Genotype and phenotype analyses of 689 individuals with PCDH19-clustering epilepsy

PCDH19-clustering epilepsy (PCDH19-CE) is an infantile-onset neurodevelopmental disorder characterised by clusters of seizures, typically triggered by fever. PCDH19-CE follows an unusual X-linked inheritance pattern whereby heterozygous females, and males with X-chromosome disomy or pathogenic postzygotic mosaic PCDH19 variants, are affected, while hemizygous males are spared. We aggregate published PCDH19 variants and their corresponding PCDH19-CE phenotypes to analyse phenotype-genotype correlations. Data extracted from 110 publications identified 689/735 (94%) individuals with PCDH19 variants and the typical PCDH19-CE phenotype. Three hundred seventy-three unique PCDH19 variants were identified; 195 were not recorded in ClinVar. Seizure onset prior to 12 months of age was associated with more severe intellectual disability (p < 0.001) and the presence of psychiatric morbidity (p = 0.001). There were no phenotypic differences between missense, nonsense, and frameshift variants or between individuals of different geographical backgrounds, which was assessed as a proxy for ancestry. Twenty-nine hemizygous males with constitutive PCDH19 variants did not exhibit the typical PCDH19-CE phenotype, suggesting that the identification of variants in these individuals likely results from chance or ascertainment bias. The correlation between earlier seizure onset and poorer neurodevelopmental outcomes emphasises a critical window for therapeutic intervention. The lack of phenotypic difference between variant types demonstrates that loss of PCDH19 function underpins PCDH19-CE. Moreover, the identification of PCDH19 cytoplasmic domain variants in 78 affected individuals challenges the traditional view that PCDH19-CE is caused primarily by defects in cell-cell adhesion, as variants in this domain are expected to disrupt the nuclear function(s) of PCDH19.