Early Infantile Epilepsies and Autism via the SCN2A Gene
Summary and Pricing 
Test Method
Sequencing and CNV Detection via NextGen Sequencing using PG-Select Capture Probes| Test Code | Test Copy Genes | Test CPT Code | Gene CPT Codes Copy CPT Code | Base Price | |
|---|---|---|---|---|---|
| 4227 | SCN2A | 81479 | 81479,81479 | $990 | Order Options and Pricing |
Pricing Comments
Testing run on PG-select capture probes includes CNV analysis for the gene(s) on the panel but does not permit the optional add on of exome-wide CNV analysis. Any of the NGS platforms allow reflex to other clinically relevant genes, up to whole exome or whole genome sequencing depending upon the base platform selected for the initial test.
An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.
This test is also offered via a custom panel (click here) on our exome or genome backbone which permits the optional add on of exome-wide CNV or genome-wide SV analysis.
Turnaround Time
3 weeks on average for standard orders or 2 weeks on average for STAT orders.
Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn more about turnaround times here.
Targeted Testing
For ordering sequencing of targeted known variants, go to our Targeted Variants page.
Clinical Features and Genetics
Clinical Features
Benign familial neonatal-infantile seizures (BFNIS; OMIM:607745) is an infantile onset epilepsy disorder. Sudden onset of seizures occurs between 2 days to 13 months, with median onset being 2-3 months (Herlenius et al. 2007). BFNIS presents as clusters of afebrile seizures with 2-20 per day. Seizures are brief, lasting 10-180 seconds and begin with eye rolling or blinking and then progress to tonic or clonic movements (Herlenius et al. 2007). EEG recording reveals that seizures have a focal onset and then secondarily generalize. Rarely do BFNIS patients experience seizures outside of the infantile period. Intellectual ability or motor skills are not impaired in BFNIS patients.
Early infantile epileptic encephalopathy (EIEE; OMIM:613721) encompasses a range of infantile onset seizure disorders which often impair cognitive and motor development. Mutations in SCN2A have been implicated in both Dravet and Ohtahara syndromes, two EIEEs with well characterized clinical phenotypes. Dravet syndrome (DS) presents as seizures within the first year of life in children with previously normal psychomotor development. DS is characterized by the presence of multiple seizure types within a patient. Early seizures are usually brought on by fever (Akiyama et al. 2012). DS patients suffer severe cognitive and motor impairments that persist throughout their lives. Ohtahara syndrome (OS) presents as tonic spasms within the first three months of life. These seizures are often resistant to treatment with anticonvulsants. OS patients display a characteristic suppression-burst pattern on EEG recordings (Saitsu et al. 2008). OS is highly progressive, resulting in severe cognitive and motor impairments (Ohtahara and Yamatogi 2006).
Autism is a communication disorder that often co-occurs with intellectual disability and epilepsy, suggesting a shared etiology. Several genome-wide sequencing studies of patients with an Autism Spectrum Disorder have revealed de novo nonsense and splice site mutations in the SCN2A gene (Jiang et al. 2013; Rauch et al. 2012; Sanders et al. 2012).
Genetics
BFNIS is inherited in an autosomal dominant manner and is caused by missense mutations in the SCN2A gene (Berkovic et al. 2004). Ohtahara syndrome, Dravet syndrome and other SCN2A-related epileptic encephalopathies can be inherited in an autosomal dominant manner but more often occur as sporadic cases resulting from de novo mutations in the SCN2A gene (Ogiwara et al. 2009; Nakamura et al. 2013).
SCN2A encodes a neuronally expressed alpha subunit of the voltage-gated sodium channel. Sodium channels are excitatory and propagate action potentials in neurons. Epilepsy disorders are characterized by hyperexcitability of neurons and improper neuronal firing. Missense mutations in SCN2A found in BFNIS have been shown to mildly impair sodium channel function whereas missense mutations seen in epileptic encephalopathy cases more strongly impair channel function (Shi et al. 2012). This suggests that loss of SCN2A activity underlies the epilepsy phenotype.
Clinical Sensitivity - Sequencing with CNV PG-Select
Inherited SCN2A mutations were found in 6 of 11 families (~54%) diagnosed with BFNIS (Berkovic et al. 2004). Pathogenic de novo variants in SCN2A were identified in 13.4% (9 of 67) of patients with Ohathara syndrome and in whom no variants in STXBP1 and KCNQ2 were identified (Nakamura et al. 2013).
Testing Strategy
This test provides full coverage of all coding exons of the SCN2A gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.
Indications for Test
SCN2A testing should be considered for patients with symptoms of BFNIS and family history consistent with autosomal dominant inheritance. SCN2A sequencing should also be considered in cases of early infantile epileptic encephalopathy, particularly in STXBP1 or KCNQ2 -negative cases of Ohtahara syndrome or SCN1A -negative cases of Dravet syndrome (Nakamura et al. 2013).
SCN2A testing should be considered for patients with symptoms of BFNIS and family history consistent with autosomal dominant inheritance. SCN2A sequencing should also be considered in cases of early infantile epileptic encephalopathy, particularly in STXBP1 or KCNQ2 -negative cases of Ohtahara syndrome or SCN1A -negative cases of Dravet syndrome (Nakamura et al. 2013).
Gene
| Official Gene Symbol | OMIM ID |
|---|---|
| SCN2A | 182390 |
| Inheritance | Abbreviation |
|---|---|
| Autosomal Dominant | AD |
| Autosomal Recessive | AR |
| X-Linked | XL |
| Mitochondrial | MT |
Diseases
| Name | Inheritance | OMIM ID |
|---|---|---|
| Benign Familial Neonatal-Infantile Seizures | AD | 607745 |
| Epileptic Encephalopathy, Early Infantile, 11 | AD | 613721 |
Citations
- Akiyama M. et al. 2012. Acta Medica Okayama. 66: 369-76. PubMed ID: 23093055
- Berkovic SF, Heron SE, Giordano L, Marini C, Guerrini R, Kaplan RE, Gambardella A, Steinlein OK, Grinton BE, Dean JT, Bordo L, Hodgson BL, et al. 2004. Benign familial neonatal-infantile seizures: Characterization of a new sodium channelopathy. Annals of Neurology 55: 550–557. PubMed ID: 15048894
- Herlenius E, Heron SE, Grinton BE, Keay D, Scheffer IE, Mulley JC, Berkovic SF. 2007. SCN2A Mutations and Benign Familial Neonatal-Infantile Seizures: The Phenotypic Spectrum. Epilepsia 48: 1138–1142. PubMed ID: 17386050
- Jiang Y, Yuen RKC, Jin X, Wang M, Chen N, Wu X, Ju J, Mei J, Shi Y, He M, Wang G, Liang J, et al. 2013. Detection of Clinically Relevant Genetic Variants in Autism Spectrum Disorder by Whole-Genome Sequencing. The American Journal of Human Genetics 93: 249–263. PubMed ID: 23849776
- Nakamura K et al. 2013. Neurology. 81: 992-8. PubMed ID: 23935176
- Ogiwara I, Ito K, Sawaishi Y, Osaka H, Mazaki E, Inoue I, Montal M, Hashikawa T, Shike T, Fujiwara T, Inoue Y, Kaneda M, et al. 2009. De novo mutations of voltage-gated sodium channel II gene SCN2A in intractable epilepsies. Neurology 73: 1046–1053. PubMed ID: 19786696
- Ohtahara S, Yamatogi Y. 2006. Epilepsy Research. 70 Suppl 1: S58-67. PubMed ID: 16829045
- Rauch A, Wieczorek D, Graf E, Wieland T, Endele S, Schwarzmayr T, Albrecht B, Bartholdi D, Beygo J, Donato N Di. 2012. Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study. The Lancet. PubMed ID: 23020937
- Saitsu H, Kato M, Mizuguchi T, Hamada K, Osaka H, Tohyama J, Uruno K, Kumada S, Nishiyama K, Nishimura A, Okada I, Yoshimura Y, Hirai S, Kumada T, Hayasaka K, Fukuda A, Ogata K, Matsumoto N. 2008. De novo mutations in the gene encoding STXBP1 (MUNC18-1) cause early infantile epileptic encephalopathy. Nat Genet 40:782-788. PubMed ID: 18469812
- Sanders SJ, Murtha MT, Gupta AR, Murdoch JD, Raubeson MJ, Willsey AJ, Ercan-Sencicek AG, DiLullo NM, Parikshak NN, Stein JL, Walker MF, Ober GT, et al. 2012. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature 485: 237–241. PubMed ID: 22495306
- Shi X, Yasumoto S, Kurahashi H, Nakagawa E, Fukasawa T, Uchiya S, Hirose S. 2012. Clinical spectrum of SCN2A mutations. Brain and Development 34: 541–545. PubMed ID: 22029951
Ordering/Specimens
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Specimen Types
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