Clinical phenotype and genetic analysis of KMT2E gene variant-associated childhood absence epilepsy
10.3760/cma.j.cn113694-20240516-00348
- VernacularTitle:KMT2E基因变异相关儿童失神癫痫临床表型及遗传学分析
- Author:
Li YANG
1
;
Shiyan QIU
;
Cuiping YOU
;
Rui TAO
;
Yufen LI
;
Fengyuan CHE
Author Information
1. 徐州医科大学附属临沂市人民医院小儿神经科，临沂 276003
- Keywords:
Epilepsy;
Epilepsy, absence;
KMT2E gene;
Mutation;
Whole exome sequencing
- From:
Chinese Journal of Neurology
2024;57(10):1111-1119
- CountryChina
- Language:Chinese
-
Abstract:
Objective:To explore the clinical phenotype and genetic characteristics of children with childhood absence epilepsy caused by KMT2E gene variants. Methods:The clinical data of 1 case of KMT2E gene variant-associated childhood absence epilepsy admitted to the Department of Pediatric Neurology of Linyi People′s Hospital in January 2023 were collected and followed up, and the child and her family were genetically examined by using whole-exome sequencing and Sanger sequencing, and the pathogenicity of mutation loci was analyzed. The Online Mendelian Inheritance in Man, Human Gene Mutation Database, PubMed database, China National Knowledge Infrastructure, and Wanfang database were consulted with the search term " KMT2E" to summarize the clinical phenotype and genetics of the children with epilepsy associated with KMT2E gene variant. Results:The child is a female, presented with typical absence seizures at the age of 3 years and 8 months, with normal development, video electroencephalogram showing widespread spikes and slow waves around 3 Hz accompanied by typical absence seizures. Seizures decreased after valproic acid was applied at full dosage, and were controlled after combination with lamotrigine. Her clinical diagnosis of childhood absence epilepsy was made. The results of whole-exome sequencing showed that the child had a de novo frameshift variant c.2404dup (p.Arg802Lysfs *8) in the KMT2E gene (NM_182931.3), which had not yet been reported domestically or internationally. The c.2404dup variant was interpreted as a pathogenic variant (PVS1+PS2_Supporting+PM2_Supporting) according to the American Society of Medical Genetics and Genomics variant classification criteria and guidelines. Her parents, older brother and younger sister did not carry the variant and had a normal clinical phenotype. A total of 22 patients with epilepsy associated with KMT2E gene variants were retrieved (including this case, a total of 23 cases), including 10 females and 13 males. All of them were autosomal dominant inheritance, with 20 minor variations, including 8 frameshift variants, 7 missense variants, 2 splicing variants, 2 nonsense variants, 1 synonymous variant, and the remaining 3 cases had large fragment deletions (including 2 cases of the whole gene). Clinical manifestations mainly included epileptic seizures (5 cases of absence seizures, 7 cases of focal seizures with or without secondary tonic-clonic seizures, 9 cases of tonic-clonic seizures, 1 case of spasm seizures, 1 case of myoclonic seizures, tonic seizures, and atonic seizures, 3 cases of epileptic status, and 5 cases of refractory epilepsy, with the onset age of epilepsy ranging from neonatal to adolescence), mental retardation (21/23 cases, 4 mild, 5 moderate, and 5 severe), peculiar facial features (11/23), and autism (3/23), etc. Conclusion:KMT2E gene variant-associated epilepsy is an autosomal dominant disorder with a wide spectrum of clinical phenotypes, and the novel variant c.2404dup in the KMT2E gene identified in the present study can lead to childhood absence epilepsy, which enriches the spectrum of mutations and clinical phenotype of the KMT2E gene.
