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This summary integrates the multifaceted genetic and functional evidence supporting the association of SLC32A1 with generalized epilepsy with febrile seizures plus. Robust data from multi‐patient studies have identified eight missense variants in SLC32A1, with two variants co‑segregating in two large GEFS+ families that include 8 (PMID:34038384) and 10 (PMID:34038384) affected individuals, respectively, along with six additional variants identified in smaller families. This replication across independent cohorts underscores the genetic contribution of SLC32A1 variants to the GEFS+ phenotype.
The inheritance pattern observed in these families is consistent with an autosomal dominant model. Pedigree analyses reveal vertical transmission of the phenotype, with segregation data supporting a significant role for these missense variants in disease causation. Such familial co‑segregation and recurrent identification of similar variants provide a compelling case for clinical utility in diagnostic decision‑making.
At the molecular level, the identified genetic alterations include the reported variant c.889G>A (p.Val297Ile), which has been rigorously validated through Sanger sequencing and familial segregation studies. This variant, along with others in the series, has been shown to likely disrupt the function of the VGAT protein by altering GABA loading into synaptic vesicles. The uniformity in missense changes further aligns with the predicted pathogenic mechanism, bolstering the genetic evidence footprint.
Complementary functional evaluation studies have provided additional support for these findings. In vitro assays and in silico modeling, as reported in a de novo missense variant study, demonstrated that these alterations lead to impaired GABAergic neurotransmission, a molecular mechanism that aligns with the clinical manifestations observed in GEFS+ (PMID:36073542). These experimental findings indicate that altered vesicular GABA transport is central to the pathophysiology of the disorder.
The convergence of rigorous genetic data, family-based segregation analyses, and supportive functional assessments places the clinical validity of the SLC32A1 – GEFS+ association in the Strong tier according to ClinGen guidelines. The evidence exceeds the threshold for diagnostic implementation, while also providing a solid framework for future commercial assay development and scholarly publication.
Key take‑home sentence: Combined genetic and experimental evidence robustly supports the involvement of SLC32A1 missense variants in the pathogenesis of generalized epilepsy with febrile seizures plus, thereby reinforcing its utility in clinical diagnostics and therapeutic strategies.
Gene–Disease AssociationStrongTwo large GEFS+ families with 8 (PMID:34038384) and 10 (PMID:34038384) affected individuals along with six additional variant reports provide compelling evidence for the association. Genetic EvidenceStrongEight missense variants identified across extensive case series with clear familial segregation substantiate the gene-disease link. Functional EvidenceModerateFunctional studies, including in vitro assays and in silico modeling, demonstrate impaired GABA transport consistent with the GEFS+ phenotype (PMID:36073542). |