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Epilepsy Advanced Sequencing EvaluationTest code(s) 5000, 5001, 5002, 5003, 5004, 5005, 5006, 5007, 5008
This is an outdated version of this FAQ. It was effective 04/02/2014 to 09/14/2017.
The current version is available here.
Question 1. Which technologies are available for genetic testing of patients with epilepsy?
Chromosomal microarray (CMA) and massively parallel sequencing, also called next-generation sequencing (NGS), are available. By testing the entire genome, CMA can detect DNA copy number variants (CNVs) or subtle chromosomal anomalies associated with conditions that may manifest with epilepsy. CMA-based studies have reported causative CNVs in 5% to 30% of patients with epilepsy.2 NGS uses a more targeted approach, testing the specific genes that cause epilepsy.1
Question 2. Why isn’t whole exome sequencing (WES) used for patients with epilepsy?
WES sequences many genes that do not harbor epilepsy-causing mutations. Thus, WES would detect many unrelated variants that would have to be analyzed and then interpreted as being nonepilepsy related. CMA and NGS, however, more specifically target the genes that would 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.
Question 3. When is it appropriate to order a chromosomal microarray test for a patient with epilepsy?
CMA is appropriate for patients in whom a clinical history and exam do not point to a specific genetic or nongenetic cause of certain epilepsy-related disorders. These disorders include global developmental delay (GDD), intellectual disability (ID), multiple congenital anomalies (MCA), and autism spectrum disorder (ASD). The American College of Medical Genetics (ACMG),3,4 the American Academy of Neurology (AAN),5 the Child Neurology Society,5 the American Academy of Pediatrics,6 and the International Collaboration for Clinical Genomics (ICCG)7 recommend CMA as the first-line test in the genetic diagnosis for such patients. The diagnostic yield for clinically relevant CNVs in patients with GDD, ID, MCA, or ASD can be as high as 15% to 20%.4,8
Question 4. 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 at a threshold of 200 kb and deletions at a threshold of 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 GDD, ID, MCA, and ASD. These specifications exceed ACMG 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. Ninety-eight percent (98%) of 2,640 OMIM morbid genes and 96% of 36,121 RefSeq genes are also covered. 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 5. When is it appropriate to order the Epilepsy Advanced Sequencing Evaluation panels?
The first tier test for a patient with GDD, ID, MCA, or ASD is a CMA test. Abnormalities on CMA are also identified in up to 30% of patients with epilepsy with or without these conditions.2 If abnormalities are not found on CMA, it is appropriate to perform the targeted sequencing of known epilepsy genes to arrive at a specific genetic diagnosis, guide treatment, and estimate the risk of recurrence. The genes included in the Epilepsy Advanced Sequencing Evaluation panels are chosen based on their known involvement in monogenic disorders in which epilepsy is a key phenotypic feature according to the Online Mendelian Inheritance in Man (OMIM) database. The Epilepsy Advanced Sequencing Evaluation panels are based on the International League Against Epilepsy (ILAE) classification.9 These panels may detect a disease-causing mutation in 48% of patients (16 of 33).10 The panels differ from other published panels by the exclusion of genes associated with metabolic disorders that can be diagnosed by biochemical testing, and those associated with obvious congenital anomalies that can be diagnosed by MRI of the brain (eg, holoprosencephaly, Joubert syndrome).
Question 6. What are the technical specifications and limitations of the next-generation sequencing tests offered by Athena Diagnostics?
The Epilepsy Advanced Sequencing Evaluation panels offered by Athena Diagnostics sequence more than 2,400 exonic regions, including the coding exons and flanking splice junctions, of 141 epilepsy-related genes. Overall mean coverage depth, excluding duplicate fragments, is ~150X. 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.
Insertions or rearrangements larger than approximately 20 base pairs and deletions larger than approximately 40 base pairs may not be reliably detected.
Question 7. Which next-generation sequencing tests does Athena Diagnostics offer for patients with epilepsy?
Question 8. What are the sample requirements?
Submit 8-10 mL (adults), 4 mL (children), or 2 mL (infants) whole blood in an EDTA (lavender-top) tube.
Ship overnight at ambient temperature, using a cool pack in hot weather. Specimens may be refrigerated for up to 7 days prior to shipping.
Alternatively, submit high quality, extracted DNA: ≥20 µg DNA at a concentration of 50 ng/µL; minimum volume of 400 µL.
Please contact one of our genetic counselors regarding specific acceptance policies and specimen requirements at 800-394-4493.
- Garofalo S, Cornacchione M, Di Costanzo A. From genetics to genomics of epilepsy. Neurol Res Int. 2012;2012:876234. doi:10.1155/2012/876234.
- Spreiz A, Haberlandt E, Baumann M, et al. Chromosomal microaberrations in patients with epilepsy, intellectual disability, and congenital anomalies [published online ahead of print September 30, 2103]. Clin Genet. doi:10.1111/cge.12288.
- 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.
- 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.
- 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.
- 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.
- 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.
- Manning M, Hudgins L. Use of array-based technology in the practice of medical genetics. Genet Med.2007;9:650-653.
- 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.
- Lemke JR, Riesch E, Scheurenbrand T, et al. Targeted next generation sequencing as a diagnostic tool in epileptic disorders. Epilepsia. 2012;53:1387-1398.
Paciorkowski AR, Thio LL, Dobyns WB. Genetic and biologic classification of infantile spasms.Pediatr Neurol. 2011;45:355-367.
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