Clinical and genetic analysis of children with developmental and epileptic encephalopathy 8 caused by ARHGEF9 gene variants
10.3760/cma.j.cn113694-20220705-00524
- VernacularTitle:ARHGEF9基因变异致发育性和癫痫性脑病8型患儿临床及遗传学分析
- Author:
Zhi LEI
1
;
Xuan ZHENG
;
Lei LIU
;
Zhipeng JIN
;
Wenhui NING
;
Daoqi MEI
;
Pengbo GUO
;
Yanhong WANG
;
Yaodong ZHANG
;
Shiyue MEI
Author Information
1. 郑州大学附属儿童医院（河南省儿童医院郑州儿童医院）儿科医学研究所 河南省儿童遗传代谢性疾病重点实验室，郑州 450018
- Keywords:
Epilepsy;
ARHGEF9 gene;
Developmental and epileptic encephalopathy 8
- From:
Chinese Journal of Neurology
2023;56(3):305-312
- CountryChina
- Language:Chinese
-
Abstract:
Objective:To analyze the clinical characteristics and genetic variation of 2 children with developmental and epileptic encephalopathy 8 (DEE8).Methods:Whole-exome sequencing (WES) was performed to determine the potential variants in the probands. Candidate variants identified by WES were validated by Sanger sequencing and quantitative real-time polymerase chain reaction. X chromosome inactivation (XCI) detection was performed in the proband 1′s mother and proband 2 to detect the allelic expression difference of ARHGEF9. Results:Both of the cases showed global developmental delay. Proband 1 presented with delayed motor and speech development, intellectual disability, and seizures. Electroencephalography of proband 1 showed slow background activity, with spikes, spike and waves in bilateral frontal and midline regions during sleep. While proband 2 showed delay in acquisition of language, motor skills, and cognition, but no seizures. It was identified that proband 1 carried a novel maternally derived heterozygous splicing variant (c.925-2A>T) in ARHGEF9 by WES, which was verified in Sanger sequencing. The XCI in proband 1′s mother was observed, and the expression ratio of mutant ARHGEF9 and wild-type was 0∶100%. A novel exon 3-10 heterozygous deletion of ARHGEF9 was identified in proband 2, and this variant was not found in his unaffected parents. Conclusions:DEE8 disorders are relatively rare. Most of the patients have varying degrees of neurodevelopmental phenotype, but epilepsy is not a specific clinical manifestation. ARHGEF9 gene deletion and splicing variation may be the genetic cause of the 2 probands, and above findings have enriched the spectrum of variation and phenotype of DEE8.
