[Analysis of KCNA2 gene variant in a Chinese pedigree affected with developmental and epileptic encephalopathy]

To carry out whole-genome sequencing (WGS) for a woman with epilepsy who was previously tested negative by panel sequencing.

A female patient and her family members (8 individuals from 3 generations) who had presented at the Affiliated Hospital of Reproductive Medicine of Shandong University in August 2024 were selected as study subjects. WGS was carried out for the pedigree. Candidate variant was verified by Sanger sequencing and classified based on the guidelines from American College of Medical Genetics and Genomics (ACMG). This study was approved by the Medical Ethics Committee of the Affiliated Hospital of Reproductive Medicine of Shandong University (Ethics No.: 2021-038).

The proband and her first daughter both had epilepsies. Targeted capture and sequencing of 757 epilepsy-associated genes detected no known pathogenic mutation. WGS identified a novel heterozygous c.921G>T (p.Leu307Phe) missense variant in the KCNA2 gene in the proband. The same variant was also carried by her first daughter, whereas her younger brother, younger sister, and second daughter were of the wild-type. Based on the ACMG guidelines, the c.921G>T variant was classified as likely pathogenic (PS2_moderate+PM2_Supporting+PP3_moderate+PP2). The variant was unreported previously. For her subsequent pregnancy, the offspring will have a 50% risk for inheriting the pathogenic variant, indicating a high risk for the disease.

This study has diagnosed a case of developmental and epileptic encephalopathy 32 by WGS. Above finding has enriched the mutational spectrum of the KCNA2 gene and provided guidance for preimplantation genetic testing and counseling for the pedigree.