A standardized patient-centered characterization of the phenotypic spectrum of PCDH19 girls clustering epilepsy

Protocadherin-19 (PCDH19) pathogenic variants cause an early-onset seizure disorder called girls clustering epilepsy (GCE). GCE is an X-chromosome disorder that affects heterozygous females and mosaic males, however hemizygous (“transmitting”) males are spared. We aimed to define the neuropsychiatric profile associated with PCDH19 pathogenic variants and determine if a clinical profile exists for transmitting males. We also examined genotype- and phenotype–phenotype associations. We developed an online PCDH19 survey comprising the following standardized assessments: The Behavior Rating Inventory of Executive Function; the Social Responsiveness Scale, 2nd edition; the Strengths and Difficulties Questionnaire; and the Dimensional Obsessive-Compulsive Scale. Genetic, seizure, and developmental information were also collected. The survey was completed by patients or by caregivers on behalf of patients. Of the 112 individuals represented (15 males), there were 70 unique variants. Thirty-five variants were novel and included a newly identified recurrent variant Ile781Asnfs*3. There were no significant differences in phenotypic outcomes between published and unpublished cases. Seizures occurred in clusters in 94% of individuals, with seizures resolving in 28% at an average age of 17.5 years. Developmental delay prior to seizure onset occurred in 18% of our cohort. Executive dysfunction and autism spectrum disorder (ASD) occurred in approximately 60% of individuals. The ASD profile included features of attention-deficit hyperactivity disorder. In addition, 21% of individuals met criteria for obsessive-compulsive disorder that appeared to be distinct from ASD. There were no phenotypic differences between heterozygous females and mosaic males. We describe a mosaic male and two hemizygous males with atypical clinical profiles. Earlier seizure onset age and increased number of seizures within a cluster were associated with more severe ASD symptoms (p = 0.001), with seizure onset also predictive of executive dysfunction (p = 4.69 × 10⁻⁴) and prosocial behavior (p = 0.040). No clinical profile was observed for transmitting males. This is the first patient-derived standardized assessment of the neuropsychiatric profile of GCE. These phenotypic insights will inform diagnosis, management, and prognostic and genetic counseling.