Submission Details

The relationship between SLC25A26 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of July 31, 2023. SLC25A26 is responsible for the transport of S-adenosylmethionine (SAM) into the mitochondria and the export of S-adenosyl-L-homoycsteine (SAH). Intramitochondrial SAM plays critical roles in cofactor biosynthesis (lipoate and coenzyme Q10), nucleic acid methylation, and protein methylation (PMID: 35730628). There is also some evidence indicating that SAH:SAM transport flux also plays a critical role in a variety of mitochondrial processes (PMID: 33608280).

SLC25A26 was first reported in relation to autosomal recessive primary mitochondrial disease in 2015 (PMID:26522469), in three children with neonatal profound lactic acidosis and respiratory insufficiency. While various names have been given to the constellation of features seen in those with SLC25A26-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the SLC25A26 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. Seven variants (five unique missense variants and two intronic variants impacting splicing) from five probands in two publications were included in this curation (PMIDs: 26522469, 35024855). Of note, an adult case that matched the phenotype was excluded from scoring given that the identified variants were missense without supporting functional evidence and segregation analysis was not performed (PMID: 34375635). Affected individuals have a range of features including the profound neonatal lactic acidosis and respiratory insufficiency described in the first case report, as well as lactic acidosis and myopathy in adulthood. Muscle biopsies in both the neonatal and adult forms show combined oxidative phosphorylation deficiencies with reductions in lipoylated proteins such as pyruvate dehydrogenase and alpha ketoglutarate dehydrogenase.

This gene-disease association is also supported by the known interaction of this protein with others including those important in coenzyme Q10 synthesis, lipoylation, methylation of mitochondrial nucleic acids, and protein methylation (PMID: 35730628) and animal models (knock-in of specific variants in Drosophila, conditional knockout study in embryonic mouse fibroblasts models; PMID: 33608280). Additional yeast models and cloned human cDNA into Escherichia coli were reviewed but not included in scoring as a maximum score was reached (PMIDs: 14674884, 37130856).

In summary, there is definitive evidence to support the relationship between SLC25A26 and primary mitochondrial disease. This has been repeatedly demonstrated and upheld over time, and no convincing evidence has emerged that contradicts this gene-disease relationship. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on July 31, 2023 (SOP Version 9).