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Unexplained Early Infantile Epileptic Encephalopathy in Han Chinese Children: Next-Generation Sequencing and
Ahmed Arafat1, Peng Jing1, Yuping Ma1
1Xiang Ya First Hospital of Central South University, China, 87 Xiang ya road, Changsha, Hunan, 410008, P.R. China.
Insights
Genetic testing identified new causes of Early Infantile Epileptic Encephalopathy (EIEE) in Chinese children. This research expands the known genetic mutations linked to this severe neurological disorder.
Area of Science:
- Genetics
- Neurology
- Pediatrics
Background:
- Early Infantile Epileptic Encephalopathy (EIEE) is a severe neonatal-onset epilepsy characterized by frequent seizures and developmental regression.
- Genetic factors are implicated in EIEE, but the spectrum of causative mutations in diverse populations remains incompletely understood.
Purpose of the Study:
- To investigate the genetic underpinnings of unexplained EIEE in a cohort of Han Chinese infants.
- To identify novel pathogenic variants and expand the known mutation spectrum for EIEE.
Main Methods:
- Targeted next-generation sequencing of 308 epilepsy-associated genes was performed on 68 Han Chinese patients with unexplained EIEE.
- Exclusion criteria included prior genetic diagnoses, brain malformations, or inborn errors of metabolism.
- Sanger sequencing and parental testing were used to confirm de novo variants.
Main Results:
- Pathogenic variants in CDKL5, STXBP1, SCN1A, KCNQ2, and SCN8A were identified in 15% of patients (10/68) as de novo or assumed de novo.
- Likely pathogenic variants, including novel ones, were found in SCN1A and ARX in 4% of patients (3/68).
- Four novel variants were discovered, contributing to the EIEE genetic landscape.
Conclusions:
- Genetic variants in key epilepsy genes are a significant cause of unexplained EIEE in Han Chinese infants.
- This study broadens the mutation spectrum for EIEE and highlights the importance of genetic diagnostics in affected children.
- The findings provide valuable data for genetic counseling and potential therapeutic strategies for EIEE patients.
Abstract:
Early Infantile Epileptic Encephalopathy (EIEE) presents shortly after birth with frequent, severe seizures and progressive disturbance of cerebral function. This study was to investigate a cohort of Chinese children with unexplained EIEE, infants with previous genetic diagnoses, causative brain malformations, or inborn errors of metabolism were excluded. We used targeted next-generation sequencing to identify potential pathogenic variants of 308 genes in 68 Han Chinese patients with unexplained EIEE. A filter process was performed to prioritize rare variants of potential functional significance. In all cases where parental testing was accessible, Sanger sequencing confirmed the variants and determined the parental origin. In 15% of patients (n = 10/68), we identified nine de novo pathogenic variants, and one assumed de novo pathogenic variant in the following genes: CDKL5 (n = 2), STXBP1 (n = 2), SCN1A (n = 3), KCNQ2 (n = 2), SCN8A (n = 1), four of the variants are novel variants. In 4% patients (n = 3/68), we identified three likely pathogenic variants; two assumed de novo and one X-linked in the following genes: SCN1A (n = 2) and ARX (n = 1), two of these variants are novel. Variants were assumed de novo when parental testing was not available. Our findings were first reported in Han Chinese patients with unexplained EIEE, enriching the EIEE mutation spectrum bank.
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