Epilepsy is a prevalent neurological condition, having a wide range of phenotypic traits, which complicate the diagnosis process. Next-generation sequencing (NGS) techniques have improved the diagnostics for unexplained epilepsies. Our goal was to evaluate the utility and impact of genetic testing in the clinical management of pediatric epilepsies. In addition, we aimed to identify clinical factors that could predict a genetic diagnosis. This was a retrospective study of 140 pediatric patients with epilepsy with or without other neurological conditions that underwent NGS testing (multigene panel, WES = whole exome sequencing and/or WGS = whole genome sequencing). A comparison between genetically diagnosed versus non-diagnosed children was performed based on different clinical features. Univariate and multivariate logistic regression analysis was performed to identify clinical predictors of a positive genetic diagnosis. Most children underwent gene panel testing, while 30 had exome sequencing and 3 had genome sequencing. The overall diagnostic yield of genetic testing was 28.6% (40/140) for more than 28 genes. The most frequently identified genes with causative variants were SCN1A (n = 4), SCN2A (n = 3), STXBP1 (n = 3), MECP2 (n = 2), KCNQ2 (n = 2), PRRT2 (n = 2), and NEXMIF (n = 2). Significant predictors from the logistic regression model were a younger age at seizure onset (p = 0.015), the presence of intellectual disability (p = 0.021), and facial dysmorphism (p = 0.049). A genetic diagnosis led to an impact on the choice or duration of medication in 85% (34/40) of the children, as well as the recommendation for screening of comorbidities or multidisciplinary referrals in 45% (18/40) of children. Epilepsy is a highly heterogeneous disorder, both genetically and phenotypically. Less than one third of patients had a genetic diagnosis identified using panels, exomes, and/or genomes. An early onset and syndromic features (including global developmental delay) were more likely to receive a diagnosis and benefit from optimized disease management.

Congenital Cataracts, Facial Dysmorphism, and Neuropathy (CCFDN) syndrome is a rare autosomal recessive disorder predominantly found among Vlax Roma populations, caused by a deep intronic founder variant in the CTDP1 gene. This review synthesizes recent advances in understanding the molecular mechanisms of CTDP1 dysfunction, highlighting its central role in transcriptional regulation, RNA splicing, DNA repair, and genome integrity. The unique splicing defect caused by the founder disease-causing variant in the Roma population results in a multisystem phenotype with early-onset neuropathy, congenital cataracts, and characteristic facial dysmorphism. Beyond its genetic homogeneity, CCFDN displays variable clinical severity and presents diagnostic challenges due to overlapping syndromic features. We discuss the emerging therapeutic landscape, focusing on antisense oligonucleotides, small molecule modulators, gene replacement, and genome or transcriptome editing strategies, while emphasizing the challenges in targeted delivery and efficacy. Ongoing insights into CTDP1’s broader biological functions and population genetics inform new directions for diagnosis, genetic counselling, and the development of effective therapies for this severe yet underrecognized disorder.