Optic neuropathy

Gene: NDUFAF8

Green List (high evidence)

Comment on list classification: There are at least 6 individuals from 3 unrelated families reported in literature with biallelic NDUFAF8 variants and optic atrophy - isolated or syndromic. Hence, this gene should be promoted to Green at the next GMS update.

Created: 26 May 2026, 3:59 p.m. | Last Modified: 26 May 2026, 5:44 p.m.

Panel Version: 6.14

PMID: 41234160 Fiorini et al., 2025
Authors identified candidate causative variants in 31 patients from 23 unrelated families, with biallelic or hemizygous variants in 11 different nuclear Complex I related genes.

5/6 patients reported with NDUFAF8 variants had isolated optic atrophy; the sixth proband had OA plus nystagmus and cerebellar ataxia.
Family U - 2 sibs hom for c.44T>G p.(L15R) - isolated OA, MRI normal
Families W & V (4 individuals from 2 families)- hom for c.195+271C>T p.? deep intronic variant - insidious isolated OA in family W, individuals in Family V had LHON-like presentation of OA + strabismus, hyperopia, non-specific white matter lesions on MRI (3/3), also mild DD, nystagmus, and unsteady gate in 1/3.

This gene is associated with AR Mitochondrial complex I deficiency, nuclear type 34, OMIM:618776 (accessed 26th May 2026).

Created: 26 May 2026, 3:58 p.m. | Last Modified: 26 May 2026, 5:44 p.m.

Panel Version: 6.14

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Mitochondrial complex I deficiency, nuclear type 34, OMIM:618776

Publications

• 41234160

Green List (high evidence)

Recently accepted publication "Recessive variants in mitochondrial Complex I nuclear subunits are an underrated cause of optic atrophy" reports Complex I genes, which pathogenic defects lead to optic atrophy; LHON-like phenotypes.
3 unrelated families were carrying NDUFS7 pathogenic variants and were diagnoses with optic neuropathy

Defects in core CI subunits in reported cohort lead 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. For 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 a partial spatial segregation was noted for missense variants causing either Leigh syndrome or isolated optic atrophy, hinting at possible disease-specific molecular defect.
Sources: Literature, Research

Created: 27 Nov 2025, 9:24 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Optic neuropathy, optic atrophy; LHON-like

Publications

• PMID: 41234160

Mode of pathogenicity
Other