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SKOR1 has emerged as a significant locus implicated in restless legs syndrome (RLS). Multiple large‐scale genome‑wide association studies have identified common intronic variants in the SKOR1 genomic region that confer an increased risk for RLS (PMID:17637780). The initial discovery paper reported associations with a greater than 50% increased risk per allele, and follow‑up studies have confirmed these findings in independent cohorts (PMID:18081164). These studies encompass diverse populations with substantial sample sizes, thereby reinforcing the statistical robustness of the association. Although SKOR1 is evaluated alongside other candidate genes, its repeated identification suggests it plays a contributory role in RLS pathogenesis. The evidence collectively supports a gene‑disease link that is relevant for both diagnostic decision‑making and potential future therapeutic targeting.
The overall clinical validity for the SKOR1–RLS association is best classified as Strong. Large‐scale association studies have consistently replicated the risk conferred by SKOR1 variants, with statistical significance maintained across independent replication cohorts (PMID:17637780) and further supported by meta‐analytic approaches (PMID:18081164). Despite the common nature of the risk variants limiting the identification of highly penetrant alleles, the repeated replication and effect size estimation strengthen the evidence. The association is supported by data from multiple populations, and the involvement of SKOR1 adds to the cumulative genetic risk evidenced by other loci in RLS. Although traditional family segregation data are limited in GWAS frameworks, the statistical power derived from large cohorts compensates for this gap. In summary, both the statistical and replication data justify a Strong designation for clinical validity.
Genetic evidence for the association is derived from common intronic variants rather than rare coding changes. The inheritance pattern of RLS in the context of SKOR1 appears to be complex, reflecting a multifactorial architecture rather than a simple Mendelian mode. The available studies did not report clear family segregation data for SKOR1; hence, the count of affected relatives with segregating variants is low (0 additional relatives). Moreover, the analyses did not capture a coding change meeting the strict HGVS criteria required for a c. variant description. Nonetheless, the consistency of the association signal across different cohorts supports the role of SKOR1 as a risk factor. This genetic evidence, while lacking a discrete coding variant, nonetheless contributes substantially to the overall association framework.
From a variant perspective, no SKOR1-specific cDNA change compliant with HGVS format is reported in the supplied evidence. Although some studies mention missense variations in SKOR1 (specifically p.W200R and p.A672V), these entries do not meet the criterion requiring a c. notation with a codified protein consequence. Consequently, the reported variant list for SKOR1 remains empty. This absence of an actionable variant should not detract from the strong association indicated by the statistical analyses. Instead, it highlights the challenges of translating GWAS signals into clinically actionable mutations in the context of non-Mendelian disorders. Future studies may resolve this gap by providing a clearer variant spectrum for SKOR1.
Regarding functional or experimental evidence, direct assays evaluating SKOR1’s role in RLS are currently limited. No model organism or cellular studies have been reported that specifically examine SKOR1 function in the context of RLS. Indirect regulatory evidence is available through the GWAS signals where SKOR1 is positioned within a locus that influences gene expression. This observation is consistent with common disease mechanisms where noncoding variants alter regulatory elements rather than protein-coding sequences. Although such evidence is less definitive compared to functional assays, it provides supportive context for the clinical association. Overall, the functional evidence for SKOR1 remains Limited based on current data.
In conclusion, the aggregate data from multi-patient studies indicate a Strong association between SKOR1 and restless legs syndrome, despite the absence of a clearly defined coding variant or direct functional studies. The genetic evidence is robust, with replicated findings across independent cohorts demonstrating a consistent risk effect. Although functional assessments are currently limited, the regulatory impact of the associated variants is in line with a non-Mendelian, multifactorial disease mechanism. This integrated narrative underscores the clinical utility of SKOR1 as a marker for RLS risk and highlights its potential for inclusion in diagnostic panels. Notably, the large-scale replication and effect size justify the inclusion of SKOR1 in both research and commercial diagnostic settings.
Key Take‑home sentence: The replicated association of SKOR1 intronic variants with restless legs syndrome provides a robust genetic marker that is highly relevant for clinical diagnostics and future translational research.
Gene–Disease AssociationStrongMultiple large-scale GWAS studies with independent replication in diverse cohorts support a significant association between SKOR1 and restless legs syndrome (PMID:17637780, PMID:18081164). Genetic EvidenceStrongCommon intronic variants in SKOR1 have been repeatedly associated with RLS risk despite the absence of a definitive cDNA change, reflecting robust statistical evidence from large cohorts. Functional EvidenceLimitedNo direct functional studies specific to SKOR1 have been performed, and current evidence is limited to indirect regulatory findings within the associated locus (PMID:17637780). |