Variant Synonymizer: Platform to identify mutations defined in different ways is available now!
Over 2,000 gene–disease validation summaries are now available—no login required!
This summary integrates multiple lines of evidence linking biallelic mutations in SLC25A10 to mitochondrial DNA depletion syndrome. The two independent case reports, one from a trio‐WES study (PMID:29211846) and another from a compound heterozygous case report (PMID:35499102), provide genetic support for this association. In both instances the affected individuals harbor pathogenic variants in SLC25A10, with one report describing a recurrent coding change, c.304A>T (p.Lys102Ter), that truncates the protein product and is consistent with the loss‑of‑function mechanism.
The inheritance pattern is autosomal recessive, which is supported by the identification of compound heterozygous mutations in affected individuals, with unaffected parents serving as carriers. Although segregation data beyond the probands are limited, the available familial trio and compound heterozygous findings are in line with recessive inheritance, reinforcing the diagnostic suspicion in patients with relevant clinical features.
The genetic evidence is characterized by two unrelated probands who each presented with severe phenotypes including intractable epileptic encephalopathy and neurodegenerative manifestations. The variant c.304A>T (p.Lys102Ter) was identified in one of these reports, and its presence along with other rare variants in SLC25A10 substantiates its role in disease pathogenesis (PMID:29211846, PMID:35499102).
Functional studies have provided robust support for the pathogenicity of SLC25A10 variants. Investigations in patient fibroblasts demonstrated a reduction in RNA quantity, aberrant RNA splicing, and a complete loss of SLC25A10 protein expression, while yeast knockout models recapitulated defects in mitochondrial respiration and mitochondrial DNA content. Additionally, transport assays confirmed the inability of the mutant protein to mediate glutathione transport, a result that dovetails with the proposed loss-of-function mechanism (PMID:29211846).
Integrating both genetic and experimental evidence, it becomes evident that disruptions in SLC25A10 lead to significant mitochondrial dysfunction which manifests clinically as a severe neurodegenerative disorder with features such as epileptic encephalopathy, hypotonia, tetraparesis, hearing impairment, and spasticity. While the number of probands is currently limited, the high-quality functional data exceed the minimal criteria required for clinical decision-making and support further investigation and testing in clinically suspicious cases.
Key take‑home sentence: Comprehensive genetic and robust functional evidence support the clinical utility of including SLC25A10 testing in patients with suspected mitochondrial DNA depletion syndrome, thereby guiding diagnostic, prognostic, and therapeutic decisions.
Gene–Disease AssociationModerate2 probands (PMID:29211846, PMID:35499102) with robust functional evidence demonstrating impaired mitochondrial function. Genetic EvidenceModerateThe genetic evidence is supported by compound heterozygous variants identified in 2 unrelated individuals, including the recurrent variant c.304A>T (p.Lys102Ter), consistent with autosomal recessive inheritance. Functional EvidenceStrongFunctional studies in patient fibroblasts and yeast models demonstrated loss-of-function effects, including aberrant RNA splicing and compromised mitochondrial respiration that recapitulate the human phenotype. |