SLC25A32

Inheritance Pattern: Unknown

Disease ID:MONDO:0014795

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

Inheritance Pattern: AR

Disease ID:MONDO:0014795

Submitter: ClinGen

*SLC25A32*, which encodes the mitochondrial flavin adenine dinucleotide (FAD) transporter, was first implicated in autosomal recessive riboflavin-responsive exercise intolerance in 2016 (Schiff et al., PMID: 26933868). The initial patient presented with recurrent exercise intolerance and was found to carry compound heterozygous c.425G>A (p.W142X) and c.440G>A (p.R147H) variants. One year later, a patient carrying a homozygous c.-264_31delinsCTCACAAATGCTCA variant was reported with a severe neuromuscular phenotype of early-onset ataxia, myoclonus, dysarthria, muscle weakness, and exercise intolerance (PMID: 28443623). Subsequently, two additional patients homozygous for the c.272G>T (p.G91V) variants were reported to experience hypoglycemia and vomiting triggered by febrile illness without muscle weakness or exercise intolerance (PMID: 34764427). Recently, a female patient carrying compound heterozygous c.521A>G (p.Y174C) and c.704A>G (p.K235R) variants was reported with a broad phenotype that included muscle weakness, exercise intolerance, dyspnea, fatigue, growth retardation, motor dysfunction, borderline intellectual disability, enlarged lateral ventricle by brain imaging, fibular hypoplasia and progressive club feet (PMID: 35727412). Biochemical abnormalities across the affected individuals included elevated acylcarnitine profiles, resembling those observed in multiple acyl-CoA carnitine dehydrogenase deficiency (MADD), elevated lactic acid and urinary organic acids. Riboflavin supplement improved clinical and biochemical phenotypes in all reported cases (PMID: 26933868, 34764427, 35727412). Therefore, five variants (four missense and one nonsense) in four probands with highly variable manifestations and severity were included in this curation. This gene-disease relationship was supported by experimental evidence. *In vitro* studies demonstrated that the p.R147H variant failed to rescue yeast growth on glycerol and was associated with reduced mitochondrial complex II/III activity, indicating impaired mitochondrial respiratory chain function (PMID: 26933868). A knock-in (KI) mouse model carrying the K235R/Y174C variants demonstrated motor dysfunction, mildly disrupted acylcarnitine profile in skeletal and brain tissues, accumulation of glutaric acid and decreased formate levels. Although riboflavin supplementation didn’t rescue the motor functions in the KI mice, the model partially recapitulated the patient phenotype (PMID: 35727412). Further studies revealed that *SLC25A32* mutant disrupted folate homeostasis by blocking FAD transport from cytosol into mitochondrial, resulting in inhibition of mitochondrial flavoenzyme activity, impairment of electron chain function, and damage of muscle and brain (PMID: 35727412). Of note, the *SLC25A32* knockout (KO) mice were embryonic lethal. Mutant embryos are presented with variable neural tube closure (NTC) defects that can be rescued by formate supplement. These embryos demonstrated glycine cleavage defect secondary to dihydrolipoamide dehydrogenase (DLDH) deficiency (PMID: 35727412). In humans, one fetus with anencephaly was reported to be compound heterozygous for c.267_268dup and c.391G>T (p.G131X) variants. Experimental studies showed these variants failed to rescue glyB auxotrophic phenotype (PMID: 29666258). Additionally, four heterozygous missense variants (p.T71A, p.A128T, p.G55V, p.S260N) were also reported in fetuses with NTC defects. However, segregation analysis and functional evidence were not provided. Because NTC defects are not currently recognized as an OMIM disease entry associated with *SLC25A32*, and the inheritance patterns reported in these cases are inconsistent with recessive disease mechanism reported in KO mice model, this association was excluded from the present curation. In summary, there is limited evidence supporting the relationship between *SLC25A32* and autosomal recessive riboflavin responsive exercise intolerance. This classification was approved by the ClinGen General Inborn Errors of Metabolism Gene Curation Expert Panel on July 10, 2026 (SOP v12).

Inheritance Pattern: AR

Disease ID:MONDO:0014795

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0014795

Submitter: Labcorp Genetics (formerly Invitae)