Recessive variants in mitochondrial complex I nuclear subunits are an underrated cause of optic atrophy

Our understanding of the genetic landscape of inherited optic neuropathies (ION) has grown significantly over the past decades, and it is now known to involve many genes found in both the nuclear and mitochondrial genomes, exhibiting all possible inheritance patterns. Furthermore, pathogenic variants in nuclear genes encoding mitochondrial respiratory complex I (CI) subunits have been identified in some cases of ION, in addition to the more common severe presentation of CI deficiencies, which usually have an early onset. We conducted next-generation sequencing screening of CI genes to identify potential causative variants in patients with optic atrophy, and performed comprehensive clinical assessments, including neuroimaging (MRI) and neurological evaluations. Detailed molecular structure modelling was performed to better evaluate the damaging effects of both novel and previously reported variants in the relevant CI subunits. We identified candidate causative variants in 31 patients from 23 unrelated families, with biallelic or hemizygous variants characterized in 11 nuclear CI-related genes encoding polypeptides involved in CI structure, including three core subunits (NDUFS7, NDUFV1, NDUFV2), four accessory subunits (NDUFA1, NDUFA10, NDUFA12, NDUFB11) and four assembly factors (NDUFAF2, NDUFAF3, NDUFAF4, NDUFAF8). Notably, defects in core CI subunits in this cohort led to isolated optic atrophy, while defects in accessory CI subunits and assembly factors resulted in a spectrum of phenotypes, from isolated to syndromic optic atrophy. In 12 cases, the subacute onset of vision loss enabled us to associate or confirm novel genes (NDUFS7, NDUFV1, NDUFAF2, NDUFAF4, NDUFAF8) with the autosomal recessive Leber hereditary optic neuropathy (arLHON) phenotype. Moreover, in the NDUFS7 subunit, partial spatial segregation was observed for missense variants associated with either Leigh syndrome or isolated optic atrophy, suggesting possible disease-specific molecular defects. Our case series broadens the genetic spectrum of ION, emphasizing the crucial role of nuclear CI genes in pathogenesis. The arLHON phenotype, reportedly associated with an insidious onset of optic atrophy, is linked to numerous nuclear CI genes, and in some cases, the same variant may underlie both phenotypes. Overall, we highlight the possibly underestimated prevalence of CI nuclear subunits in the molecular diagnosis of ION, prompting the inclusion of all CI-related genes in the standard diagnostic screening.