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This summary describes the association between PYROXD2 (HGNC:23517) and mitochondrial disease (MONDO_0044970). The reported evidence comes from a single proband with biallelic variants in PYROXD2 presenting with a severe infantile metabolic disorder. The patient presented with acute neurological deterioration, unresponsive episodes, and extreme metabolic acidosis, with neuroimaging findings resembling Leigh syndrome. Segregation data are limited with no additional affected relatives reported (PMID:35055180).
Genetic evidence supporting this association is limited. The critical variant reported is c.1276G>A (p.Gly426Ser) observed in the proband, and it has been identified as recurrent in the patient cohort provided (PMID:35055180). Functional studies in patient fibroblasts demonstrated heightened sensitivity to mitochondrial metabolic stress and a reduction in key mitochondrial respiratory chain components, lending support to a pathogenic mechanism consistent with mitochondrial dysfunction.
Experimental work in cellular models recapitulated the patient phenotype through decreased levels of subunits from mitochondrial complex I and mitoribosomal components. These functional data further substantiate a mechanism whereby biallelic alterations in PYROXD2 lead to impaired mitochondrial function. The functional evidence provides moderate support, as the in vitro findings align with the clinical presentation.
No conflicting data or alternative phenotypic associations have been reported to date. Although the amount of clinical genetic data is limited to a single proband, the corroborating experimental findings enhance the overall confidence in the association.
In summary, while the genetic evidence is currently limited, the strong concordance with functional data and the consistent mechanistic rationale underscore the clinical utility of considering PYROXD2 variation in the differential diagnosis of mitochondrial disease. Further studies and additional cases are warranted to fully establish this association for diagnostic and commercial applications.
Gene–Disease AssociationLimitedA single proband with biallelic PYROXD2 variants (PMID:35055180) supports the association, but the limited case count restricts the overall strength. Genetic EvidenceLimitedThe recurrent variant c.1276G>A (p.Gly426Ser) was observed in one proband, and although it is supported by case data, additional cases are required to exceed the scoring ceiling. Functional EvidenceModeratePatient fibroblast studies demonstrated mitochondrial metabolic stress with decreased levels of complex I and mitoribosomal subunits, providing a clear mechanistic link to the phenotype (PMID:35055180). |