Abstracts

Rationale: Neuronal Ceroid Lipofuscinosis (NCL) Type 2 disease (CLN2), a type of Batten disease and often presenting with epilepsy, presents at approximately three years of age with seizures and history of language delay. According to the literature, the average age of diagnosis is around five years, two years after symptom onset and after progressive neurodegeneration that can lead to compromises in ambulation and speech. The purpose of the program is to provide a no-cost, targeted epilepsy gene panel program [Behind the SeizureTM (BTS)] to US-based children suspected to have genetic epilepsy, in attempts to lower the age of CLN2 disease diagnosis. Here we present the updated results on diagnostic yield of 682 tests. Methods: Eligibility criteria were: (I) age at test order between 24 and 48 months; and (II) unprovoked seizure onset after 24 months. Upon test order, physicians reported clinical history and any suspicion of: (I) genetic basis for seizures, (II) specific recognizable syndrome, (III) mitochondrial disease, (IV) any NCL disease, or (V) specifically CLN2 disease. The program uses an epilepsy gene panel of 180+ genes with the option to include preliminarily associated genes (genes with emerging published evidence for involvement in epilepsy), with an average turn-around time of 14 days. Results: Non-BTS epilepsy gene panel testing, which includes all ages for age at test order and age of seizure onset, has shown a 15.5% molecular diagnostic yield overall (n=1234/7939) and 0.05% specifically involving TPP1 (CLN2 disease). Within the BTS program and its eligibility criteria restrictions, the molecular diagnostic yield was 6.74% (n=46/682) overall. However, the yield of TPP1 positive results for CLN2 disease in the program was 0.88% (n=6/682), representing a 17.6-fold increase in comparison to the non-BTS cohort. Age of diagnosis of CLN2 disease was earlier than as described in the literature (3.89 years versus five years). In the BTS program, CLN2 disease was not a suspected diagnosis for 5 out of 6 individuals with bi-allelic pathogenic variants in TPP1 before they were tested with the epilepsy gene panel. Other genes that contributed positive molecular diagnoses in the BTS program included CACNA1A, CHD2, EHMT1, FOXG1, FRRS1L, GRIN2A, IQSEC2, KANSL1, KIAA2022, MECP2, PACS1, PCDH19, PPT1, PURA, SCN1A, SCN2A, SLC6A1, STX1B, SYNGAP1, TSC1 and ZEB2. Conclusions: The BTS program has facilitated earlier CLN2 disease identification and in cases in which CLN2 disease was not clinically suspected. These findings indicate that broad epilepsy gene panel tests can increase diagnostic yield for CLN2 disease and simultaneously identify other genetic causes of epilepsy. Funding: This study was funded by BioMarin.