Variant Synonymizer: Platform to identify mutations defined in different ways is available now!
Over 2,000 gene–disease validation summaries are now available—no login required!
The association between GPR37L1 (HGNC:14923) and epilepsy (MONDO_0005027) has been explored using large‐scale exome sequencing and detailed functional studies. Analyses of 51,289 whole exome sequences have revealed multiple rare coding variants in GPR37L1 that are significantly associated with epilepsy diagnostic codes (PMID:37461723). This genetic evidence underscores the potential clinical impact of GPR37L1 variants in neuropsychiatric conditions, including epilepsy.
Genetic evaluations have identified a spectrum of missense variants. Among these, the representative variant, c.925C>G (p.Arg309Gly), typifies the recurrent alterations noted in independent analyses. Although classical segregation data are limited, the identification of several independent rare variants in such an expansive cohort supports a strong genetic contribution to the disorder (PMID:37461723).
Functional investigations in SK-N-MC cell models have demonstrated that these GPR37L1 variants disrupt canonical signaling pathways. In particular, altered cAMP modulation and activation of MAPK signaling in response to the agonist TX14(A) were observed, providing functional validation of the deleterious impact of these genetic alterations (PMID:37461723, PMID:38569927).
Animal studies, including knockout mouse models, have offered additional experimental insights. Although the KO mice did not recapitulate an acute epileptic phenotype, the observed neuronal functional abnormalities lend further support to the role of GPR37L1 in maintaining normal neurophysiological processes.
Collectively, both genetic and experimental data converge on a strong association between rare GPR37L1 variants and epilepsy. The combination of a robust large‐cohort analysis with concordant functional assays supports the clinical relevance of this gene in the pathogenesis of epilepsy, even as traditional segregation evidence remains sparse.
While additional genetic, segregation, and functional data may further refine the understanding of this association, the current evidence is sufficient to inform both diagnostic decision‑making and the development of targeted therapeutic strategies. This integration of data from diverse sources emphasizes the utility of rare variant analyses in uncovering critical gene‑disease relationships.
Key take‑home: GPR37L1 represents a promising candidate in epilepsy diagnostics, as its rare coding variants disrupt key signaling pathways, underscoring its clinical utility and potential as a therapeutic target.
Gene–Disease AssociationStrongMultiple rare variants identified in a cohort of 51,289 exomes ([PMID:37461723]) with functional studies demonstrating altered receptor signaling ([PMID:37461723], [PMID:38569927]). Genetic EvidenceStrongLarge-scale sequencing has uncovered several pathogenic missense variants, including c.925C>G (p.Arg309Gly), supporting a genetic link with epilepsy. Functional EvidenceModerateCellular assays reveal disrupted cAMP and MAPK signaling in variant-expressing models, with animal studies further implicating GPR37L1 in neuronal dysfunction. |