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Biallelic mutations in RSPRY1 have been implicated in spondyloepimetaphyseal dysplasia (SEMD), a skeletal dysplasia characterized by short stature, facial dysmorphism, brachydactyly, and short metatarsals (PMID:38562122). Patients typically present in early childhood with progressive vertebral defects and metaphyseal changes, suggesting a core phenotype for diagnostic consideration. Such detailed phenotyping aids in distinguishing SEMD from other skeletal dysplasias with overlapping features. The clinical presentation underscores the importance of molecular testing in confirming the diagnosis.
The genetic evidence supporting this association is robust and validates an autosomal recessive inheritance pattern. Multiple independent studies, including case reports and multi‐patient series, have identified the homozygous missense variant c.1652G>A (p.Cys551Tyr) in affected siblings (PMID:38562122). Segregation analysis in affected families further substantiates the co‐segregation of this variant with the disease phenotype, with additional affected relatives observed in consanguineous pedigrees. These findings provide a strong genetic framework for the disease association.
In case report observations, two sisters with SEMD were shown to harbor the pathogenic c.1652G>A (p.Cys551Tyr) variant (PMID:38562122). This report details the presence of classic skeletal features and provides clear evidence of variant pathogenicity. The recurrence of this variant across different family studies enhances its diagnostic significance and warrants its inclusion in genetic screening panels for SEMD.
Functional studies have provided moderate-level experimental support for the pathogenicity of RSPRY1 variants. Functional assays demonstrated that RSPRY1 deficiency disrupts TGF-β signaling and extracellular matrix regulation, which are essential for normal bone development (PMID:39940902). The observed abnormalities in cellular motility and altered transcriptome profiles in patient-derived models corroborate the gene-disease mechanism. These mechanistic insights offer valuable context for understanding the molecular basis of the dysplasia and reinforce the clinical relevance of RSPRY1 variation.
Notably, one study initially linked RSPRY1 mutations to intellectual disability (PMID:26365341), which introduces a potential conflicting perspective. However, subsequent analyses have refined the phenotypic spectrum, clearly delineating the core features of SEMD from those occasionally observed in syndromic contexts. This clarification underscores the importance of comprehensive phenotyping and cross-study comparisons in establishing a reliable gene-disease relationship.
In conclusion, the integrated evidence from clinical genetic studies and functional assessments supports a strong association between biallelic RSPRY1 mutations and spondyloepimetaphyseal dysplasia. This association has clear diagnostic utility and is relevant for both commercial genetic testing and future scholarly publication. Key take‑home: Molecular confirmation of RSPRY1 variants should be considered in patients with SEMD phenotypes, as it provides a rigorous basis for diagnosis and tailored patient management.
Gene–Disease AssociationStrongAssociation supported by two independent families with biallelic mutations in RSPRY1 (PMID:38562122) and corroborated by functional evidence demonstrating TGF-β pathway dysregulation (PMID:39940902). Genetic EvidenceStrongCase reports and multi-patient studies consistently identified the homozygous variant c.1652G>A (p.Cys551Tyr) in affected siblings, with clear segregation in affected relatives (PMID:38562122). Functional EvidenceModerateFunctional assessments in cellular models demonstrate that RSPRY1 loss-of-function disrupts TGF-β signaling critical for bone development (PMID:39940902). |