Abstracts

Rationale: Mutations in the PCDH19 gene cause PCDH19-related epilepsy, a disorder characterized by early-onset epilepsy with seizure clusters, intellectual disability, developmental delay and behavioral disturbances. Although X-linked, there appears to be a unique sex-limited pattern of expression in which females manifest the phenotype while carrier males do not. While mutations had classically been described as paternally transmitted or de novo, maternally inherited mutations have been reported. We have identified patients with in which predicted pathogenic variants have been transmitted from seemingly unaffected mothers, as well as patients with de novo variants whose features are not consistent with the PCDH19 phenotype. We aimed to systematically analyze a cohort of individuals with PCDH19 variants to aid in the understanding of this disorder in terms of phenotypic spectrum, inheritance patterns and possible genotype-phenotype correlations.Methods: We reviewed medical records of individuals who have PCDH19 variants identified by CLIA approved laboratories. Individuals were identified through the PCDH19 Patient Registry and the Epilepsy Genetics Program at Boston Children’s Hospital. Our analysis included 18 of 26 identified probands with reported variants in PCDH19 (excluding those with likely benign variants) for whom clinical and genetic information was available.Results: Our cohort included 18 females with 17 unique variants, including 9 missense variants, 4 nonsense variants, 3 frameshift deletions and 1 gene deletion. Inheritance patterns include: 4 maternal, 3 paternal, 5 de novo and 6 unknown. The median age of seizure onset was 9.75 months (range 4-36 months); 14/18 (78%) of individuals had seizures that occurred in clusters; 9/18 (44%) had reported developmental delays; 4/18 (22%) had reportedly normal development with regression at seizure onset; 8/18 (44%) had reported autistic features. Notable atypical presentations include: 1 ""classic"" phenotype with a maternally inherited variant of uncertain significance, 2 maternally inherited pathogenic mutations and 2 typically developing females with pathogenic mutations with well-controlled seizures as the only presenting feature.Conclusions: Within our cohort, we have identified both typical and atypical presentations of PCDH19-related epilepsy. PCDH19 mutations have been identified in individuals whose clinical features are not consistent with what has been reported to date, suggesting either an expanded phenotypic spectrum or the possibility of alternate genetic explanations for some patients. Additionally, a maternally inherited PCDH19 variant has been identified in a patient with a “classic” phenotype. Since inheritance patterns are often utilized to assist in determining pathogenicity of novel variants, such findings complicate PCDH19 variant interpretation. Our cohort of females with PCDH19 variants suggests that there is still much to be learned about both the phenotype and transmission pattern of this unusual X-linked condition. Functional studies and investigation of other possible genetic contributors are underway to help address these gaps in knowledge.