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The gene RGL1 (HGNC:30281) has recently emerged as a candidate associated with intellectual disability (MONDO_0001071), based primarily on data from a large genomic cohort of 337 individuals (PMID:27431290). Although the overall number of probands with RGL1 variants is not explicitly delineated, the gene was identified among a panel of candidates with rare deleterious variation in individuals with ID, suggesting a potential role in the molecular etiology of the disorder.
Genetic evidence for RGL1 is currently limited. In the cited multi‐patient study, rare variants in RGL1 were observed in affected individuals in a setting where most identified point mutations followed an autosomal recessive inheritance pattern (PMID:27431290). However, the absence of detailed segregation data or replication in independent families constrains the strength of the genetic evidence. No single pathogenic HGVS variant uniquely reported for RGL1 is available from the provided data, which further reflects the early stage of the gene’s clinical characterization.
Functional assessments add an important layer of support to the candidate status of RGL1. Two independent studies have investigated the molecular interactions involving RGL1. In one study, a double‐mutant analysis demonstrated that alterations in key residues of the RGL1 protein significantly affect its binding affinity to Ras, thereby disrupting normal signal transduction pathways critical for neurodevelopment (PMID:10213614). A subsequent molecular dynamics study further confirmed that RGL1 contributes to the stability of the Ras complex, with oncogenic mutations in interacting partners accentuating these effects (PMID:38153169).
While there is robust functional data reinforcing RGL1’s biochemical role, the genetic evidence remains in an emerging phase. The current data do not present any conflicting studies that refute the association; however, the limited number of segregation analyses and absence of recurrent or founder variants necessitate cautious interpretation. Replication and further delineation of genotype–phenotype correlations will be essential to firmly establish the clinical validity of the association.
Integration of the genetic and experimental findings suggests that alterations in RGL1 may impair Ras-mediated signaling, a pathway pivotal for proper neuronal development. This integrated evidence, although presently classified as limited in genetic strength, is bolstered by functional assays that are concordant with the neurodevelopmental phenotype associated with intellectual disability. The combined observations thus support ongoing consideration of RGL1 in diagnostic gene panels and further research on its pathogenic role.
Key take‑home sentence: RGL1 represents an emerging candidate gene for intellectual disability with promising functional evidence, warranting additional studies to fully unlock its clinical utility.
Gene–Disease AssociationLimitedRGL1 was flagged as a candidate gene in a large cohort of 337 intellectual disability cases (PMID:27431290), but detailed segregation and replication data across independent families are lacking. Genetic EvidenceLimitedThe genetic evidence is based on rare candidate variants identified in affected individuals with ID, without clear recurrence or segregation data, limiting the strength of the association (PMID:27431290). Functional EvidenceModerateFunctional studies employing double‑mutant analyses and molecular dynamics simulations demonstrate that RGL1 modulates Ras interactions, supporting its putative pathogenic role in neurodevelopmental processes (PMID:10213614, PMID:38153169). |