected individuals, which suggests that the m.11778G>A mutation alone fails to cause disease. Full mitochondrial DNA sequencing and haplogroup screening identify multiple mitochondrial genetic modifiers. Haplogroups D4j, M7, M9, and M10 are significantly enriched in maternally inherited families with elevated disease penetrance. Haplotype-specific variants ND4 11696G>A, ND1 3394T>C, and ND6 14502T>C synergistically aggravate mitochondrial dysfunction together with m.11778G>A, and secondary mtDNA mutations disrupting complex I or mitochondrial tRNA metabolism also raise disease susceptibility. Nuclear modifiers PRICKLE3 and YARS2, as well as X-linked sex-specific regulatory factors, are also identified. Overall, LHON results from the interaction of mitochondrial and nuclear genetic factors. This research constructs a comprehensive genetic landscape of LHON, highlights the vital role of modifier genes, and provides theoretical support for precision therapies targeting mitochondrial and nuclear pathways.