Submission Details

TMEM126A was first reported in relation to autosomal recessive TMEM126A-related optic atrophy with or without extraocular features (MONDO:0013069), also called optic atrophy (OPA7 type), in 2009 (Hanein S et al., PMID:19327736). Individuals with the disease present with bilateral optic atrophy, temporal disc pallor and poor visual acuity in childhood, usually in early childhood. Some cases have also reported color vision defects, sensorineural hearing loss, and/or neuropathy. Individuals reported in the literature have experienced both the gradual and sudden onset of symptoms, always in the first two decades of life.

This curation includes one nonsense variant, two missense variants, a splice variant and a frameshift variant that have been reported in 10 probands across 6 publications (PMID: 19327736, PMID: 20405026, PMID: 22815638, PMID: 31119195, PMID: 30961538, PMID: 36071901). Notably, the nonsense variant, c.163C>T;p.Arg55Ter, has been reported in at least six of North African consanguineous families and makes up for a large proportion of the cases both in the literature and in this curation. Functional studies are not reported on this variant but the premature stop codon occurs in exon 3/5 upstream of a known alternative start codon of a protein coding transcript (ENST00000528105.5) (PMID: 19327736, PMID: 20405026, PMID: 22815638). One proband of Korean descent has also been published with the p.Arg55Ter variant in trans with another presumed null TMEM126A variant. More evidence may be available in the literature, but the maximum score for genetic evidence has been exceeded. The mechanism of pathogenicity appears to be loss of function.

This gene-disease relationship is also supported by in vitro functional assays and a cell culture model (PMID: 23500070, PMID: 33882309, PMID: 33879611). In vitro functional analysis reveals that TMEM126A is an integral mitochondrial protein anchored to the mitochondrial inner membrane (PMID: 23500070) and that it functions as an assembly factor for mitochondrial respiratory complex I (PMID: 33882309). Given the relationship between mitochondrial function and optic atrophy, this serves as evidence that a disruption of the biochemical function of TMEM126A is consistent with the phenotype reported in OPA7 type patients. As an assembly factor, TMEM126A associates with the ND4 subunit encoded by the gene mt-ND4, which has been curated by the ClinGen Mitochondrial Diseases Gene Curation Expert panel to have a definitive relationship with mitochondrial disease which can present with optic atrophy. HEK293T cells with TMEM126A deleted via genome editing show complex I deficiency (PMID: 33879611), matching one of the TMEM126A:p.Arg55Ter probands (PMID:19327736). This complex I deficiency was rescued in the cell model by the introduction of a construct expressing TMEM126A (PMID: 33879611).

In summary, there is definitive evidence supporting the relationship between TMEM126A and autosomal recessive* TMEM126A*-related optic atrophy with or without extraocular features. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Glaucoma and Neuro-Ophthalmology GCEP on the meeting date September 19, 2024 (SOP Version 11).