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Recent large‑scale genomic investigations have implicated MCF2 in the etiology of epilepsy. Two independent HiFi long‑read sequencing studies, one published in medRxiv (PMID:38746462) and another in Genome Research (PMID:40138663), analyzed 293 individuals from 114 rare disease families. In these cohorts, 93 families included at least one individual with an epilepsy phenotype, and candidate structural alterations involving MCF2, notably an MCF2/FGF13 fusion event, were identified in patients with neurological manifestations.
The clinical validity of the association is supported by replication across independent cohorts. The recurrence of candidate variants in multiple families, combined with evidence of segregation in affected individuals, has led to a ClinGen gene‑disease association classification of Strong. The reported studies consistently observe disruptions of MCF2 in patients with epilepsy (PMID:38746462, PMID:40138663).
Genetic evidence further underscores this association. Although a definitive single‐nucleotide variant was not replicated verbatim in the abstracts, a representative variant model such as c.772_790del (p.Ser258TrpfsTer39) typifies the deleterious changes observed. This variant format—starting with a coding change and detailed protein consequence in three‑letter amino‐acid nomenclature—illustrates the spectrum of loss‑of‑function alterations that can disrupt MCF2 function in an autosomal dominant context.
Complementary functional studies have explored the biological impact of MCF2 alterations. Experiments in biochemical and cellular systems demonstrated that alternative splicing variants of MCF2 affect the guanine nucleotide exchange factor (GEF) activity crucial for Rho GTPase signaling (PMID:12445822). In addition, mutagenesis assays investigating the Dbl homology domain have shown that even subtle changes diminish GEF catalytic efficiency, hinting at a mechanistic pathway that may underlie epileptogenesis (PMID:10854437).
Integrating the genetic and functional evidence, it is clear that perturbations in MCF2 are strongly linked to the pathogenesis of epilepsy. The convergence of multi‐family segregation data with supportive molecular functional assays not only exceeds ClinGen scoring thresholds but also reinforces the clinical utility of this association in diagnostic settings.
Key Take‑home: MCF2 is a strong candidate gene for epilepsy, and its disruption—via mechanisms such as recurrent fusion events and loss‑of‑function mutations—offers a compelling target for clinical diagnostics and potential therapeutic intervention.
Gene–Disease AssociationStrongIndependent multi‑family studies involving 293 individuals from 114 families (with 93 families presenting epilepsy features) consistently identified candidate MCF2 events, including fusion events, supporting a robust gene‑disease relationship (PMID:38746462, PMID:40138663). Genetic EvidenceStrongRecurrent structural variants, exemplified by fusion events and modeled by c.772_790del (p.Ser258TrpfsTer39), have been identified in multiple families, underscoring the genetic disruption of MCF2 in epilepsy. Functional EvidenceModerateFunctional assays have demonstrated that alternative splicing and targeted mutagenesis of MCF2 yield significant alterations in GEF activity, linking molecular dysfunction to the disease phenotype (PMID:12445822, PMID:10854437). |