Optic neuropathy

Gene: NDUFAF2

Green List (high evidence)

Comment on list classification: There are at least 3 unrelated cases reported in literature with biallelic NDUFAF2 variants and optic neuropathy (either isolated OA or syndromic). Based on available evidence, this gene should be promoted to Green at the next GMS update.

Created: 26 May 2026, 2:35 p.m. | Last Modified: 26 May 2026, 2:35 p.m.

Panel Version: 6.5

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.

2 unrelated probands carried NDUFAF2 variants:
Two sibs from family P - carrying variants in NDUFAF2: c.95A>G p.(Y32C) and c.148del p.(R50Efs*3), showed OA and peripheral axonal neuropathy - "OA-Plus"
Proband from family Q - homozygous for NDUFAF2 c.114C>G, p.(Y38*), showed OA and peripheral axonal neuropathy - "OA-Plus"

PMID: 37938061 Chen et al., 2024
Report of a 35yo patient with AR LHON - isolated optic atrophy, no Leigh-like encephalopathy. He reported vision problems starting at age 15yrs. Brain MRI showed bilateral thin optic nerve. WES detected comp het variants in NDUFAF2: c.139C>T, p.Arg47*, and c.148del, p.Arg50Glufs*3 - confirmed in trans.

This gene is associated with AR Mitochondrial complex I deficiency, nuclear type 10, OMIM:618233 (accessed 26th May 2026).

Created: 26 May 2026, 2:33 p.m. | Last Modified: 26 May 2026, 2:38 p.m.

Panel Version: 6.5

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Mitochondrial complex I deficiency, nuclear type 10, OMIM:618233

Publications

• 37938061
• 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.
2 unrelated families were carrying NDUFAF2 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, 9:20 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Optic neuropathy, optic atrophy; LHON-like

Publications

• PMID: 41234160

Mode of pathogenicity
Other