Abstracts

Rationale:
Studies have demonstrated that up to 40% of individuals with early-onset epilepsy have a genetic etiology. Physicians are increasingly utilizing genetic testing to confirm clinical diagnoses and manage patient care. As precision medicine treatments for rare diseases continue to increase, it is imperative for individuals with genetic epilepsy to obtain a molecular diagnosis as early as possible. However, many older children and adults with epilepsy have not benefited from this recent trend of incorporating genetic testing into clinical care and therefore remain undiagnosed. Studies of adults with epilepsy (most with intellectual disability), recently reported that 22-23% of these individuals have a genetic etiology (Johannesen et.al. 2020, Borlot et. al., 2019). In this study, we report the outcomes from using an epilepsy gene panel for an unselected clinical cohort of individuals who were ≥18 years of age at the time of molecular testing.
Method:
We used a multi‐gene next‐generation sequencing panel with simultaneous sequence and exonic copy number variant detection to investigate up to 186 epilepsy-related genes in 22,058 individuals, 2078 individuals aged ≥18 years and 19,980 individuals aged < 18 years at the time of testing. The age range of the adult cohort was 18-84 years and the average was 28.7 years. A definitive, positive molecular diagnosis (PosMD) included either single pathogenic/likely pathogenic (P/LP) variants in genes associated with dominant or X‐linked inheritance, or two P/LP (in homozygous or compound heterozygous states) in genes associated with recessive inheritance.
Results:
The PosMD rate was 14.6% (3227/22058) across all individuals tested in this cohort regardless of age. There was a statistically significant difference in the PosMD rate between individuals ≥18 years old (10.9%; 227/2078) compared to those who were < 18 years old (15.0%; 3000/19980). Notably, the PosMD genes were similar between the two cohorts: they shared in common 11/13 genes that accounted for ~60% of all PosMD in each cohort (SCN1A, UBE3A, DEPDC5, MECP2, PRRT2, CHD2, PCDH19, NPRL3, SCN2A, KCNQ2, STXBP1). Almost half of these PosMD genes have possible precision medicine implications, as determined by current literature.
Conclusion:
These data clearly indicate that many adult patients can benefit from genetic testing. A limitation of these data is the lack of deep clinical phenotyping. However, because many of the PosMD genes were common between the < 18 and ≥18 years age cohorts, and because of what is currently known about the phenotypic spectrum associated with pathogenic variants in those genes, it is likely that many of the adults had childhood-onset seizures and most likely had some degree of intellectual disability. With increasing numbers of epilepsy-related genes that are associated with precision medicine therapies, it becomes important to identify all individuals who may benefit from these, including adults who are newly diagnosed or those who have been searching for a diagnosis since childhood.
Funding:
:N/A