Whole Exome Sequencing as a First-Line Molecular Genetic Test in Developmental and Epileptic Encephalopathies

• Published in: International journal of molecular sciences 2024-01, Vol.25 (2), p.1146
• Main Authors: Vetri, Luigi, Calì, Francesco, Saccone, Salvatore, Vinci, Mirella, Chiavetta, Natalia Valeria, Carotenuto, Marco, Roccella, Michele, Costanza, Carola, Elia, Maurizio
• Format: Article
• Language: English
• Subjects: Convulsions & seizures; Cytogenetics; DEE; developmental and epileptic encephalopathy; Drug resistance; Epilepsy; Epilepsy, Generalized; Exome Sequencing; Genes; Genetic screening; Genetic testing; Humans; Intellectual disabilities; Molecular Biology; Mosaicism; Mutation; Neurodevelopmental Disorders; next-generation sequencing; NGS; Patients; Potassium; Scientific equipment and supplies industry; Seizures (Medicine); Shaw Potassium Channels; WES; whole-exome sequencing
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms25021146

Developmental and epileptic encephalopathies (DEE) are severe neurodevelopmental disorders characterized by recurrent, usually early-onset, epileptic seizures accompanied by developmental impairment often related to both underlying genetic etiology and abnormal epileptiform activity. Today, next-generation sequencing technologies (NGS) allow us to sequence large portions of DNA quickly and with low costs. The aim of this study is to evaluate the use of whole-exome sequencing (WES) as a first-line molecular genetic test in a sample of subjects with DEEs characterized by early-onset drug-resistant epilepsies, associated with global developmental delay and/or intellectual disability (ID). We performed 82 WESs, identifying 35 pathogenic variants with a detection rate of 43%. The identified variants were highlighted on 29 different genes including, 3 new candidate genes ( , , ) for DEEs never identified before. In total, 23 out of 35 (66%) de novo variants were identified. The most frequently identified type of inheritance was autosomal dominant de novo (60%) followed by autosomal recessive in homozygosity (17%) and heterozygosity (11%), autosomal dominant inherited from parental mosaicism (6%) and X-linked dominant de novo (6%). The most frequent mutations identified were missense (75%) followed by frameshift deletions (16%), frameshift duplications (5%), and splicing mutations (3%). Considering the results obtained in the present study we support the use of WES as a form of first-line molecular genetic testing in DEEs.