High-depth multi-gene panel analysis with integrated sequence and copy number detection is a useful first-tier test with a high diagnostic yield and broad mutation spectrum detection in childhood epilepsy
Abstract number :
1.171
Submission category :
4. Clinical Epilepsy / 4B. Clinical Diagnosis
Year :
2017
Submission ID :
344566
Source :
www.aesnet.org
Presentation date :
12/2/2017 5:02:24 PM
Published date :
Nov 20, 2017, 11:02 AM
Authors :
Ali Entezam, Invitae Corporation; Rebecca Truty, Invitae Corporation; Nila Patil, Invitae Corporation; Darlene Riethmaier, Invitae Corporation; Laura Elias, Invitae Corporation; Amy Fuller, Invitae Corporation; Tina Hambuch, Invitae Corporation; Michelle
Rationale: Epilepsy is a common disorder that is increasingly known to result from genetic causes, particularly when it occurs in early childhood. Understanding the genetic etiology can inform treatment strategies, prognosis, and recurrence risk. The objective of this study was to use a multi-gene panel with simultaneous sequence and exonic copy number variant detection to evaluate the clinical yield and assess its utility relative to exome sequencing. Methods: Using high depth next-generation sequencing, we investigated subsets of 186 genes in 1131 unrelated individuals diagnosed with epilepsy. Results: We observed a total of 1840 clinically reportable variants in 885 individuals. 14% of patients received a definitive molecular diagnosis by panel testing, and another 29% had results that in some cases would likely reach clinical significance with additional evidence. 14% of positive results were chromosomal or exonic copy number changes or large indels. Most pathogenic variants were in genes for early-onset epilepsy and 22% of molecular diagnoses had treatment implications. Mosaic variants were seen in three genes and one individual had diagnostic results in two genes. Half of the variants of unknown significance identified were likely not clinically significant since they were found alone in an autosomal recessive gene or in the presence of a diagnostic result in another gene. A meta-analysis of published exome data showed that >70% of positive results for individuals with seizures were in genes present in available gene panels. We also evaluated sequence data for epilepsy genes in exome data derived from three different exome kits and bioinformatics pipelines and found a risk of up to 1.6% for false negative results, and that does not consider novel deleterious variants. Conclusions: These observations emphasize that a multi-gene panel for epilepsy is a useful first test prior to exome sequencing because of a high diagnostic yield and reliable detection of a broad range of mutations, including both sequence and copy number variants. Funding: Fully funded by Invitae Corporation
Clinical Epilepsy