Disentangling the paradox of the PCDH19 clustering epilepsy, a disorder of cellular mosaics

PCDH19 Clustering Epilepsy (CE) is an intriguing early-onset seizure, autism and neurocognitive disorder with unique inheritance. The causative gene, PCDH19, is on the X-chromosome and encodes a cell–cell adhesion protein with restricted expression during brain development. Unlike other X-linked disorders, PCDH19-CE manifests in heterozygous females. Strikingly, hemizygous males are not affected. However, males with postzygotic somatic mutation in PCDH19 are affected and clinically similar to the affected females. PCDH19-CE is a disorder of cellular mosaicism. The coexistence of two different, but otherwise ‘normal’ cells in a PCDH19-CE individual, that is the wild type and the variant PCDH19 cells, has been proposed as the driving force of the disorder. This ‘cellular interference’ hypothesis could and has now been tested using sophisticated mouse models.