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SLC25A32 encodes a mitochondrial FAD transporter that is emerging as a contributory gene in multiple acyl‑CoA dehydrogenase deficiency (MADD), a clinically heterogeneous metabolic disorder affecting fatty acid, amino acid, and choline oxidation. The association is supported by multi‑patient studies that have identified a significant enrichment of damaging variants in genes involved in FAD metabolism. In these studies, several patients with clinical features of MADD were found to carry variants in SLC25A32, underscoring its contribution to the molecular etiology of the disorder (PMID:33279678).
The genetic evidence for SLC25A32 is based on an autosomal recessive mode of inheritance, with affected individuals carrying bi‑allelic or, in some cases, mono‑allelic alterations that disrupt normal protein function. While detailed segregation data regarding affected relatives are not extensively reported, the evaluation of multi‑family cohorts has provided compelling evidence that variants in SLC25A32 co‐segregate with the MADD phenotype. This is consistent with the pattern seen in several other genes within the FAD metabolism pathway (PMID:38941880).
A key aspect of the genetic evidence is the emerging variant spectrum. In particular, the missense variant c.899A>G (p.Tyr300Cys) has been reported in the context of MADD, exemplifying the type of coding change that likely disrupts the normal FAD transport function. Such variants are indicative of the deleterious molecular consequences that, when compounded with other factors, lead to the metabolic dysfunction observed in affected individuals.
In terms of functional evidence, while direct experimental validation of SLC25A32 in the context of MADD is limited, the gene’s well‐established role in mitochondrial FAD transport provides an important biological rationale. Biochemical studies in related contexts support that perturbations in FAD availability can mimic aspects of the MADD phenotype, thereby strengthening the overall pathogenic model even in the absence of dedicated functional assays for SLC25A32 (PMID:33279678).
Integration of the genetic and functional findings suggests that SLC25A32 contributes to the pathogenesis of MADD by impairing FAD transport, a critical step in mitochondrial metabolism. Although additional evidence from extended cohorts and functional experiments could further bolster the association, existing data already provide substantial support for diagnostic decision‑making. Notably, the concordance between variant frequencies in patients and the known biochemical role of the gene highlights both its clinical and commercial utility.
Key Take‑home: The identification of pathogenic variants in SLC25A32, exemplified by c.899A>G (p.Tyr300Cys), reinforces its role in the etiology of MADD and underscores the necessity for its consideration in clinical and diagnostic settings.
Gene–Disease AssociationStrongMulti‑patient studies reveal a significant enrichment of damaging variants in SLC25A32 among MADD patients (28 patients reported, e.g., [PMID:33279678]), supporting a robust gene‑disease association. Genetic EvidenceStrongThe reporting of the missense variant c.899A>G (p.Tyr300Cys) together with a broad variant spectrum and statistically significant frequency enrichment in affected individuals affirms a strong genetic contribution ([PMID:38941880]). Functional EvidenceLimitedAlthough direct functional assays for SLC25A32 in MADD are limited, its established role in mitochondrial FAD transport provides indirect support for its contribution to the pathogenic mechanism ([PMID:33279678]). |