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Familial focal epilepsy with variable foci is characterized by partial seizures arising from multiple cortical regions in an autosomal dominant pattern. Heterozygous LoF variants in NPRL3 have been identified as causative, with two independent Chinese families demonstrating co‐segregation of truncating alleles and functional assays confirming mTOR pathway dysregulation. The overall clinical validity is classified as Strong based on segregation in two families and concordant experimental data.
NPRL3‐related FFEVF follows autosomal dominant inheritance with incomplete penetrance. Segregation analysis in a six‐generation pedigree revealed a novel nonsense variant c.316C>T (p.Gln106Ter) present in four affected individuals across four generations (PMID:34868250). A separate family of four affected and one unaffected member harbored the frameshift c.1137dup (p.Pro380SerfsTer), with eight affected individuals across both families (PMID:37099548). These LoF variants co‐segregate with disease and are absent from controls, supporting a Moderate level of genetic evidence.
Genetic evidence (Moderate): Two independent families, eight affected relatives, two truncating NPRL3 variants with co‐segregation and absence in population databases. Reported pathogenic alleles include c.316C>T (p.Gln106Ter) and c.1137dup (p.Pro380SerfsTer).
Functional studies demonstrate that NPRL3 haploinsufficiency disrupts mRNA splicing and protein expression, leading to mTORC1 hyperactivation. The c.1137dup allele showed reduced transcript levels and aberrant splice products by qPCR and RT‐PCR (PMID:37099548). The c.316C>T variant decreased mRNA and protein levels in patient blood cells with increased phospho‐p70 S6 kinase (PMID:34868250). In vitro GATOR1 assays of NPRL3 missense variants further confirmed loss of mTOR repression (PMID:31639411), and a cortical organoid model of c.767G>C (p.Arg256Pro) revealed impaired NPRL3–NPRL2 binding and elevated p‐S6 (PMID:39729176). These concordant data meet Strong functional evidence criteria.
Conflicting evidence arises from a cohort study where rare NPRL3 missense variants lacked segregation with epilepsy, underscoring the necessity of co‐segregation and functional validation (PMID:36604176).
In summary, heterozygous truncating NPRL3 variants cause familial focal epilepsy with variable foci via haploinsufficiency of the GATOR1 complex and subsequent mTORC1 pathway activation. While additional rare missense variants require cautious interpretation, LoF alleles in multiple families with supportive functional assays firmly establish a Strong gene–disease association. Key take‐home: NPRL3 testing guides diagnosis and management of FFEVF patients by identifying pathogenic LoF variants that deregulate mTOR signaling.
Gene–Disease AssociationStrongSegregation in two unrelated families and concordant functional data Genetic EvidenceModerateEight affected relatives across two pedigrees with LoF variants co-segregating Functional EvidenceStrongmRNA splicing assays, protein expression and mTORC1 pathway activation in patient cells, in vitro GATOR1 assays, and organoid models demonstrating loss-of-function mechanism |