Submission Details

The relationship between SLC25A1 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of December 18, 2023. This gene encodes the mitochondrial citrate transporter, an electroneutral antiporter that exports citrate from the mitochondria into the cytosol, in exchange for malate. SLC25A1 also mediates the exchange of citrate for isocitrate, cis-aconitate, phosphoenolpyruvate, and malate (and to a lesser extent maleate and succinate). Citrate exported from the mitochondria is needed for cytosolic production of acetyl-CoA required for synthesis of lipids, sterols, and dolichols .

SLC25A1 was first reported in relation to autosomal recessive primary mitochondrial disease in 2013 (PMID: 23561848), in several individuals with combined D-2- and L-2-hydroxyglutaric aciduria (HGA) and severe neonatal epileptic encephalopathy. While various names have been given to the constellation of features seen in those with SLC25A1-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the SLC25A1 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 12 unique variants (nine missense, two frameshift, one nonsense) identified in 11 probands from two publications (PMIDs: 23561848, 23393310), although there are more cases reported in the medical literature. Age of onset is within the first year of life and the outcome ranges from an early infantile epileptic encephalopathy without skills development and early death to early infancy-onset nonprogressive myasthenic syndrome. Affected individuals typically present with combined D-2- and L-2-hydroxyglutaric aciduria (HGA) or a congenital myasthenia syndrome phenotype. Clinical features observed in affected individuals include profound developmental delay, intellectual disability, learning disabilities, irritability, infantile epileptic encephalopathy, seizures, dystonia, myasthenic syndrome, muscle weakness, easy fatigability, distal and proximal weakness, hypotonia, optic nerve atrophy, ptosis, cortical blindness, poor eye contact, central apnea, and respiratory insufficiency. Muscle biopsies were not routinely performed in the reported cases. Brain imaging has shown agenesis of the corpus callosum, delayed brain development and gyration, ventriculomegaly, caudate cysts, and cerebellar hypoplasia.

This gene-disease association is also supported by its known biochemical function (PMID: 33340416), functional alteration in patient cells (PMID: 23561848), zebrafish model (PMID: 26870663), drosophila model (PMID: 30108060), and rescue in patient cells (PMID: 29238895).

In summary, there is definitive evidence to support the relationship between SL25A1 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 December 18, 2023 (SOP Version 10).