A Retrospective Study of the High Diagnostic Yield and Clinical Utility of Next-generation Sequencing in Children with Epilepsy and Neurodevelopmental Delays
Abstract number :
3.115
Submission category :
12. Genetics / 12A. Human Studies
Year :
2024
Submission ID :
3
Source :
www.aesnet.org
Presentation date :
12/9/2024 12:00:00 AM
Published date :
Authors :
Daniel Charouf, MD – American University of Beirut Medical Center
Presenting Author: Derryl Miller, MD – Indiana University School of Medicine and IU Health Physicians
Laith Haddad, MD – American University of Beirut Medical Center
Fletcher White, PhD – Indiana University School of Medicine
Rose-Mary Boustany, MD – American University of Beirut Medical Center
Makram Obeid, MD – Indiana University School of Medicine, Indianapolis, Indiana
Rationale: Despite electroencephalography and brain imaging, many patients with epilepsy have unexplained etiologies. Advances in genetics have identified hundreds of epilepsy-related genes which may be treatable with etiology-specific interventions. Genetic testing can reveal inherited metabolic epilepsies treatable with specific supplements, vitamins, dietary restrictions, or the ketogenic diet. The diagnostic yield of next-generation sequencing (NGS) in unexplained epilepsy is highly variable (10%-50%). We sought to determine the diagnostic yield and clinical utility of NGS in children with unexplained epilepsy that is accompanied by neurodevelopmental delays and/or is medically intractable.
Methods: A 6-year retrospective review at the AUB Medical Center identified children who received whole exome sequencing (WES) or whole genome sequencing (WGS). Data on patient demographics, neurodevelopment, seizures, and treatments were analyzed.
Results: Forty-nine children had NGS with an overall diagnostic rate of 67.3% including 28/40 for WES and 5/9 for WGS. There were 26 boys and 23 girls with median ages of 1 year and 6 months and range of 0-17 years. Age at seizure onset did not correlate with diagnostic yield. Neurodevelopmental delays were found in 46 children with medically intractable epilepsy in 19 and with medically responsive epilepsy in 27. Only 3 patients had refractory epilepsy without developmental delays. Global delays were present in 34 and 10 had significant motor and/or language delays. Only two patients had isolated mild language delays, and one had a learning disability. The diagnostic yield of NGS was 70% for patients with non-refractory epilepsy and delays (19/27) and 68.5% for those with medically intractable epilepsy and delays (13/19). Only three had refractory epilepsy without delays, and one had a genetic defect. The diagnostic yield was 78.9% in 19 consanguineous families, and 58.6% in 29 non-consanguineous families (Table 1). Information on consanguinity was not available in one family. Results led to anti-seizure medication optimization or dietary therapies in 14% (7/49), with improvements in seizure control and developmental trajectory (Table 2). Identified genetic defects prompted genetic counseling in a dedicated clinical visit. During this visit, the prognosis of disease and required specialist referrals were broached. In 25 families with inherited diseases, pre-pregnancy counseling regarding potential future siblings was performed. Fifteen patients required specialist referrals that included screening and surveillance for potential non-CNS organ system anomalies and associated comorbidities including cardiac, renal, ophthalmologic, auditory and orthopedic disturbances.
Conclusions: The diagnostic rate of NGS is high in children with unexplained epilepsy and neurodevelopmental delays. Genetic testing in this patient population often leads to potentially life-altering interventions both with regard to seizure control and neurodevelopmental trajectory.
Funding: No sources of funding.
Genetics