SURF1 p.D202H variant is not associated with Leigh syndrome but may contribute to impaired pregnancy outcomes

The SURF1 gene encodes a mitochondrial protein critical for cytochrome c oxidase (COX) assembly. The c.604G>C (p.D202H) variant, identified in the homozygous state, has conflicting pathogenicity classifications in ClinVar and was found in 6.7 % of individuals with recurrent ART failure or pregnancy loss. This study included 30 Japanese women with infertility, 25 with recurrent ART failure and 5 with recurrent pregnancy loss, and 23 Japanese women with normal fertility, including 12 with successful ART outcomes and 11 with natural conception histories. The median ages of the infertility and control groups were 41.5 and 36 years, respectively. Participants were recruited from Hanabusa Women's Clinic and Okayama University Hospital. Whole-exome sequencing (WES) was performed using DNA extracted from peripheral blood mononuclear cells. Variant prioritization focused on 1136 mitochondrial-related nuclear genes listed in the MitoCarta3.0 database. Analysis was restricted to homozygous missense variants absent in the control group and with minor allele frequency < 0.05 in Japanese databases. SURF1 (p.D202H) was significantly enriched in the infertility group compared to population databases. Structural modeling with AlphaFold2 and ChimeraX revealed local hydrogen bonding alterations caused by the substitution of aspartate with histidine at position 202. These findings suggest that while p.D202H is not pathogenic for Leigh syndrome, it may contribute to mitochondrial dysfunction in reproductive tissues. Further investigation into its tissue-specific effects is warranted.