When a child presents with epilepsy, finding the right diagnosis becomes an urgent challenge. The choice of treatment may depend on it, and providing important answers to the family, and the prognostic information that may come with it, can help ease uncertainty in a tremendously stressful time.
Enormous advances in understanding the genetics of epilepsy have enabled clinicians to identify a cause in an ever-increasing number of patients. But these advances have made choosing the right genetic test even more complex. To make that choice easier for physicians, Athena Diagnostics has employed its highly successful Phenotype-based Next Generation Sequencing Panels for Epilepsy for the past 3 years. This approach links the physician’s clinical observations to panels of specific genes that have a phenotype related to those observations to streamline the testing process. This focuses the testing on the most likely causative genes without distracting and extraneous information from less relevant genes while limiting costs by avoiding unnecessary tests.
Now, Athena is proud to announce its most comprehensive and up-to-date epilepsy testing program yet, bringing the latest understanding of epilepsy genetics to phenotype-based next generation sequencing. The comprehensive test panel includes 234 genes linked to epilepsy. The panel also includes analysis of copy number variants, a significant source of disease-linked genetic variability.
The field of epilepsy genetics is one of the most rapidly changing branches of neurology, according to Edward Ginns, MD, PhD, Medical Director at Quest Diagnostics. Since the development of the original panel, new genes have been linked to epilepsy, while others have receded in importance, and the new panel reflects those important changes. Most significant has been the growing appreciation of the role of copy number variants, in which duplication or deletion of a gene-bearing portion of the DNA can cause or increase the risk for epilepsy.
“Copy number variants may account for approximately 5% of all cases of epilepsy,” Dr. Ginns says, “and so searching for copy number variants is now a critical part of making a genetic diagnosis.” The new panel analyzes copy number variants in all 234 genes. “That increases sensitivity and improves the likelihood of obtaining a diagnosis. This is a major improvement in the diagnostic process, providing a benefit to the clinician, the family, and the patient.”
Next Generation Sequencing (NGS), also called “massively parallel sequencing,” allows simultaneous testing of many genes, ideal for any complex inheritance disease, like epilepsy. Athena Diagnostics’ NGS platform has been rigorously developed and quality-tested to provide a high minimum coverage across all genes tested, ensuring accuracy even in challenging portions of the genome. The assay sequences approximately 4,200 exonic regions, including the coding exons and flanking splice junctions, of 234 epilepsy-related genes. At Athena, 99% of the regions sequenced have a mean coverage depth of ≥30X, Dr. Ginns notes, and 99% of regions sequenced have an overall minimum coverage depth of ≥20X. Sanger sequencing is used to compensate for low coverage in regions having known mutations.
The targeted approach of the Athena phenotype-based NGS avoids the diagnostic quandary that arises with whole-exome (WES) approaches to epilepsy: the potential for too much information of little clinical relevance. WES detects many unrelated variants that would have to be analyzed and then interpreted as being non-epilepsy related. By specifically targeting genes that harbor epilepsy-causing mutations, Athena’s new test panel allows a significant increase in coverage for the target sequences. Additionally, gene panels allow for the inclusion of known pathogenic intronic variants, which would not be detected in WES. This gene targeting and the addition of CNVs greatly simplifies analysis and interpretation of the variants detected.
“This approach hits the ‘sweet spot’ for epilepsy genes,” says Susan Hahn, MS, Certified Genetic Counselor at Athena. “We know from our field visits to clinicians that they appreciate this comprehensive but targeted approach.”
Within the phenotype-based NGS group of tests, there are separate panels for genes associated with specific phenotypes, such as epileptic encephalopathy, epilepsy with migraine, infantile spasms, and others. For patients in whom it is not possible to narrow the phenotype, the Epilepsy Advanced Sequencing Evaluation provides testing of a total of 234 genes.
A team of board-certified genetic counselors is available at Athena to help with making the best choice of the test for the individual patient and can provide guidance for counseling the family once the results are in hand.
“We have a team of seven genetic counselors with a primary focus on neurology,” points out Ms. Hahn. “This is unmatched in the field of commercial genetic testing.” Ms. Hahn and other members of the counseling team worked with Athena scientists to help tailor the new panel to what they were hearing from customers about their needs.
“The development of the new test panels have been a real group effort,” Dr. Ginns says. The panels were developed with inputs from customers, key opinion leaders, updates with the latest scientific information, and examination of trends in patient results. When the updated genetic panels are coupled with patient clinical data, it becomes a very strong diagnostic tool. “The best yield from any sequencing endeavor is to have a very thorough and accurate clinical and neurologic examination,” Dr. Ginns says, “so that the phenotype is defined in as much detail as possible. The clinician is bringing vital information which helps direct the analysis of variants found in the sequencing phase. This is essential for obtaining the best result.”
The Athena Insight report that accompanies every test result provides essential information for interpreting the results of the test. Athena Diagnostics’ database of test results and the team of scientists who evaluate the pathogenicity of every new variant provide an unparalleled depth of knowledge when interpreting variants of unknown significance.
The new phenotype-based NGS approach combines the skill of the clinician with the power of next-generation sequencing to offer the patient and family the highest chance of finding the gene involved. “The goal is more efficient delivery of care, more targeted therapies and better value by identifying the molecular cause of the seizures,” Dr. Ginns says.