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SLC25A1-related mitochondrial disease follows an autosomal recessive inheritance pattern. A single proband presented with severe neurodevelopmental disease manifesting as agenesis of the corpus callosum (HP:0001274) and optic nerve hypoplasia (HP:0000609). Biochemical investigations revealed prominent excretion of 2-hydroxyglutaric acid and Krebs cycle intermediates in urine, increased reactive oxygen species, and decreased mitochondrial membrane potential in patient fibroblasts. Whole exome sequencing identified compound heterozygous SLC25A1 variants c.389G>A (p.Gly130Asp) and c.845G>A (p.Arg282His), which segregated in the family and are extremely rare in controls (1 proband) (PMID:23393310).
Functional studies demonstrated that yeast cells harboring equivalent mutations exhibited growth defects under stress and that mutant human proteins reconstituted into liposomes lost citrate transport activity, confirming a loss-of-function mechanism in the mitochondrial citrate carrier (PMID:23393310). No conflicting evidence has been reported. Additional unrelated cases and segregation data are required to bolster genetic evidence.
Key take-home: Consider SLC25A1 deficiency in patients with neurodevelopmental anomalies and metabolic signatures of citric acid cycle dysfunction; molecular diagnosis informs targeted management and genetic counseling.
Gene–Disease AssociationLimitedSingle proband with compound heterozygous variants and segregation in one family, limited case-level evidence Genetic EvidenceLimitedOne case with AR inheritance, no additional affected relatives Functional EvidenceModerateYeast model and liposome assays demonstrating loss of transport function |