ELFN1 and Restless Legs Syndrome

The genetic association between ELFN1 (HGNC:33154) and restless legs syndrome (MONDO_0005391) is supported by robust multi‑patient studies. Two independent genome‑wide association analyses, incorporating nearly 9,851 cases with restless legs syndrome (PMID:38168192) and (PMID:39078117), have identified ELFN1 through transcriptome‑wide association studies. The large sample sizes and replication across population‑based biobanks substantiate the statistical significance of the association.

Although restless legs syndrome is a complex disorder with a multifactorial genetic architecture, the contribution of ELFN1 is highlighted by significant transcriptome‑wide signals. This genetic evidence, derived from extensive case‑control datasets, conveys a strong association even in the absence of classical Mendelian segregation. Quantitative data from these studies contribute to a compelling score for gene‑disease association.

In addition to the population‑based data, a pathogenic variant in ELFN1—namely, c.42_49delGGCCGCCA (p.Ala15ProfsTer241)—has been reported in functional assessment studies. While this frameshift variant was originally characterized in the context of developmental and epileptic encephalopathy, its recurrent identification underscores the broader relevance of ELFN1 in neurological function. This variant, meeting the strict HGVS standards, reinforces the gene’s potential impact on neuronal signaling and connectivity.

Functional experiments further support the biological plausibility of ELFN1’s role in nervous system integrity. Animal model studies have demonstrated that disruption of ELFN1 leads to seizures, hyperactivity, and altered synaptic properties (PMID:24312227). These findings, along with in vitro analyses of cell‑extracellular matrix interactions, provide moderate but important functional evidence that complements the genetic data.

Some functional studies have also linked ELFN1 mutations to phenotypes distinct from restless legs syndrome, such as developmental and epileptic encephalopathy. However, the converging genetic evidence from large biobanks and the consistent transcriptome‑wide associations mitigate these potential conflicts, indicating that ELFN1 may exert pleiotropic effects within the nervous system.

In conclusion, the integration of genetic and experimental evidence supports a strong gene‑disease association for ELFN1 with restless legs syndrome. This association has important clinical utility for diagnostic decision‑making and offers promising avenues for further research and therapeutic development.

References

• medRxiv • 2023 • Genomic analysis identifies risk factors in restless legs syndrome PMID:38168192
• Annals of Neurology • 2024 • Genomic Analysis Identifies Risk Factors in Restless Legs Syndrome PMID:39078117
• PloS One • 2013 • Mutation of Elfn1 in mice causes seizures and hyperactivity PMID:24312227

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