Hereditary neuropathy or pain disorder

Gene: NDUFS6

Green List (high evidence)

The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.

Created: 24 Feb 2025, 5:02 p.m. | Last Modified: 24 Feb 2025, 5:02 p.m.

Panel Version: 6.148

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Comment on list classification: Promoting to amber with a recommendation for green rating following GMS review. 3 separate publications report variants in this gene in patients with peripheral neuropathies. 2 different variants are reported.

Created: 31 Oct 2024, 10:26 p.m. | Last Modified: 31 Oct 2024, 10:26 p.m.

Panel Version: 6.15

Associated with Mitochondrial complex I deficiency, nuclear type 9, OMIM: 618232 (AR)

Biallelic loss of function variants are associated with severe CI deficiency and Leigh syndrome in previous reports (PubMed: 19259137 Spiegal et al 2009 and PubMed: 15372108 Kirby et al 2004, PMID: 30948790 - Rouzier et al 2019, PMID: 22474353 Ke et al 2012).

There is now phenotypic expansion with 5 families reported with a less severe phenotype. 4 families share a common variant.

PMID: 38459834 - Armirola-Ricaurte et al 2024. Describe 5 patients from 3 unrelated families from Spain, Turkey and Greece. They share a homozygous NDUFS6 NM_004553.6:c.309+5G>A variant found be exome sequencing and an axonal Charcot-Marie-Tooth (CMT) neuropathy. Age of onset ranged from 1 to 10 years. In all cases the unaffected parents were heterozygous for the variant. The variant is predicted to affect splicing and in family 1 was shown to cause the expression of aberrantly spliced transcripts and negligible levels of the canonical transcript. Haplotype analysis showed that the variant lies on a shared haplotype of 0.74MB on chromosome 5 and estimate the most recent common ancestor with the haplotype would have lived 740 years ago

PMID: 38549004 – Ferreira et al 2024 – screened nearly 11,000 patients with peripheral neuropathy for variants in known mitochondrial disease genes. 1 male was found with a homozygous variant c.320_323delCAAA, p.Thr107LysfsTer40 in NDUFS6.

PMID: 38217609 - Gangfuß et al 2024 - identified a homozygous variant (c.309 + 5 G > A) in NDUFS6 in one male patient aged 10 with axonal neuropathy accompanied by loss of small fibers in skin biopsy. The patient also showed optic atrophy and borderline intellectual disability.

Created: 31 Oct 2024, 6:27 p.m. | Last Modified: 31 Oct 2024, 10:25 p.m.

Panel Version: 6.14

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Mitochondrial complex I deficiency, nuclear type 9, OMIM: 618232; mitochondrial complex 1 deficiency, nuclear type 9, MONDO:0032615

Publications

• 38459834
• 38549004

Green List (high evidence)

Sources: Expert list

Created: 19 Oct 2024, 10:55 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
peripheral neuropathy; nystagmus

Publications

• 38459834 : 38549004