Missense and truncating variants in protocadherin 19 (PCDH19) cause PCDH19-related epilepsy. In this study, we aimed to investigate variations in distributional characteristics and the clinical implications of variant type in PCDH19-related epilepsy. We comprehensively collected PCDH19 missense and truncating variants from the literature and by sequencing six exons and intron–exon boundaries of PCDH19 in our cohort. We investigated the distribution of each type of variant using the cumulative distribution function and tested for associations between variant types and phenotypes. The distribution of missense variants in patients was clearly different from that of healthy individuals and was uniform throughout the extracellular cadherin (EC) domain, which consisted of six highly conserved domains. Truncating variants showed two types of distributions: (1) located from EC domain 1 to EC domain 4, and (2) located from EC domain 5 to the cytoplasmic domain. Furthermore, we also found that later onset seizures and milder intellectual disability occurred in patients with truncating variants located from EC domain 5 to the cytoplasmic domain compared with those of patients with other variants. Our findings provide the first evidence of two types of truncating variants in the PCDH19 gene with regard to distribution and the resulting clinical phenotype.

原钙粘蛋白 19 ( PCDH19 ) 中的错义和截短变体导致PCDH19相关癫痫。在这项研究中，我们旨在调查PCDH19相关癫痫中分布特征的变化和变异类型的临床意义。我们从文献中并通过对PCDH19 的六个外显子和内含子-外显子边界进行测序，全面收集了PCDH19错义和截短变体在我们的队列中。我们使用累积分布函数调查了每种变异类型的分布，并测试了变异类型和表型之间的关联。患者中错义变异的分布与健康个体明显不同，并且在整个细胞外钙粘蛋白 (EC) 域中是一致的，该域由六个高度保守的域组成。截断变体显示出两种类型的分布：(1) 从 EC 结构域 1 到 EC 结构域 4，和 (2) 从 EC 结构域 5 到细胞质结构域。此外，我们还发现，与其他变异的患者相比，位于从 EC 结构域 5 到细胞质结构域的截短变异的患者发生的癫痫发作较晚，智力障碍较轻。PCDH19基因的分布和由此产生的临床表型。