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Epilepsy Advanced Sequencing and CNV Evaluation

Test code(s) 6000, 6008, 6010, 6018, 6019, 6022, 6023, 6033, 6038

Question 1. Which technologies are used in the Epilepsy Advanced Sequencing and CNV Evaluation?

Massively parallel sequencing, also called next-generation sequencing (NGS), with copy-number variant (CNV) analysis, is used for genetic testing of patients with epilepsy. Our NGS technology can detect single-nucleotide variants (SNVs), small insertions or deletions (indels), and CNVs. The Epilepsy Advanced Sequencing and CNV Evaluation tests for CNVs (both deletions and duplications) in the coding regions of selected genes that have been associated with epilepsy.1 Several different Epilepsy Advance Sequencing and CNV Evaluation panels are available to assess the genetic cause of epilepsy in patients. Selection of the specific NGS panel depends on clinical presentation and other factors (see Question 7). CNV’s identified by NGS will be confirmed by alternative methodologies including multiplex ligation-dependent probe amplification (MLPA) or targeted microarray analysis specific to the genes in the panel.

Unlike targeted NGS, whole-genome chromosomal microarray (CMA) tests for large contiguous CNVs and structural variants that involve both coding and non-coding genomic regions. CMA-based studies have reported causative CNVs in 5% to 30% of patients with epilepsy, especially when it is associated with global developmental delay, intellectual disability, multiple congenital anomalies, or autism spectrum disorder.2-8

Question 2. Why isn’t whole exome sequencing (WES) preferred for patients with epilepsy?

WES includes many genes that do not harbor epilepsy-causing mutations and will detect many variants that are not related to epilepsy. Epilepsy Advanced Sequencing and CNV Evaluation uses targeted NGS exome sequencing and differs from WES by providing a depth of coverage that makes CNV calling possible in a single test-- specifically in genes that harbor epilepsy-causing mutations. The increase in coverage for the target sequences greatly simplifies analysis and interpretation.

Question 3. When is it appropriate to order the Epilepsy Advanced Sequencing and CNV Evaluation panels?

Many epilepsies have a genetic component. When a clinician suspects a genetic etiology of the disease, the Epilepsy Advanced Sequencing and CNV Evaluation panels may be a good laboratory test to include in the patient’s work-up. Given that the Epilepsy Advanced Sequencing and CNV panels (see Question 6) incorporate both sequencing and CNV evaluation, other tests including MLPA and CMA may not be required. Performing the targeted sequencing of known epilepsy genes coupled with CNV analysis can assist in arriving at a specific genetic diagnosis, guide treatment, and estimate the risk of recurrence. The genes included in the Epilepsy Advanced Sequencing and CNV Evaluation panels are chosen based on their known involvement in monogenic disorders in which epilepsy is a key phenotypic feature (See Question 7). The Epilepsy Advanced Sequencing Evaluation panels are based on the International League Against Epilepsy (ILAE) classification.9 These panels have been reported to detect a disease-causing mutation in 48% of selected patients (16 of 33).10, 11

Question 4. When is it appropriate to order CMA for epilepsy?

The American College of Medical Genetics and Genomics (ACMGG) recommends CMA as the first-tier test for patients with global developmental delay, intellectual disability, multiple congenital anomalies, or autism spectrum disorder because of the high diagnostic yield for these disorders.3 CMA-based studies have reported causative CNVs in 5% to 30% of patients with epilepsy.2 CMA tests for CNVs and chromosomal changes associated with epilepsy throughout the entire genome, and not just the genes that are targeted in the panel. While both the Epilepsy Advanced Sequencing and CNV panels and CMA will show CNV’s in the targeted genes, only the Epilepsy Advanced Sequencing and CNV panels will give information on other types of variants in the target genes such as SNVs (e.g. point mutations), indels, and CNVs involving the coding regions of epilepsy genes. CMA will show large genomic CNVs in chromosomal areas that involve other genes besides those associated with epilepsy. The decision to perform CMA or NGS as a first-tier test to evaluate patients with epilepsy is up to the clinician, and is based on family history, in addition to information from other clinical and diagnostic evaluations.

Question 5. What are the technical specifications of the chromosomal microarray test offered by Quest Diagnostics®?

The CMA test offered by Quest Diagnostics (Chromosomal Microarray, Postnatal, ClariSure® Oligo-SNP [test code 16478]) detects duplications larger than 200 kb and deletions larger than 50 kb. The array consists of almost 2.7 million probes, including ~1.9 million copy-number probes and ~750,000 single-nucleotide polymorphism probes. The array is enriched for probes that target dosage-sensitive genes known to result in phenotypes consistent with global developmental delay, intellectual disability, multiple congenital anomalies, and autism spectrum disorder. These specifications exceed ACMGG recommendations to detect CNVs smaller than 400 kb in regions of known clinical relevance.3 The genes covered encompass 100% of the ICCG constitutional genes, cancer genes, and X-linked OMIM morbid genes. The assay also covers 98% of the 2,640 OMIM morbid genes and 96% of the 36,121 RefSeq genes. The assay has a 99% analytical sensitivity for CNVs >400 kb in the regions covered and a false-positive rate of <1% per CNV call.

Question 6. What are the technical specifications and limitations of the NGS tests offered by Athena Diagnostics®?

The Epilepsy Advanced Sequencing and CNV Evaluation panels offered by Athena Diagnostics sequence more than 4,000 exonic regions, including the coding exons and flanking splice junctions, of 234 epilepsy-related genes. Overall mean coverage depth, excluding duplicate fragments, is >900X. Generally, 99% of 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. The analytical sensitivity of NGS is >99% relative to Sanger sequencing.

The panels use dosage testing to detect CNVs for all the genes in the panel, and can detect down to the level of single-exon deletions and duplications by either MLPA or target microarray analysis.

Question 7. Which next-generation sequencing tests does Athena Diagnostics offer for patients with epilepsy?

Athena Diagnostics offers the following 9 panels:

(Internet Explorer users: right-click on link to open file) 

Question 8. What are the sample requirements?

See web site for specific details:  http://www.athenadiagnostics.com/

Specimen Type: Whole blood
Collection Tube: Lavender top (EDTA)
Adult Preferred Volume: 8 mL (minimum 6 mL)
Pediatric Preferred Volume: 2 mL (minimum 1 mL)
Shipping Conditions: Ship room temperature, avoid freezing. Frozen samples will not be accepted.
Test Turnaround: 28-35 days

Please contact one of our genetic counselors regarding specific acceptance policies and specimen requirements at 1.800.394.4493.


  1. Garofalo S, Cornacchione M, Di Costanzo A. From genetics to genomics of epilepsy. Neurol Res Int. 2012;2012:876234.doi:10.1155/2012/876234.
  2. Spreiz A, Haberlandt E, Baumann M, et al. Chromosomal microaberrations in patients with epilepsy, intellectual disability, and congenital anomalies. Clin Genet. 2013;86(4):361-366. doi:10.1111/cge.12288.
  3. Kearney HM, South ST, Wolff DJ, et al. American College of Medical Genetics recommendations for the design and performance expectations for clinical genomic copy number microarrays intended for use in the postnatal setting for detection of constitutional abnormalities. Genet Med. 2011;13:676-679.
  4. Manning M, Hudgins L, Professional Practice and Guidelines Committee. Array-based technology and recommendations for utilization in medical genetics practice for detection of chromosomal abnormalities. Genet Med. 2010;12:742-745.doi: 10.1097/GIM.0b013e3181f8baad
  5. Michelson DJ, Shevell MI, Sherr EH, et al. Evidence report: Genetic and metabolic testing on children with global developmental delay: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology. 2011;77:1629-1635.
  6. American Academy of Pediatrics. Statement of Endorsement: Genetic and metabolic testing on children with global developmental delay. Pediatrics. 2012;129:e825.doi:10.1542/peds.2011-3485.
  7. Miller DT, Adam MP, Aradhya S, et al. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet.2010;86:749-764.doi: 10.1016/j.ajhg.2010.04.006
  8. Manning M, Hudgins L. Use of array-based technology in the practice of medical genetics. Genet Med.2007;9:650-653.
  9. Berg AT, Berkovic SF, Brodie MJ, et al. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005-2009. Epilepsia. 2010;51:676-685.
  10. Lemke JR, Riesch E, Scheurenbrand T, et al. Targeted next generation sequencing as a diagnostic tool in epileptic disorders. Epilepsia. 2012;53:1387-1398.
  11. Paciorkowski AR, Thio LL, Dobyns WB. Genetic and biologic classification of infantile spasms.Pediatr Neurol. 2011;45:355-367.
This FAQ is provided for informational purposes only and is not intended as medical advice. A physician’s test selection and interpretation, diagnosis, and patient management decisions should be based on his/her education, clinical expertise, and assessment of the patient.
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