Abstracts

Rationale:
Neurologic and metabolic disorders that include epileptic seizures are among the most common genetic disorders presenting in childhood. A molecular diagnosis for patients with epilepsy may allow for etiologically based treatment and management therefore maximizing the diagnostic yield in this group of patients has important implications. The existing research on the diagnostic yield and clinical utility of genetic testing for these patients has focused on early-onset (< 2 years) epilepsies while data regarding later-onset epilepsies is limited.
Method:
This program offers genetic testing to patients with epilepsy in Europe and the Middle East.  The goals of the program are to determine, in a selected pediatric epilepsy cohort, the overall molecular diagnostic yield and the impact on diagnosing neuronal ceroid-lipofuscinosis type 2 (CLN2). CLN2 is a severe, rapidly progressive neurodegenerative disease with seizure onset at or after 2 years of age and average age of diagnosis at 5 years. A next generation sequencing (NGS)-based epilepsy panel (Blueprint Genetics) was used. Copy number variant (CNV) detection from NGS data was included. Variant interpretation was performed according to ACMG guidelines.
Results:
The program results are reported from 541 patients with the following inclusion criteria: age 24-48 months, first seizure at or after 24 months, and at least one additional clinical finding (EEG, MRI abnormalities, speech delay or motor symptoms). The median age at testing was 39 months while the median age at first seizure was 28 months.  The average delay from first seizure to genetic testing was 8.6 months. A genetic diagnosis was established in 115 patients for a molecular diagnostic yield of 21.3%, higher than previously reported (Moller, 2016; Oates, 2018). CNVs were reported in 20% of diagnosed patients and 28% of the CNVs identified were intragenic. Several studies have previously reported the detection of CNVs in patients with epilepsy as 10% or less (Olson, 2014; Mahmutoglu, 2015; Lindy, 2018).  Molecular diagnoses included 12 patients with MECP2 variants, 11 with TPP1 (typically associated with CLN2 disease), 10 with SCN1A, 9 with SCN2A, 3 with UBE3A, SYNGAP1, STCBP1, PCDH19, MFSD8, KCNA2, GRIN2A, CLN6, CHD2, and 2 with STX1B, PRRT2, KCNB1, CLN8 and CDKL5. CLN2 cases received a molecular diagnosis at an average age of 3 years 11 months, 1-2 years earlier than natural history data. At least 72 (62.6%) patients who received a molecular diagnosis had a disorder that has a targeted treatment, evidence for optimizing pharmaceutical treatment, or on-going clinical trials available. 
Conclusion:
This genetic testing program demonstrates the clinical utility of a comprehensive epilepsy gene panel for patients whose first seizure occurs at or after 2 years of age for the molecular diagnosis of pediatric epilepsy and CLN2 disease to inform management and treatment.  In addition, it highlights the importance of including high-resolution CNV detection to maximize the diagnostic yield.
Funding:
:Source of funding: BioMarin Pharmaceutical Inc