The relationship between TMEM126A and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of August 22, 2024. The TMEM126A gene encodes an inner mitochondrial membrane protein that is an important complex I assembly factor in ND4-module assembly.
TMEM126A was first reported in relation to autosomal recessive primary mitochondrial disease in 2009 (PMID: 19327736). While various names have been given to the constellation of features seen in those with TMEM126A-related disorders, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the TMEM126A phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework.
Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included five variants (one nonsense, two missense, one splice site, one frameshift) in 11 probands from seven publications (PMIDs: 19327736, 20405026, 22815638, 30961538, 31119195, 32855858, 36071901). Optic atrophy was the most common clinical feature in affected individuals. Additional clinical features noted include hearing loss, migraines, hypertrophic cardiomyopathy, myoclonic jerks, and brisk reflexes.
The mechanism of disease is loss of function. This gene-disease association is also supported by the known biochemical function of TMEM126A in complex I assembly, functional alteration in non-patient cells, and rescue studies (PMIDs: 33882309, 33879611).
In summary, there is definitive evidence to support the relationship between TMEM126A and primary mitochondrial disease. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on August 22, 2024 (SOP Version 10).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. The GenCC does not independently verify the submitted information. Though the information is obtained from sources believed to be reliable, no warranty, expressed or implied, is made regarding accuracy, adequacy, completeness, reliability or usefulness of any information. This disclaimer applies to both isolated and aggregate uses of the information. The information is provided on an "as is" basis, collected through periodic submission and therefore may not represent the most up-to-date information from the submitters. If you have questions about the medical relevance of information contained on this website, please see a healthcare professional; if you have questions about specific gene-disease claims, please contact the relevant sources; and if you have questions about the representation of the data on this website, please contact gencc@thegencc.org.