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

ABSTRACT: 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 (KCNC2, STXBP6, DHRS9) 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.

SUBMITTER: Vetri L

PROVIDER: S-EPMC10816140 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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

Vetri Luigi L Calì Francesco F Saccone Salvatore S Vinci Mirella M Chiavetta Natalia Valeria NV Carotenuto Marco M Roccella Michele M Costanza Carola C Elia Maurizio M

International journal of molecular sciences 20240117 2

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-lin ...[more]

PMID: 38256219

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Project description:Developmental and epileptic encephalopathies constitute a group of severe epilepsies, with seizure onset typically occurring in infancy or childhood, and diverse clinical manifestations, including neurodevelopmental deficits and multimorbidities. Many have genetic aetiologies, identified in up to 50% of individuals. Whilst classically considered paediatric disorders, most are compatible with survival into adulthood, but their adult phenotypes remain inadequately understood. This cross-sectional study presents detailed phenotypes of 129 adults (age range 17-71 years), with genetic developmental and epileptic encephalopathies involving causal variants in 42 genes. We describe diverse disease aspects, and we sought genetic insights from the age-related trends of expression of the genes involved. Most developmental and epileptic encephalopathies (69.7%) are epileptic encephalopathies in adulthood, with the presence of epileptic encephalopathy correlating with worse cognitive phenotypes (P = 0.0007). However, phenotypic variability was observed, ranging from those with epileptic encephalopathy to seizure-free individuals with normal EEG or intermediate clinical and EEG phenotypes. This variability was found across individual genes and age-related gene expression trends, suggesting that other influential factors are likely at play. Mobility, feeding and communication impairments were common, with significant dependence on others for activities of daily living. Neurological and psychiatric comorbidities were most prevalent, along with additional systemic comorbidities observed, particularly musculoskeletal, cardiac and gastrointestinal conditions, highlighting the need for comprehensive and multisystemic monitoring. Despite an average diagnostic delay of 25.2 years, aetiology-based therapeutic interventions were feasible for 54.8% of the cohort, underscoring the critical need for genome-wide genetic testing for adults with these phenotypes. Optimizing seizure control remains necessary, but it may not be sufficient to ensure good outcomes, which may differ significantly from childhood metrics, like cognitive function and independence in daily living. Therapies addressing additional aspects beyond seizures are necessary for improving overall outcomes. Understanding the intricate relationship between molecular pathways and the age-related trends of gene expression is crucial for development of appropriate gene-specific therapies and timely intervention. Whilst prospective data are also needed to define these complexities, such studies of necessity take years to acquire: insights from adults can inform care strategies for both paediatric and adult populations now.

Project description:Background: Epileptic encephalopathies (EEs) are a pediatric entity with highly phenotypic and genetic heterogeneity. Both single nucleotide variants (SNVs)/Indels and copy number variations (CNVs) could be the causes. Whole exome sequencing (WES) is widely applied to detect SNVs/Indels, but the bioinformatics approach for detecting CNVs is still limited and weak. In the current study, the possibility of profiling both disease-causing SNVs/Indels and CNVs in a single test based on WES in EEs was evaluated. Methods: The infants diagnosed with EEs were enrolled from a single pediatric epilepsy center between January 2018 and February 2020. Demographic and clinical data were collected. In WES data, the pathogenic SNVs were identified through an in-house pipeline, and pathogenic CNVs were identified by CNVkit. The diagnostic rate was evaluated, and the molecular findings were characterized. Results: A total of 73 infants were included; 36 (49.32%) of them were males. The median age was 7 months. Thirty-two (43.84%) infants had been diagnosed with epilepsy syndrome. The most common type of syndrome was West syndrome (22/73, 30.1%), followed by Dravet syndrome (20/77, 27.4%). Fifty-four (73.97%) had intellectual development delay. The genetic cause of EEs, pathogenic or likely pathogenic variants, were successfully discovered in 46.6% (34/73) of the infants, and 29 (39.7%) infants carried SNVs/Indels, while 5 (6.8%) carried CNVs. The majority of the disease-causing variants were inherited in de novo pattern (25, 71.4%). In addition to showing that the variants in the ion channel encoding genes accounted for the main etiology, we discovered and confirmed two new disease-causing genes, CACNA1E and WDR26. Five discovered CNVs were deletions of 2q24.3, 1p36, 15q11-q13, 16p11.2, and 17p13.3, and all were confirmed by array comparative genomic hybridization. Conclusion: The application of both SNVs/Indels and CNVs detection in a single test based on WES yielded a high diagnosis rate in EEs. WES may serve as a first-tier test with cost-effective benefit in EEs.

Dataset Information

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

Publications

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

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