Genotype–Phenotype Correlations and Their Implications for Personalized Genetic Counseling in 103 Patients With PRRT2 Mutations

Abstract

Objective PRRT2 mutations are associated with a wide spectrum of paroxysmal neurologic disorders. In this study, we analyze clinical and genetic data from a large pediatric cohort to define genotype–phenotype correlations and to provide a basis for individualized genetic counseling. Methods This retrospective study included 103 children with PRRT2 mutations treated at the Children′s Hospital Affiliated to Nanjing Medical University from August 2018 to August 2023. Detailed clinical data and genetic results were collected and systematically analyzed. Results Among the 103 children, self‐limited familial infantile epilepsy (SeLFIE) was the most common phenotype. A total of 26 different PRRT2 mutations were identified, 93.2% of which were predicted loss‐of‐function (LOF) mutations. These mutations were highly enriched in the N‐terminal cytoplasmic region of the protein, particularly in the proline‐rich domain. Predicted LOF mutations accounted for nearly all cases of SeLFIE and infantile convulsions with paroxysmal choreoathetosis. Clinical features, including age of onset, rates of abnormal EEG and brain MRI findings, and treatment response, showed a gradient across the three phenotypic groups, with the most pronounced abnormalities in SeLFIE and the mildest in paroxysmal kinesigenic dyskinesia. Additionally, 12 novel variants were identified. Conclusion This study confirms that PRRT2‐associated disorders are primarily driven by predicted LOF mutations and, using a large cohort, establishes a genotype‐phenotype‐treatment response continuum model based on residual PRRT2 protein activity. This model provides a critical framework for prognosis assessment and personalized genetic counseling.