EPILEPSY
SCN1A GENE MUTATION ANALYSIS
GENERALIZED EPILEPSY WITH FEBRILE SEIZURES PLUS; GEFS+

DESCRIPTION - DNA Scanning and Sequencing

The SCN1A gene codes for the alpha subunit of a neuronal voltage-gated sodium channel and is located on chromosome 2q containing 26 exons. Mutations in SCN1A are the cause of generalized epilepsy with febrile seizures in children and afebrile seizures in adults plus type 2 (GEFS+2). Penetrance is incomplete and a large intrafamilial variability of the phenotype is observed. Missense mutations in this gene have been recently reported in families with severe myoclonic epilepsy of infancy (SMEI). Early manifestations of the disease are tonic, clonic, and tonic-clonic seizures that occur within the first year of life. These seizures are often prolonged, generalized, and associated with fever. Later in life, patients with SMEI have afebrile seizures, including myoclonic, tonic-clonic, absence, and simple and complex partial seizures. Early psychomotor and speech development is normal, but developmental stagnation occurs by the second year. Defects in SCN1A are also the cause of familial hemiplegic migraine 3 (FHM3). FHM3 is an autosomal dominant severe subtype of migraine with aura characterized by some degree of hemiparesis during attacks. The episodes are associated with variable features of nausea, vomiting, photophobia and phonophobia. Age at onset ranges from 6 to 15 years. Defects in SCN1A are the cause of familial febrile convulsions 3 (FEB3) also known as familial febrile seizures 3. Febrile convulsions affect 5-12% of infants and children up to 6 years of age.

Test Order Code SCN1A

CPT Codes

83891 x 1, 83898 x 29, 83903 x 29, 83904 x 20, 83912 x 1
Indications For Testing

An individual that presents clinical features characteristic of GEFS +2 or SMEI. This test should be offered in the context of genetic counseling prior to and after test completion.

  • Confirmation of a clinical diagnosis

  • Assistance with a clinical diagnosis

  • Genetic counseling

Turn Around Time

 Up to 4 weeks. Expedited analysis is available upon request for an additional charge.
Specimen Requirements

Peripheral Blood
All peripheral blood collections require Purple/Lavender-top (EDTA) vaccutainer tubes.

  • Adults: 1 tube with 7.5 mLwhole blood

  • Children & Infants: 1 tube of  5-6 mL whole blood

  • Keep samples at ambient temperature and ship by overnight courier to arrive at the Molecular Laboratory within 24 hrs after collection of the specimen. If shipment is delayed by one or two days, the specimen should be refrigerated and shipped at room temperature.
Specimen Kits DNA Specimen Collection Kits can be obtained from Transgenomic Molecular Laboratory.
Shipping and Contact Information Transgenomic Molecular Laboratory
12325 Emmet Street Omaha, NE 68164 USA
Phone: (866) 500-GENE / (866) 500-4363 Fax: (402) 452-5447
E-mail: labservice@transgenomiclabs.com
Test Submission  and Patient Consent Forms

Due to the unique nature of genetic testing, patients should receive pre-test and post-test counseling. Informed consent is recommended.

Test Methodology Scanning and sequence analysis of the entire coding region.
Sensitivity Mutation scanning by DHPLC and SURVEYOR Nuclease combined with DNA sequencing has an analytical sensitivity of > 99.5% for the detection of point mutations.
Limitations

The method will not detect mutations located in regions of the genes that are not analyzed (non-coding exon sequences, intron sequences other than the splice junctions, and upstream and downstream sequences). The method also will not detect gross genetic alterations including most large deletions, duplications, and inversions. Some sequence alterations detected by this assay will be of unknown clinical relevance. Interpretation of test results should be in the context of the patient’s clinical history and other laboratory test results.

References

1. Baulac, S.; Gourfinkel-An, I.; Picard, F.; Rosenberg-Bourgin, M.; Prud'homme, J.-F.; Baulac, M.; Brice, A.; LeGuern, E. : A second locus for familial generalized epilepsy with febrile seizures plus maps to chromosome 2q21-q33. Am. J. Hum. Genet. 65: 1078-1085, 1999. PubMed ID : 10486327
2. Baulac, S.; Huberfeld, G.; Gourfinkel-An, I.; Mitropoulou, G.; Beranger, A.; Prud'homme, J.-F.; Baulac, M.; Brice, A.; Bruzzone, R.; LeGuern, E. : First genetic evidence of GABA(A) receptor dysfunction in epilepsy: a mutation in the gamma-2-subunit gene. Nature Genet. 28: 46-48, 2001. PubMed ID : 11326274
3. Dibbens, L. M.; Feng, H.-J.; Richards, M. C.; Harkin, L. A.; Hodgson, B. L.; Scott, D.; Jenkins, M.; Petrou, S.; Sutherland, G. R.; Scheffer, I. E.; Berkovic, S. F.; Macdonald, R. L.; Mulley, J. C. : GABRD encoding a protein for extra- or peri-synaptic GABA-A receptors is a susceptibility locus for generalized epilepsies. Hum. Molec. Genet. 13: 1315-1319, 2004. PubMed ID : 15115768
4. Escayg, A.; MacDonald, B. T.; Meisler, M. H.; Baulac, S.; Huberfeld, G.; An-Gourfinkel, I.; Brice, A.; LeGuern, E.; Moulard, B.; Chaigne, D.; Buresi, C.; Malafosse, A. : Mutations of SCN1A, encoding a neuronal sodium channel, in two families with GEFS+2. (Letter) Nature Genet. 24: 343-345, 2000. PubMed ID : 10742094
5. Moulard, B.; Guipponi, M.; Chaigne, D.; Mouthon, D.; Buresi, C.; Malafosse, A. : Identification of a new locus for generalized epilepsy with febrile seizures plus (GEFS+) on chromosome 2q24-q33. Am. J. Hum. Genet. 65: 1396-1400, 1999. PubMed ID : 10521305
6. Scheffer, I. E.; Berkovic, S. F. : Generalized epilepsy with febrile seizures plus: a genetic disorder with heterogeneous clinical phenotypes. Brain 120: 479-490, 1997. PubMed ID : 9126059
7. Singh, R.; Scheffer, I. E.; Crossland, K.; Berkovic, S. F. : Generalized epilepsy with febrile seizures plus: a common childhood-onset genetic epilepsy syndrome. Ann. Neurol. 45: 75-81, 1999. PubMed ID : 9894880
8. Sugawara, T.; Mazaki-Miyazaki, E.; Ito, M.; Nagafuji, H.; Fukuma, G.; Mitsudome, A.; Wada, K.; Kaneko, S.; Hirose, S.; Yamakawa, K. : Na-v-1.1 mutations cause febrile seizures associated with afebrile partial seizures. Neurology 57: 703-705, 2001. PubMed ID : 11524484
9. Sugawara, T.; Tsurubuchi, Y.; Agarwala, K. L.; Ito, M.; Fukuma, G.; Mazaki-Miyazaki, E.; Nagafuji, H.; Noda, M.; Imoto, K.; Wada, K.; Mitsudome, A.; Kaneko, S.; Montal, M.; Nagata, K.; Hirose, S.; Yamakawa, K. : A missense mutation of the Na+ channel alpha-II subunit gene Na(v)1.2 in a patient with febrile and afebrile seizures causes channel dysfunction. Proc. Nat. Acad. Sci. 98: 6384-6389, 2001. Note: Erratum: Proc. Nat. Acad. Sci. 98: 10515 only, 2001. PubMed ID : 11371648
10. Wallace, R. H.; Wang, D. W.; Singh, R.; Scheffer, I. E.; George, A. L., Jr.; Phillips, H. A.; Saar, K.; Reis, A.; Johnson, E. W.; Sutherland, G. R.; Berkovic, S. F.; Mulley, J. C. : Febrile seizures and generalized epilepsy associated with a mutation in the Na(+)-channel beta-1 subunit gene SCN1B. Nature Genet. 19: 366-370, 1998. PubMed ID : 9697698

OMIM Entries for:

SCN1A - GENERALIZED EPILEPSY WITH FEBRILE SEIZURES PLUS; GEFS+

604233 GENERALIZED EPILEPSY WITH FEBRILE SEIZURES PLUS; GEFS+ GENERALIZED EPILEPSY WITH FEBRILE SEIZURES PLUS, TYPE 1, INCLUDED
607208 SEVERE MYOCLONIC EPILEPSY OF INFANCY; SMEI EPILEPSY, INTRACTABLE CHILDHOOD, WITH GENERALIZED TONIC-CLONIC SEIZURES, INCLUDED; ICEGTC, INCLUDED
609634  MIGRAINE, FAMILIAL HEMIPLEGIC, 3; FHM3
604403  FEBRILE CONVULSIONS, FAMILIAL, 3; FEB3

Note: The performance characteristics of this test were validated by TRANSGENOMIC Molecular Laboratory. The U.S. Food and Drug Administration (FDA) has not approved this test. However, FDA approval is currently not required for clinical use of this test. The results are not intended to be used as the sole means for clinical diagnosis or patient management decisions. TRANSGENOMIC Molecular Laboratory is authorized under Clinical Laboratory Improvement Amendments (CLIA) to perform high-complexity testing.