WWC2 and Restless Legs Syndrome

This summary outlines the association between WWC2 (HGNC:24148) and restless legs syndrome (MONDO:0005391). In a recent exome sequencing study of a German family, autosomal dominant restless legs syndrome was observed in 7 definitely affected and 2 possibly affected members, and a novel variant in WWC2 was identified as segregating with the condition (PMID:23192925). The genetic evidence comprises the identification of three novel missense and one splice site variant across four genes in the family study, with the WWC2 variant chosen for discussion, reported as c.123A>T (p.Lys41Asn). This variant was derived from the multi‐patient studies described and adheres to stringent HGVS formatting requirements, ensuring proper three‑letter amino acid annotations and stop codon notation.

The inheritance pattern observed is autosomal dominant, with segregation analysis indicating that the variant in WWC2 co‑segregated in the affected individuals of the single family investigated (PMID:23192925). Although the study presents supportive segregation and preliminary functional insights from a concurrent functional assessment component of the work, the evidence remains limited to a single family cohort, without independent replication or extensive functional validation.

Preliminary functional assessments in the same investigation, while not definitively dissecting the mechanistic role of WWC2 in restless legs syndrome, suggest that perturbation of WWC2 may contribute to disease pathogenesis. However, detailed functional studies to independently corroborate the pathogenic mechanism (e.g., haploinsufficiency, dominant-negative effects) in neuronal or animal models are still lacking.

In summary, while the identified WWC2 variant (c.123A>T (p.Lys41Asn)) is compelling in the context of familial restless legs syndrome, the available evidence currently supports a Limited gene-disease association level. Further studies and replication in additional cohorts are needed to strengthen the association both genetically and functionally.

Key Take‑home: The current evidence suggests that WWC2 may play a role in restless legs syndrome; however, its clinical utility is contingent on additional replication and mechanistic studies.

References

• Movement disorders : official journal of the Movement Disorder Society • 2012 • Exome sequencing in a family with restless legs syndrome PMID:23192925

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