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

Abstract

Objective 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. Methods 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. Results 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. Significance 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.

Why we urgently need improved seizure and epilepsy therapies for children and neonates

“…Newer treatment options therefore should be explored. The discovery of genetic variations/mutations as the cause of epilepsy in many young children with epilepsy is a doorway to precision treatment (Ellis et al 2019, Sisodiya et al, 2019, Orsini et al, 2019, Kearney et al, 2019, Fitzgerald et al, 2019, Truty et al, 2019, Milh et al, 2016. With the advances in understanding the molecular basis of many epilepsies, targeted therapies become available, in contrast with the broad-spectrum non-specific efficacy of most existing drugs.…”

Current knowledge of SLC6A1-related neurodevelopmental disorders

“…Disruption of SLC6A1 is a prominent cause of neurodevelopmental disorders, including autism spectrum disorder, intellectual disability and seizures of varying types and severity. In the current three largest genomic screens of individuals with epilepsy (8565, 9170 and 9769 patients, respectively), SLC6A1 was listed among the top 10–20 genes with the highest number of pathogenic variants ( Lindy et al , 2018 ; Epi25 Collaborative, 2019 , p. 25; Truty et al., 2019 ) . In the most extensive autism sequencing study to date ( N = 11 986), SLC6A1 was among the top 10 genes, with the most significant variant enrichment in autism patients compared to 23 598 controls ( Satterstrom et al , 2019 ).…”

Clinical sequencing yield in epilepsy, autism spectrum disorder, and intellectual disability: A systematic review and meta‐analysis

“…It may also guide the identification of more genetically homogeneous subgroups within the spectrum of NDDs 3 . A recent study showed that 33% of children with a molecularly confirmed genetic epilepsy would benefit from precision medicine 4 . However, the proportion of individuals with NDDs who carry a genetic abnormality that can be identified using next‐generation sequencing (NGS) has yet to be well established.…”