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

PCDH19

PCDH19 loss of function, with no phenotypic difference by variant type; cytoplasmic domain variants suggest disrupted nuclear functions beyond cell-cell adhesion

PCDH19-clustering epilepsy is an infantile-onset neurodevelopmental disorder with seizure clusters often triggered by fever, and an unusual X-linked inheritance: heterozygous females and males with X-chromosome disomy or postzygotic mosaic variants are affected, while hemizygous males are spared. The authors aggregated 110 publications and identified 689 of 735 individuals (94%) with PCDH19 variants and the typical phenotype, carrying 373 unique variants, 195 of which were absent from ClinVar. Seizure onset before 12 months was associated with more severe intellectual disability (p < 0.001) and psychiatric morbidity (p = 0.001), with no phenotypic difference between missense, nonsense and frameshift variants or across geographical backgrounds. The 29 hemizygous males with constitutive variants did not show the typical phenotype, pointing to chance or ascertainment bias. Cytoplasmic domain variants in 78 affected individuals challenge the view that the disorder is caused primarily by cell-cell adhesion defects.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

Two practical messages for interpretation: in a hemizygous male without mosaicism, a PCDH19 variant does not explain a suggestive phenotype and should prompt the search for another cause, and the 195 variants absent from ClinVar deserve submission. The link between early onset and poorer neurodevelopmental outcome supports the authors' idea of a critical window for intervention. This is a literature aggregation, hence heterogeneous in phenotyping and exposed to publication bias.

Analysis by Dr Thibaut Benquey