Risk PCDH19 variants and strategies for reproductive management of PCDH19-clustering epilepsy

Reproductive risk assessment and genetic counseling are important aspects of application of genetic testing. PCDH19 gene is associated with PCDH19 -clustering epilepsy ( PCDH19 -CE), which is estimated to be the second most relevant form of genetic epilepsy. Only heterozygous females or mosaic males with PCDH19 variants are affected, due to the specific mechanism involving cellular interference. Although hemizygous males with pathogenic variants are asymptomatic, their female offspring would be at risk of developing PCDH19 -CE. Here we studied the inheritance origin and risk of potential pathogenic PCDH19 variants in general population, aimed to establish strategies for reproductive management of PCDH19 -CE. Trios-based whole-exome sequencing was performed on patients with epilepsy without acquired etiologies through the China Epilepsy Project 1.0 platform. The inheritance origin of patients with pathogenic PCDH19 variants were analyzed. Previously reported pathogenic PCDH19 variants were systematically reviewed to analyze the correlation between risk and sub-molecular effect. The pathogenicity and risk of PCDH19 variants in general populations were evaluated. Strategies for reproductive management of PCDH19 -CE were established. PCDH19 variants were identified in 10 unrelated family cases involving 16 individuals affected. These variants were evaluated as “pathogenic” or “likely pathogenic” according to American College of Medical Genetics and Genomics guidelines. Inheritance origin analysis showed that 50% of the affected individuals were of male-related in inheritance. Analysis on previously reported PCDH19 variants showed that 98.18% of pathogenic missense variants were located in the extracellular cadherin region; whereas the remaining few (1.82%) were situated in the transmembrane/intracellular domains with hydrophobicity changes and were associated with mild phenotype, suggesting a sub-molecular effect. Data from gnomAD database showed that the frequency of pathogenic/potential pathogenic (risk) PCDH19 variants in general population is 0.785‰ (95% CI: 0.646–0.945‰). Based on the specific inheritance pattern, we proposed individualized reproductive management strategies to facilitate informed decision-making for families at risk, which included prenatal fetal sex determination and prenatal identification of PCDH19 variants, depending on the occurrence of variants in parents. The asymptomatic male carriers with PCDH19 variants imply a significance in the occurrence of PCDH19 -CE. Reproductive risk in PCDH19 -CE can be reduced through individualized strategies based on genetic testing.