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Phenotype-based Next Generation Sequencing for Epilepsy: Comprehensive and Cost-effective

When a child presents with epilepsy, finding the right diagnosis becomes an urgent challenge. The choice of treatment may depend on it, and providing a diagnosis 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 developed Phenotype-based Next Generation Sequencing for Epilepsy. This approach uses the physician’s clinical observations to streamline the testing process, increasing the likelihood of finding the causative gene while limiting costs by avoiding unnecessary tests.

“If a neurologist uses an electroclinical approach and defines the patient’s phenotype, the chances of identifying the causative gene is much greater,” says Joseph J. Higgins, MD, Medical Director of Neurology at Athena Diagnostics, who spearheaded the development of the new epilepsy panels.

Next Generation Sequencing (NGS), also called “massively parallel sequencing,” allows simultaneous testing of many genes, ideal for 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 design of our assay sequences more than 2,400 exonic regions, including the coding exons and flanking splice junctions, of 141 epilepsy-related genes. Generally, 99% of the regions sequenced have a mean coverage depth of ≥30X, and 98% 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. We make sure we provide adequate coverage with an analytical sensitivity of >99% relative to Sanger sequencing,” Dr. Higgins says, “to increase chances of finding a causative mutation.”

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. “We specifically target genes that harbor epilepsy-causing mutations. This allows a significant increase in coverage for the target sequences and greatly simplifies analysis and interpretation of the variants detected. We have a lot of experience with epilepsy genetics and have a state-of-the-art variant analysis system called Athena Insight. So we are confident when we find a mutation,” says Dr. Higgins.

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, and infantile spasms. For patients in which it is not possible to narrow the phenotype, the Epilepsy Advanced Sequencing Evaluation provides testing of a total of 141 genes.

Not every epilepsy patient is appropriate for the NGS approach, Dr. Higgins points out. When the clinical picture points strongly to a specific etiology, such as an inborn error of metabolism, structural abnormality, or autoimmune disorder other types of diagnostic testing should be considered.

A team of board-certified genetic counselors is available 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.

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 pathogenicity of every new variant provide unparalleled depth of knowledge when interpreting variants of unknown significance.

“The 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. This can result in the more efficient delivery of care, more targeted therapies and provide value by identifying the molecular cause of the seizures,” Dr. Higgins said.

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