Developmental and Epileptic Encephalopathies Diagnosed Via Long-read Genome Sequencing

This study evaluates the clinical utility of Long-read Whole Genome Sequencing (lrWGS) as a secondary diagnostic tool for Developmental and Epileptic Encephalopathies (DEEs). While current standard-of-care "short-read" sequencing (srWGS) is effective at identifying small genetic mutations, it often fails to detect complex structural changes, leaving over 50% of patients without a diagnosis.

Technically, lrWGS overcomes these limitations by analyzing DNA fragments that are thousands of bases long. This allows researchers to map "dark regions" of the genome and identify Structural Variants (SVs), such as large insertions, deletions, or repeat expansions, which are often the hidden causes of severe epilepsy.

By identifying these elusive genetic drivers, the study aims to move beyond a simple diagnosis toward precision medicine. A clear molecular result can directly influence clinical decisions, such as selecting targeted medications, avoiding contraindicated drugs, or determining eligibility for emerging gene therapies. Additionally, the project assesses the feasibility of integrating this technology into routine clinical practice by evaluating bioinformatic complexity and diagnostic turnaround times.

Inclusion criteria

Pediatric Participants:

• Age < 18 years.
• Diagnosis of Developmental and Epileptic Encephalopathy (DEE) according to 2022 ILAE criteria (severe epilepsy, encephalopathic EEG, multiple drug-resistant seizures, and neurodevelopmental disorder).
• Brain MRI without markers of perinatal anoxia.
• Negative molecular diagnosis after short-read Whole Genome Sequencing (srWGS) via the French Genomic Medicine Plan 2025 (AURAGEN).
• Available banked DNA at a participating center.

Parents/Legal Guardians:

• Age ≥ 18 years.
• Able to understand study objectives and risks.
• Signed and dated informed consent.
• Affiliated with or beneficiary of a social security scheme.

Exclusion criteria

Pediatric Participants:

• Brain MRI findings in favor of perinatal cerebral anoxia.
• Intercurrent diseases preventing the completion of protocol examinations.
• Subject currently in an exclusion period from another study.

Parents/Legal Guardians:

• Inability to receive or understand informed information (e.g., life-threatening emergency).
• Subject under judicial protection, tutelage, or curatorship.
• Language barriers where an official interpreter is unavailable.