Genotypic and phenotypic spectrum of PRRT2-related variations: clinical analysis and treatment response in fourteen unrelated Chinese patients

BACKGROUND: PRRT2 gene mutations are one of the most common genetic factors leading to neurodevelopmental disorders, such as autism spectrum disorder, intellectual disability, and epilepsy. This gene encodes a proline-rich transmembrane protein 2, which plays a crucial role in neuronal development and synaptic transmission. Mutations in this gene can result in a variety of clinical phenotypes. METHODS: We retrospectively analyzed 14 pediatric patients from unrelated families with epilepsy or paroxysmal motor disorders, all genetically confirmed to harbor PRRT2 mutations. Comprehensive clinical data were collected, including seizure semiology, EEG, MRI, treatment response, and developmental outcomes. Genetic analysis involved whole-genome sequencing or a customized epilepsy gene panel, with single nucleotide variants validated by Sanger sequencing. The pathogenesis of both mutations((c.189delC p.Lys64Argfs*26) and c.971G > C p.Gly324Ala)) was studied by in vitro experiments. RESULTS: The cohort comprised 6 females and 8 males with onset ages ranging from 3 to 7 months. We identified 13 patients with point mutations and one with an exon 2–4 deletion.The hotspot mutation c.649dupC p.Arg217Profs*8 was most prevalent (11/14). Eleven patients exhibited the Self-limited Infantile Epilepsy (SeLIE) phenotype, one had PKD, and two were unclassifiable. Most patients (12/14, 85.7%) achieved seizure freedom, showing favorable responses to oxcarbazepine or levetiracetam. Developmental delays were observed in 5 patients, of which only 2 carried non-c.649dupC classical variants (c.189delC p.Lys64Argfs*26 and exon 2–4 deletion). Functional studies confirmed that the c.189delC p.Lys64Argfs*26 mutation significantly reduced mRNA and protein expression, while the c.971G > C p.Gly324Ala variant did not affect splicing but was predicted pathogenic.