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

Truty R1, Patil N2, Sankar R2, Sullivan J3, Millichap J4, Carvill G5, Entezam A1, Esplin ED1, Fuller A1, Hogue M1, Johnson B1, Khouzam A1, Kobayashi Y1, Lewis R1, Nykamp K1, Riethmaier D1, Westbrook J1, Zeman M1, Nussbaum RL1,6, Aradhya S1.

Author information

1: Invitae San Francisco California.
2: Departments of Pediatrics and Neurology University of California Los Angeles Los Angeles California.
3: Pediatric Epilepsy Center University of California San Francisco San Francisco California.
4: Lurie Children's Hospital and Northwestern University Chicago Illinois.
5: Ken and Ruth Davee Department of Neurology Northwestern University Chicago Illinois.
6: Volunteer Faculty University of California San Francisco San Francisco California.

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.

KEYWORDS:

clinical management; copy number variant; diagnostic genetic testing; next‐generation sequencing panel; precision medicine; variant of uncertain significance