Clinical phenotype and genetic analysis of four cases of epileptic encephalopathy caused by PCDH19 variant
10.3760/cma.j.cn511374-20241009-00523
- VernacularTitle:PCDH19基因变异相关癫痫性脑病患者4例的临床表型及遗传学分析
- Author:
Lu WEI
1
;
Jiwen WANG
;
Ruen YAO
;
Jian WANG
;
Tingting YU
Author Information
1. 上海交通大学医学院附属上海儿童医学中心遗传分子诊断科，上海 200127
- Publication Type:Journal Article
- Keywords:
PCDH19 gene;
Gene mutation;
Epileptic encephalopathy;
Mosaicism
- From:
Chinese Journal of Medical Genetics
2025;42(5):556-562
- CountryChina
- Language:Chinese
-
Abstract:
Objective:To investigate the clinical phenotype and genotype features of children with Epileptic encephalopathy caused by PCDH19 variant. Methods:Four children with epilepsy caused by PCDH19 gene variant who were treated at Shanghai Children′s Medical Center from August 2015 to May 2024 were selected as study subjects. A retrospective study method was used to collect the clinical data of the patients. Peripheral venous blood samples (2 mL each) were collected from the patients and their parents. Genomic DNA was extracted, and whole exome sequencing (WES) was performed, followed by family verification of candidate variants by Sanger sequencing. Pathogenicity of the candidate variants was classified according to the " Genetic Variation Classification Standards and Guidelines" established by the American College of Medical Genetics and Genomics (ACMG). This study was approved by the Medical Ethics Committee of Shanghai Children′s Medical Center (Approval No. SCMCIRB-K2020060-1). Results:The patients comprised of 3 females and 1 male, all presenting symptoms before the age of 3. Patients 1-3 exhibited generalized tonic-clonic seizures, while patient 4 manifested focal seizures accompanied by impaired consciousness. In addition to epilepsy, patient 2 showed language delay and patient 3 had frequent panic attacks. WES results identified four pathogenic PCDH19 variants in these patients, including 2 previously unreported frameshifting mutations, 1 hotspot missense mutation, and 1 mosaic missense mutation with a 32.4%mutation rate. The pathogenic variant in patient 2 was inherited from her father, while the remaining 3 patients had de novo pathogenic variant. Conclusion:Children with PCDH19 gene mutations may exhibit early-onset refractory epilepsy, cognitive impairment, and developmental delay. Females are predominantly affected by the PCDH19 variant, although males with mosaic variant can also be affected. The genetic and clinical heterogeneity observed among patients 1-4 indicated the diverse nature of epilepsy related to the PCDH19 gene variant. PCDH19 gene variant may be the genetic cause of epilepsy in these affected children, which also enriched the mutational spectrum of the PCDH19 gene.
