Wei Lu, Wang Jiwen, Yao Ruen, Wang Jian, Yu Tingting
Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children's Medical Center Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200127, China.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2025 May 10;42(5):556-562. doi: 10.3760/cma.j.cn511374-20241009-00523.
To investigate the clinical phenotype and genotype features of children with Epileptic encephalopathy caused by PCDH19 mutations.
Four children with epilepsy caused by PCDH19 gene mutations 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).
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 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 mutation in patient 2 was inherited from her father, while the remaining 3 patients had de novo pathogenic mutations.
Children with PCDH19 gene mutations may exhibit early-onset refractory epilepsy, cognitive impairment, and developmental delay. Females are predominantly affected by the PCDH19 mutations, although males with mosaic mutations 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 mutations. PCDH19 gene mutations may be the genetic cause of epilepsy in these affected children, which also enriched the mutational spectrum of the PCDH19 gene.
探讨由原钙黏蛋白19（PCDH19）基因突变引起的癫痫性脑病患儿的临床表型和基因型特征。
选取2015年8月至2024年5月在上海儿童医学中心接受治疗的4例由PCDH19基因突变引起癫痫的患儿作为研究对象。采用回顾性研究方法收集患者的临床资料。从患者及其父母处采集外周静脉血样本（各2 mL）。提取基因组DNA，进行全外显子测序（WES），随后通过Sanger测序对候选变异进行家系验证。根据美国医学遗传学与基因组学学会（ACMG）制定的“遗传变异分类标准和指南”对候选变异的致病性进行分类。本研究经上海儿童医学中心医学伦理委员会批准（批准号：SCMCIRB-K2020060-1）。
患者包括3名女性和1名男性，均在3岁前出现症状。患者1至3表现为全身强直阵挛发作，而患者4表现为局灶性发作伴意识障碍。除癫痫外，患者2表现出语言发育迟缓，患者3频繁惊恐发作。WES结果在这些患者中鉴定出4个致病性PCDH19变异，包括2个先前未报道的移码突变、1个热点错义突变和1个突变率为32.4%的嵌合错义突变。患者2的致病性突变遗传自其父亲，其余3例患者为新发致病性突变。
PCDH19基因突变的儿童可能表现为早发性难治性癫痫、认知障碍和发育迟缓。虽然具有嵌合突变的男性也可能受影响，但女性受PCDH19突变的影响更为显著。在患者1至4中观察到的遗传和临床异质性表明与PCDH19基因突变相关的癫痫具有多样性。PCDH19基因突变可能是这些患病儿童癫痫的遗传病因，这也丰富了PCDH19基因的突变谱。
