Clinical and genetic analysis of PRRT2 gene mutations in a cohort of 21 pediatric patients: a case series.

Background: The Proline-Rich Transmembrane Protein 2 (PRRT2) gene is associated with a spectrum of autosomal dominant paroxysmal disorders, including Benign Familial Infantile Epilepsy (BFIE), Paroxysmal Kinesigenic Dyskinesia (PKD), and Hemiplegic Migraine (HM). However, the correlation between specific mutation types and clinical phenotypes, particularly for rare variants, remains to be fully elucidated. Methods: We conducted a retrospective analysis of 21 pediatric patients (12 males, 9 females) with PRRT2-related disorders diagnosed at Xiamen Children's Hospital between June 2014 and December 2025. Clinical data were collected from electronic medical records. Genetic analysis was performed using family-based whole-exome sequencing. Variants were classified according to ACMG guidelines, and novel variants were assessed using bioinformatics tools (PolyPhen-2, PROVEAN, SIFT). Results: The cohort included 14 patients with BFIE, 2 with non-BFIE epilepsy, 4 with PKD, and 1 with HM. Frameshift mutations were predominant (90.5%), with c.649dupC (p.Arg217Profs*8) being the most frequent (71.4%). A novel heterozygous missense variant, c.811C > T (p.Leu271Phe), was identified in a patient with drug-resistant focal epilepsy; in silico tools predicted it to be damaging. Functional analysis revealed that the intronic variant c.880-34G > A (p.?) causes aberrant mRNA splicing, leading to a premature termination codon (p.Ser294Leufs*29). The phenotypes demonstrated a temporal succession, with BFIE manifesting in infancy (median onset 4.3 months), PKD in childhood/adolescence (mean onset 8.5 years), and HM in adolescence (onset 13 years). While most patients responded well to sodium channel blockers, one patient with a novel missense variant exhibited pharmacoresistance. Conclusions: This study expands the known mutational spectrum of PRRT2 by identifying a novel missense variant (c.811C > T) associated with refractory epilepsy and providing functional evidence for the pathogenic intronic variant c.880-34G > A. The findings highlight the time-dependent evolution of PRRT2-related phenotypes and underscore that PRRT2 mutations are not invariably associated with a benign prognosis, emphasizing the need for comprehensive genetic evaluation and personalized long-term management.