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The association between MRPL49 and combined oxidative phosphorylation deficiency is supported by robust genetic and functional evidence. Two independent studies identified biallelic variants in MRPL49 in individuals presenting with a spectrum of clinical features. In one study, five unrelated families were described (PMID:39417135), and a second study reported findings in nine unrelated families (PMID:40043708). The consistency of clinical features across these studies bolsters the link between MRPL49 mutations and the disease. Moreover, the clinical presentations encompass core features such as sensorineural hearing impairment, retinal dystrophy, microcephaly, and premature ovarian insufficiency. This body of evidence justifies a strong level of confidence in the gene-disease association.
Genetic data from these studies underscore an autosomal recessive inheritance pattern. The identification of biallelic variants, including both missense and loss-of-function alterations, in unrelated families supports the notion of recessive transmission. The reported evidence includes segregating variants in additional affected relatives, further reinforcing the genetic linkage. The uniformity of the phenotypic spectrum among patients across different families enhances the diagnostic yield. Detailed case reports reveal that the clinical variability does not preclude the recognition of a unified molecular etiology. These findings are highly relevant in guiding diagnostic genetic testing.
Variant analysis reveals a compelling mutational spectrum. Among the reported variants, the change c.275A>C (p.His92Pro) stands out as a representative coding alteration. This variant, along with others identified in the studies, fits the criteria for pathogenicity with a complete coding change as denoted by the HGVS nomenclature. The combination of missense and frameshift mutations across the studies indicates a critical need for functional integrity of MRPL49. This specific variant substantiates the role of MRPL49 and provides an actionable target for molecular diagnostics. The evidence further supports clinical decision‑making and eventual commercial application.
Segregation evidence adds an additional layer of validation. A total of 19 affected relatives have been documented to carry the segregating MRPL49 variants, which reinforces the autosomal recessive inheritance pattern. This finding is critical in clinical settings, particularly for risk assessment and family counseling. The aggregation of multiple affected individuals from distinct families supports the reliability and reproducibility of the genetic association. Segregation data, when combined with case‐series findings, significantly increases the confidence in the causal role of MRPL49 variants. This is a pivotal factor for clinicians evaluating candidates for molecular testing.
Complementary functional assessments have provided further corroboration. Functional studies, notably complexome profiling on patient-derived fibroblasts, reveal a significant reduction in both small and large mitochondrial ribosomal subunits. In addition, diminished levels of oxidative phosphorylation enzyme complexes I and IV have been consistently observed. These experimental findings are in line with the clinical manifestations and provide mechanistic insight into the disease process. Experimental data demonstrating concordance with the patient phenotype serve as an important adjunct to genetic evidence. Together, these observations support a mechanism involving impaired mitochondrial protein synthesis.
In conclusion, the accumulated genetic and functional evidence strongly supports the association of biallelic MRPL49 variants with combined oxidative phosphorylation deficiency. The genetic findings from 14 unrelated families, reinforced by robust segregation and functional studies, firmly establish the disease mechanism and inheritance pattern. This consolidated evidence provides essential information for diagnostic laboratories, guides clinical management, and informs future research. Key take‑home message: MRPL49 testing should be integrated into diagnostic panels for patients with suspected mitochondrial disorders presenting with sensorineural, ocular, or reproductive phenotypes.
Gene–Disease AssociationStrong14 unrelated families (5 from medRxiv (PMID:39417135) and 9 from AJHG (PMID:40043708)) show a consistent clinical phenotype, with extensive segregation and experimental concordance. Genetic EvidenceStrongBiallelic MRPL49 variants, including the missense variant c.275A>C (p.His92Pro), and additional loss‑of‑function mutations identified in 14 unrelated families provide compelling evidence for an autosomal recessive association. Functional EvidenceModerateFunctional studies, such as complexome profiling of patient fibroblasts, demonstrate reduced mitochondrial ribosomal subunits and OXPHOS enzyme complexes, aligning with the pathophysiology of the disorder. |