Optic neuropathy

Gene: NDUFA10

Green List (high evidence)

Comment on list classification: There are 4 individuals from 3 unrelated families with homozygous NDUFA10 variants and optic atrophy (isolated or syndromic). Based on the available evidence, this gene should be promoted to Green for Optic neuropathy.

Created: 16 Dec 2025, 12:17 p.m. | Last Modified: 16 Dec 2025, 12:18 p.m.

Panel Version: 5.32

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.

3 unrelated families with NDUFA10 variants:
Family K II-1: female, homozygous for c.233_235del, p.Ala78del, parents confirmed as het; insidious onset <1yr; phenotype: Multiple sclerosis, Pendular nystagmus, Decreased mean corpuscular volume, CNS demyelination; Diffuse optic nerve pallor

Family L: male, homozygous for c.233_235del, p.Ala78del, parents confirmed as het; insidious onset at 5yo; phenotype: Cerebellar atrophy, abnormality of extrapyramidal motor function, cerebral cortical atrophy, generalized-onset seizure, intellectual disability (borderline), mild neurosensory hearing impairment, cognitive impairment; fundus not examined. MRI:Cerebellar and mild cerebral cortical atrophy.

The p.(Ala78del) variant has been previously reported in a case of Leigh syndrome, in trans with c.296G>A, p.G99E (PMID: 36270260).

Family M II-2, II-3: 2 male siblings, homozygous for NDUFA10:c.1009C>T, p.(R337C) - onset at 2-12yo. Parents confirmed as heterozygous. Patient phenotype: isolated optic atrophy, temporal optic nerve pallor; insidious onset at 2-12 years; no other symptoms. MRI normal for both sibs. Variant previously reported in a 10yo female patient with ataxia, hypotonia and developmental regression (PMID: 31130284).

Authors highlight the clinical variability between patients with the same variant.

This gene is associated with AR Mitochondrial complex I deficiency, nuclear type 22, OMIM:618243 (accessed 16th Dec 2025).

Created: 16 Dec 2025, 12:12 p.m. | Last Modified: 16 Dec 2025, 12:12 p.m.

Panel Version: 5.32

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Mitochondrial complex I deficiency, nuclear type 22, OMIM:618243; mitochondrial complex I deficiency, nuclear type 22, MONDO:0032626

Publications

• 31130284
• 36270260
• 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 NDUFA10 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, 9:16 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Optic neuropathy, optic atrophy; LHON-like

Publications

• PMID: 41234160

Mode of pathogenicity
Other