Clinical Utility of a Sponsored Gene Panel Testing Program for Pediatric Epilepsy and CLN2 Disease Diagnosis: Results from 14,589 Tests
Abstract number :
2.322
Submission category :
12. Genetics / 12A. Human Studies
Year :
2021
Submission ID :
1825527
Source :
www.aesnet.org
Presentation date :
12/5/2021 12:00:00 PM
Published date :
Nov 22, 2021, 06:44 AM
Authors :
Guillermo Seratti, MD - BioMarin Pharmaceutical Inc.; Tiffany Yar Pang, MS - BioMarin Pharmaceutical Inc.; Sarah Poll, PhD – Invitae; Dianalee A. McKnight, PhD – Invitae; Britt Johnson, PhD – Invitae; Ana Morales, MS – Invitae; Sara L. Bristow, PhD – Invitae; Emanuela Izzo, PhD – BioMarin Pharmaceutical Inc.; Sookyong Koh, MD, PhD – University of Nebraska Medical Center; Elaine C. Wirrell, MD – Mayo Clinic; John J. Millichap, MD – Northwestern University Feinberg School of Medicine; Swaroop Aradhya, PhD – Invitae
Rationale: Neuronal ceroid lipofuscinosis type 2 (CLN2) disease is a rare, inherited, neurodegenerative lysosomal storage disorder caused by deficient activity of the enzyme tripeptidyl peptidase (TPP1), encoded by the TPP1 gene. CLN2 disease often presents with epilepsy between 2 and 4 years of age, accompanied by history of language delay. However, limited disease awareness and the nonspecific nature of initial symptoms mean that diagnostic delays are common. Behind the Seizure® (BTS) is a sponsored, next-generation sequencing gene panel for children with suspected genetic epilepsy, which was initiated with the goal of lowering the age of CLN2 disease diagnosis.
Methods: The BTS program uses a panel of more than 300 genes associated with both syndromic and non-syndromic causes of epilepsy. During the initial phase of the program (December 2016 - February 2019), individuals were eligible for testing through BTS if they were aged ≥24 to ≤60 months with unprovoked seizure onset at or after 24 months. The program was expanded in February 2019 to include individuals aged 0 to ≤60 months with unprovoked seizure onset at any age, and was further expanded in January 2020 to extend to individuals aged up to 108 months with unprovoked seizure onset at any age.
Results: Between December 2016 and April 2021, a total of 14,589 tests were conducted through the BTS program. The molecular diagnostic yield was 13.3% overall (n=1946; 142 genes) and 0.16% for TPP1 (n=24). In the subset of individuals tested through BTS who were aged 24-60 months with seizure onset at or after 24 months (n=4,165), the molecular diagnostic yield was 7.8% overall (n=324) and 0.6% for TPP1 (n=23). Mean age at CLN2 disease diagnosis through the BTS program was 3.5 years, which is earlier than the natural history reported average of 5 years. The genes with most frequent positive molecular diagnoses in order of frequency were PRRT2, SCN1A, KCNQ2, MECP2, SCN2A, PCDH19, UBE3A, DEPDC5, TSC2, and NPRL3. TPP1 was the highest positive yield gene for autosomal recessive disorders.
Conclusions: These findings demonstrate that the use of broad epilepsy gene panel tests can facilitate the earlier diagnosis of CLN2 disease, and simultaneously identify other genetic causes of epilepsy.
Funding: Please list any funding that was received in support of this abstract.: BioMarin Pharmaceutical Inc.
Genetics