Abstracts

Rationale: CLN2 disease, a form of neuronal ceroid lipofuscinosis (NCL), commonly presents ~3 years-of-age with seizures and history of language delay. Average diagnosis occurs ~5 years: two years after symptom onset and after neurodegeneration marked by loss of ambulation and speaking ability. Our objective is to understand the molecular diagnostic yield of a US-based, targeted, no-cost epilepsy gene panel program, Behind the Seizure™ (BTS), and determine if this can decrease the age of diagnosis in CLN2 disease. Methods: Eligibility criteria are: (I) child age at test order =24 months to <60 months; and (II) unprovoked seizure onset at =24 months. Upon test order, physicians report clinical history and any suspicion of: (I) genetic basis for seizures, (II) specific syndrome, (III) mitochondrial disease, (IV) NCL disease, or (V) CLN2 disease. The program provides an epilepsy gene panel with an average turnaround time of 10-14 days (Invitae Epilepsy Panel) with the option to add preliminary-evidence genes (genes associated with epilepsy based on literature review and expert opinion). Results: Non-BTS epilepsy gene panel testing (all ages, age of seizure onset) resulted in a 17.1% molecular diagnostic yield (n=277/1620) and 0.12% for TPP1 (CLN2 disease). For BTS testing, the yield for CLN2 disease was 2.3% (n=4/176), a 19-fold improvement. Age-at-diagnosis of CLN2 disease was earlier than average (3.3 years versus 5 years). From BTS, 3 of 4 molecular diagnoses in TPP1, CLN2 disease was unsuspected. Other genes with molecular diagnoses: MECP2, CHD2, SYNGAP1, SCN1A, GPHN, GRIN2A. Conclusions: Behind the Seizure™ facilitated CLN2 disease identification earlier than average and in cases which CLN2 was not suspected. While there is no direct comparator for the BTS group, these findings may indicate that broad epilepsy gene panel tests implemented with clinical criteria can increase diagnostic yield for CLN2 disease and simultaneously identify other genetic causes of epilepsy. Funding: This study was funded by BioMarin Pharmaceutical Inc.