Abstracts

Rationale: Recent advances in next-generation gene sequencing have led to an increase in the discovery of monogenic causes of epilepsy, which in turn has raised the promise for development of targeted therapies. At the forefront is PCDH19 female-limited epilepsy, associated with early-onset epilepsy (often with cluster seizures), intellectual disability, developmental delay, autism spectrum disorder and behavioral dysregulation in females. The clinical spectrum is wide, and currently no genotype-phenotype correlation exists. The development of rational treatments for monogenic epilepsies requires robust genotype and phenotype characterization. Here, we present comprehensive phenotyping of a PCDH19 female-limited epilepsy cohort such that future clinical trials will target the appropriate features. Methods: Participants were selected from the PCDH19 Registry, maintained at Boston Children’s Hospital and the University of California, San Francisco. The Registry includes genotypic and phenotypic data for patients and their genotype-positive family members. We performed a retrospective analysis of probands’ medical records. Additionally, we administered a medical and family history questionnaire to probands and family members. Individuals were excluded from analysis if clinical and/or genetic information was unavailable at the time of review or if an alternative genetic diagnosis was likely. Results: Our analysis included 35 of 48 enrolled probands, 5 genotype-positive mothers and 3 genotype-positive fathers. All probands had epilepsy with a mean age of onset of 11.6 months (range 4-48 months). Semiologies included 22/37 (59%) focal, 3/37 (8%) generalized, and 8 (22%) both focal and generalized; data were inconclusive for the remaining 4. Thirty-four (92%) had clustered seizures and 25/37 (66%) were refractory to medication.  Three (60%) of the genotype-positive mothers had a history of epilepsy in childhood. Eight probands (21.6%) and all 5 genotype-positive mothers had normal development. Twelve probands were diagnosed with autism spectrum disorder, and an additional 9 probands were reported to have autistic features. Twenty-eight (76%) probands were reported to have behavioral dysregulation, most notably aggression and impulsivity. Nineteen (51%) were reported to have abnormal sleeping patterns. Conclusions: We have identified a wide phenotypic spectrum among participants in the PCDH19 Registry in which individuals had none, some, or all of the features associated with pathogenic PCDH19 variants. The presence of unaffected and mildly-affected mothers of more severely-affected daughters suggests a complicated pathophysiology beyond simple genotype-phenotype correlation. Interestingly, a majority of families reported the neurobehavioral sequelae as having a greater impact on quality of life than seizures. Systematic characterization of these features would be beneficial in identifying appropriate interventions. Both continued clinical phenotyping and the development of functional model systems are imperative toward understanding PCDH19 female-limited epilepsy and for the subsequent development of targeted therapies. Funding: Not Applicable.