Comprehensive genetic diagnosis and therapeutic perspectives in 155 children with developmental and epileptic
R van Heurck1, E B Hammar1, D Ville2
1Genetic Medicine Division, Diagnostics Department, University Hospitals of Geneva, Switzerland.
Insights
Genetic testing identified the cause in 68% of children with developmental and epileptic encephalopathy (DEE). Early diagnosis before age one significantly improves genetic variant detection rates for these rare neurological conditions.
Area of Science:
- Genetics
- Neurology
- Pediatrics
Background:
- Developmental and epileptic encephalopathy (DEE) is a severe neurological condition with early onset epilepsy and developmental delay.
- Genetic factors are increasingly recognized as key contributors to DEE etiology.
- Accurate genetic diagnosis is crucial for prognosis, treatment, and genetic counseling.
Purpose of the Study:
- To investigate the diagnostic yield of genetic testing in a cohort of children with DEE.
- To identify common and rare genetic causes of DEE.
- To assess the potential for targeted therapies, such as antisense oligonucleotides (ASOs).
Main Methods:
- Retrospective cohort study of 155 children diagnosed with DEE.
- Clinical data collected from three university hospitals.
- Genetic analysis including array-comparative genomic hybridization (array-CGH) and exome-based gene panels.
Main Results:
- A genetic diagnosis was achieved in 105 (68%) of the subjects.
- In children with symptom onset before age one, a disease-causing variant was identified in 73% of cases.
- High genetic heterogeneity was observed, involving 40 genes, with SCN1A being the most prevalent.
- Nearly half of the identified variants were theoretically amenable to personalized therapy with ASOs.
Conclusions:
- Genetic investigations are highly effective in diagnosing DEE, particularly in infants.
- Molecular diagnosis facilitates treatment adjustments and genetic counseling.
- The findings support the growing importance of genetic testing for early-onset neurological disorders and highlight potential therapeutic avenues.
Abstract:
We studied a retrospective cohort of children with developmental and epileptic encephalopathy (DEE), a group of neurological conditions characterized by early onset epilepsy and severe developmental delay. Cases were recruited from three university hospitals based on clinical criteria, after a blinded cross-validation process, and most were subject to both array-CGH and exome-based gene panel analyses. 155 subjects were included. A genetic diagnosis was identified in 105 (68 %). A majority of patients (71 %) had onset of symptoms before the age of one year. In this age group a disease-causing variant was identified in 73 % of children, the highest proportion of cases reported so far. Genetic heterogeneity was high, involving 40 different genes. The most prevalent gene was SCN1A. Eight genes were identified in multiple patients and accounted for 50 % of all diagnoses. The remaining genes represented ultra-rare disorders. In many cases, molecular diagnosis leads to treatment adaptation and allows for genetic counseling. Those results highlight the growing importance of genetic investigations especially in children with symptoms onset before the age of 1. Finally, we evaluated the disease-causing variants in an intention-to-treat approach and found that almost half would theoretically be amenable to personalized therapy using antisense oligonucleotides (ASOs).
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