Hereditary neuropathy or pain disorder

Gene: COX18

Green List (high evidence)

Comment on list classification: There is sufficient evidence available (four unrelated families and functional studies) for the association of biallelic COX18 variants with Charcot-Marie-Tooth disease. Hence, this gene can be promoted to green rating in the next GMS update.

Created: 9 Sep 2025, 5:06 p.m. | Last Modified: 9 Sep 2025, 5:06 p.m.

Panel Version: 7.8

PMID:37468577 (2023) reported a 19-months old female patient displaying hypertrophic cardiomyopathy at birth and myopathy with axonal sensory neuropathy and failure to thrive developing in the first months of life. She was identified with previously unreported homozygous substitution (c.667 G > C/ p.Asp223His) in COX18 via WES. Patient's muscle biopsy showed severe and diffuse COX deficiency and striking mitochondrial abnormalities. In addition, biochemical and enzymatic studies in patient's myoblasts and in HEK293 cells after COX18 silencing confirmed severe impairment of COX activity, which was partially rescued by delivery of wild-type COX18 cDNA into patient's myoblasts.

PMID:40830826 (2025) reported the identification of a homozygous splice variant (c.435-6A>G) in COX18 in two siblings with early-onset progressive axonal sensory-motor peripheral neuropathy via WES coupled with homozygosity mapping. This study also identified two additional families with rare deleterious biallelic variants in COX18 gene (c.215T>G/ p.Leu72Arg in one family and c.328G>C/p.Ala110Pro & c.893G>C/ p.Arg297Pro in the other family). All eight affected individuals from the three families presented with axonal Charcot-Marie-Tooth disease, and some patients also exhibited central nervous system symptoms, such as dystonia and spasticity. Functional characterisation of the c.435-6A>G variant demonstrated that it leads to the expression of an alternative transcript that lacks exon 2, resulting in a premature stop codon in exon 3 and is normally degraded by NMD. The mutant protein impairs CIV assembly and activity, leading to a reduction in mitochondrial membrane potential. Down-regulation of the COX18 homolog in Drosophila melanogaster displayed signs of neurodegeneration, including locomotor deficit and progressive axonal degeneration of sensory neurons.

This gene has already been associated with COX18-related peripheral neuropathy on the DD panel of Gene2Phenotype (with 'limited' rating) and on Hereditary Neuropathy - complex panel of PanelApp Australia (with green rating). However, it has not yet been associated with relevant phenotypes in OMIM.

Created: 9 Sep 2025, 5:01 p.m. | Last Modified: 9 Sep 2025, 5:01 p.m.

Panel Version: 7.5

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
mitochondrial disease, MONDO:0044970; Charcot-Marie-Tooth disease, MONDO:0015626

Publications

• 37468577
• 40830826

Green List (high evidence)

8 individuals from 3 families
Sources: Literature

Created: 25 Aug 2025, 11:16 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
peripheral neuropathy

Publications

• 40830826