Possible precision medicine implications from genetic testing using combined detection of sequence and intragenic copy number variants in a large cohort with childhood epilepsy

<jats:title>Abstract</jats:title><jats:sec><jats:title>Objective</jats:title><jats:p>Molecular genetic etiologies in epilepsy have become better understood in recent years, creating important opportunities for precision medicine. Building on these advances, detailed studies of the complexities and outcomes of genetic testing for epilepsy can provide useful insights that inform and refine diagnostic approaches and illuminate the potential for precision medicine in epilepsy.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We used a multi‐gene next‐generation sequencing (NGS) panel with simultaneous sequence and exonic copy number variant detection to investigate up to 183 epilepsy‐related genes in 9769 individuals. Clinical variant interpretation was performed using a semi‐quantitative scoring system based on existing professional practice guidelines.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Molecular genetic testing provided a diagnosis in 14.9%‐24.4% of individuals with epilepsy, depending on the NGS panel used. More than half of these diagnoses were in children younger than 5 years. Notably, the testing had possible precision medicine implications in 33% of individuals who received definitive diagnostic results. Only 30 genes provided 80% of molecular diagnoses. While most clinically significant findings were single‐nucleotide variants, ~15% were other types that are often challenging to detect with traditional methods. In addition to clinically significant variants, there were many others that initially had uncertain significance; reclassification of 1612 such variants with parental testing or other evidence contributed to 18.5% of diagnostic results overall and 6.1% of results with precision medicine implications.</jats:p></jats:sec><jats:sec><jats:title>Significance</jats:title><jats:p>Using an NGS gene panel with key high‐yield genes and robust analytic sensitivity as a first‐tier test early in the diagnostic process, especially for children younger than 5 years, can possibly enable precision medicine approaches in a significant number of individuals with epilepsy.</jats:p></jats:sec>