Genotype-Phenotype Correlations, Genetic Mechanisms of Phenotypic Heterogeneity, Optimized Diagnosis and Targeted Therapies in Epilepsy and Neurodevelopmental Disorders

Epilepsy and neurodevelopmental disorders (NDDs) form a clinically heterogeneous group of neurological conditions with shared genetic etiologies, affecting millions globally and imposing heavy burdens on individuals, families, and healthcare systems. With advances in next-generation sequencing and multi-omics technologies, researchers have recently identified novel pathogenic variants and causative genes associated with both epilepsy and NDDs. The developmental stage-dependent expression patterns of causative genes have also been found to play a key role in determining phenotypic severity and treatment response.

Yet, the molecular drivers behind phenotypic variability—spanning from mild self-limited epilepsy with favorable outcomes to severe, drug-resistant epileptic encephalopathies with profound cognitive impairment—remain incompletely understood. Critical gaps persist, including the poorly defined roles of oligogenic interactions: how double, triple, or multiple genetic variants synergize or antagonize each other to modulate phenotypes remains largely unclear, complicating efforts to map genotype-phenotype relationships. Additionally, the role of developmental trajectories, environmental modifiers, and epigenetic regulation in shaping clinical outcomes demands deeper investigation.

This Research Topic aims to synthesize cutting-edge research on genotype-phenotype correlations in genetic epilepsies and NDDs, fostering a comprehensive understanding of their genetic architecture. We welcome original studies, systematic reviews, and other contributions covering:

(1) novel gene-disease associations, including rare variants in understudied genes and their clinical implications;

(2) novel genetic mechanisms underlying phenotypic heterogeneity, such as allele-specific expression, copy number variations, and epistatic interactions;

(3) in silico and functional analyses of variant pathogenicity, integrating tools like CADD scores, 3D protein modeling, and CRISPR-based functional assays;

(4) new variants that validate newly identified genotype-phenotype correlations, especially those clarifying variable expressivity in familial cases;

(5) emerging targeted therapies, including gene editing strategies, antisense oligonucleotides, and precision medicine approaches tailored to specific genetic subtypes.

By bridging basic neuroscience, clinical genetics, and therapeutic development, this collection will not only advance mechanistic insights but also accelerate the translation of genetic discoveries into improved diagnostic accuracy, prognostic stratification, and personalized treatment strategies for affected individuals.