Optic neuropathy

Gene: NDUFAF4

Green List (high evidence)

Comment on list classification: There are now 3 unrelated individuals reported with biallelic NDUFAF4 variants and isolated optic atrophy. Hence, this gene should be promoted to Green at the next GMS update.

Created: 26 May 2026, 3:45 p.m. | Last Modified: 26 May 2026, 3:45 p.m.

Panel Version: 6.9

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 NDUFAF4 variants:
Family S - proband with NDUFAF4 comp het variants c.224del p.(P75Lfs*7) and c.413T>C p.(I138T), with isolated optic atrophy
Family T - 2 sibs homozygous for c.413T>C p.(I138T) variant in NDUFAF4 with isolated optic atrophy

PMID: 38381526 Barboni et al., 2025
Report of a 17yo boy with subacute bilateral visual loss with no pain - atypical LHON diagnosis. He was comp het for NDUFAF4: c.413T>C, p.Ile138Thr and c.224del, p.Pro75LeufsTer7. Temporal pallor of both the optic discs, optic disc microangiopathy, and temporal retinal nerve fiber layer (RNFL) thinning noted at 12 yrs old.

This gene is associated with AR Mitochondrial complex I deficiency, nuclear type 15, OMIM:618237 (accessed 26th May 2026).

Created: 26 May 2026, 3:26 p.m. | Last Modified: 26 May 2026, 3:43 p.m.

Panel Version: 6.8

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Mitochondrial complex I deficiency, nuclear type 15, OMIM:618237

Publications

• 38381526
• 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 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, 9:23 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Optic neuropathy, optic atrophy; LHON-like

Publications

• PMID: 41234160

Mode of pathogenicity
Other