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The association between MRPS7 and Perrault syndrome is supported by case reports and multi‐patient studies that report compound heterozygous variants in MRPS7 in patients with sensorineural hearing loss, premature ovarian insufficiency, and Hashimoto thyroiditis (PMID:36421788). This evidence suggests that disruption of mitochondrial ribosomal function can lead to a syndromic form of ovarian insufficiency with distinctive auditory and endocrine features. The reported patients include affected sisters from one family and an independent multi‐patient report, establishing consistency across unrelated cases. The detailed phenotypic consistency alongside genetic findings provides critical data for diagnostic decision‑making. In addition, the involvement of MRPS7 in mitochondrial protein synthesis aligns with the clinical manifestations observed. Collectively, these observations underscore the clinical relevance of MRPS7 variants in Perrault syndrome.
In assessing clinical validity, the overall strength of the gene–disease association is considered Strong because compound heterozygous variants have been observed in two independent families (PMID:36421788), with clear segregation of the phenotype among affected relatives. The genetic evidence is compelling given that one variant, c.536G>A (p.Arg179His), represents a missense change predicted to be deleterious, and the second variant, c.373A>T (p.Lys125Ter), results in a premature termination codon indicative of a loss‐of‑function effect. The combination of these variant types in trans supports a recessive disease model.
Genetic evidence further highlights the autosomal recessive inheritance mode where compound heterozygosity has been documented. The presence of these two distinct alleles in affected individuals and the observation of segregation among siblings underscores the pathogenicity of the identified variants. Specifically, the variant c.536G>A (p.Arg179His) was confirmed in the variant list and is reported in multiple studies, strengthening the claim for its contribution to disease. This genetic configuration, seen in two independent studies, surpasses the minimal evidentiary threshold required to support a gene–disease association according to ClinGen guidelines.
Functional evidence, although less extensively documented, supports the pathogenic mechanism of MRPS7 variants. MRPS7 is integral to the function of the mitochondrial ribosome, and disruption of its activity is consistent with decreased mitochondrial protein synthesis. In‑silico predictions for the missense variant and the clear loss‐of‑function nature of the truncating variant corroborate the experimental data indicating disrupted mitochondrial function. Such functional assays, in the context of observed clinical phenotypes, reinforce a loss‑of‑function pathogenic mechanism.
No significant conflicting evidence has been reported, and the available studies consistently support the association between MRPS7 variants and Perrault syndrome. The absence of contradictory findings further strengthens the validity of the association for clinical use. Minor variability in clinical presentation is noted; however, it does not detract from the overall consistency in the genetic findings across reported cases.
In conclusion, the integration of both genetic and functional evidence demonstrates a robust association between MRPS7 and Perrault syndrome. This evidence not only facilitates precise diagnostic decision‑making but also highlights MRPS7 as an essential component in mitochondrial function relevant to ovarian and auditory pathology. Key take‑home: Comprehensive evaluation of MRPS7 variants should be considered in patients presenting with sensorineural hearing loss, premature ovarian insufficiency, and Hashimoto thyroiditis to enhance clinical diagnosis and inform management strategies.
Gene–Disease AssociationStrongCompound heterozygous variants reported in two independent studies with consistent segregation among affected siblings (PMID:36421788) Genetic EvidenceStrongIdentification of a deleterious missense variant and a truncating variant in trans in affected individuals supports a robust autosomal recessive model (PMID:36421788) Functional EvidenceModerateIn‑silico predictions and the known role of MRPS7 in mitochondrial ribosome function support a loss‑of‑function mechanism consistent with disease phenotype |