Finding Seizure-Associated Genes in a Large Neurodevelopmental Disorders Cohort Undergoing Whole-Exome Sequencing
Abstract number :
1.346
Submission category :
12. Genetics / 12A. Human Studies
Year :
2021
Submission ID :
1826436
Source :
www.aesnet.org
Presentation date :
12/9/2021 12:00:00 PM
Published date :
Nov 22, 2021, 06:54 AM
Authors :
Young Jun Ko, MD - Seoul National University Bundang Hospital; Soo Yeon Kim – Seoul National University Children's Hospital; Anna Cho – Seoul National University Bundang Hospital; Hunmin Kim – Seoul National University Bundang Hospital; Hee Hwang – Seoul National University Bundang Hospital; Jong-Hee Chae – Seoul National University Children's Hospital; Ji-Eun Choi – Seoul National University Boramae Hospital; Ki Joong Kim – Seoul National University Children's Hospital; Byung Chan Lim – Seoul National University Children's Hospital
Rationale: Seizure has become one of the clinical features in pediatric neurodevelopmental disorders (NDDs) including developmental or epilpetic encephalopathy, subclassified by their genetic background. We aimed to identify the molecular basis and describe detailed phenotypes in children with seizures from pediatric NDDs cohort.
Methods: We reviewed medical records of pediatric patients presented with unprovoked seizures from NDDs cohort who performed whole exome sequencing for diagnosis.
Results: Whole exome sequencing was performed in total 906 patients. Causative sequence variants were identified in 399 patients (399/906, 44.0%). Among them, 154 patients (154/399, 38.6%) presented with seizures and pathogenic variants were identified in 122 genes. The age at seizure onset of the 154 patients was median 1.1 years old (range, 0-20 years old) and various epilepsy syndromes like West syndrome or Dravet syndrome were identified in 44 patients. The associated neurologic symptoms included development delay (146/154, 94.8%), intellectual disability (145/154, 94.2%), brain anomalies (67/154, 43.5%), hypotonia (67/154, 43.5%), microcephaly (32/154, 20.8%), spasticitiy (27/154, 17.5%), facial dysmorphism (25/154, 16.2%), ataxia (23/154, 14.9%), autism (18/154, 11.7%), dyskinesia (15/154, 9.7%), and macrocephaly (15/154, 9.7%). According to updated literatures, 26 genes were annotated to developmental/epileptic encephalopathy and 83 genes to NDDs which might present seizures. However, 13 genes which had no evidence of seizure-association were categorized by main phenotype including developmental delay with/without facial dysmorphism (OGT, RAB3GAP1, SMC3, HDAC8, SETD5, and WDFY3), spinocerebllar ataxia (ITPR1 and WDR81), mitochondrial dysfunction (ACADVL and PTPN1), and early onset epilepsy (KCND1).
Conclusions: This study adds to the clinical and genetic data in pediatric patients with NDDs and seizures. Genetic etiologies of seizures in children with NDDs were not limited in known seizure-associated variants. These findings suggest under-recognized genes related with seizures. For declaration of pathogenicity of genetic variants and discovering new seizure-associated genes, genome-wide approach will be more appropriate than targeted-approach.
Funding: Please list any funding that was received in support of this abstract.: There was no funding associated with this study.
Genetics