A mutation update for the PCDH19 gene causing early-onset epilepsy in females with an unusual expression pattern

Abstract

The PCDH19 gene consists of six exons encoding a 1,148 amino acid transmembrane protein, Protocadherin 19, which is involved in brain development. Heterozygous pathogenic variants in this gene are inherited in an unusual X‐linked dominant pattern in which heterozygous females are affected, while hemizygous males are typically unaffected, although they pass on the pathogenic variant to each affected daughter. PCDH19‐related disorder is known to cause early‐onset epilepsy in females characterized by seizure clusters exacerbated by fever and in most cases, onset is within the first year of life. This condition was initially described in 1971 and in 2008 PCDH19 was identified as the underlying genetic etiology. This condition is the result of pathogenic loss‐of‐function variants that may be de novo or inherited from an affected mother or unaffected father and cellular interference has been hypothesized to be the culprit. Heterozygous females are symptomatic because of the presence of both wild‐type and mutant cells that interfere with one another due to the production of different surface proteins, whereas nonmosaic hemizygous males produce a homogenous population of cells. Here, we review novel pathogenic variants in the PCDH19 gene since 2012 to date, and summarize any genotype‐phenotype correlations.

Febrile Seizure Plus and PCDH19-Related Epilepsy Syndromes

“…PCDH19 gene located on the X-chromosome was identified as an underlying genetic etiology for such patients in 2008. 38 This is the second most clinically relevant gene after SCN1A. The gene consists of six exons encoding 1,148 proteins.…”

“…Cellular interference has been hypothesized to be the underlying mechanism. 38 The clinical syndrome affects heterozygous females and mosaic males. [39][40][41] Interestingly, complete deletion in heterozygous females or homozygous males does not result in epilepsy.…”

A Rat Model of a Focal Mosaic Expression of PCDH19 Replicates Human Brain Developmental Abnormalities and Behaviors

“…In particular, together with areas of normal architecture, focal dysplasia, heterotopia and abnormal morphology of individual neurons in the cortex as well as hippocampal sclerosis have been reported (Ryan et al 1997;Lotte et al 2016;Trivisano and Specchio 2018;Kurian et al 2018;Pederick et al 2018). Due to random X-chromosome inactivation EIEE9-affected females are composed of a mosaic population of healthy and Pcdh19-mutant cells, whereas hemizygous male carriers are asymptomatic or show much reduced psychiatric and behavioral deficits ; van Harssel et al 2013;Terracciano et al 2012;Niazi et al 2019). To explain gender differences, a cellular interference model has been proposed.…”

“…To explain gender differences, a cellular interference model has been proposed. According to this model, random X-inactivation in females leads to tissue mosaicism in which cells expressing the wild type PCDH19 protein and cells expressing a mutant PCDH19 protein co-exist and thus scramble the cell-cell communication and integration in the neuronal circuits Dibbens et al 2008;Ryan et al 1997;Niazi et al 2019). Thus, it is the cellular interference between two populations of cells (i.e., WT and PCDH19 mutated cells) the possible cause of brain dysfunctional development, leading to symptoms in EIEE9 people (Lindhout 2008).…”

“…Thus, it is the cellular interference between two populations of cells (i.e., WT and PCDH19 mutated cells) the possible cause of brain dysfunctional development, leading to symptoms in EIEE9 people (Lindhout 2008). Accordingly, the rare cases of fully affected males that have been described, arise from somatic mutations that display mosaicism Scheffer et al 2008;Terracciano et al 2016;Niazi et al 2019).…”