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Generalized Epilepsy with Febrile Seizures Plus and Dravet syndrome via the SCN1B Gene

  • Summary and Pricing
  • Clinical Features and Genetics
  • Citations
  • Methods
  • Ordering/Specimens
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TEST METHODS

Sequencing

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
634 SCN1B$680.00 81404 Add to Order
Targeted Testing

For ordering targeted known variants, please proceed to our Targeted Variants landing page.

Turnaround Time

The great majority of tests are completed within 18 days.

Clinical Sensitivity

SCN1B mutations are found in 1-2% of patients with idiopathic childhood epilepsies and ~4% of cases where febrile seizures are a key clinical feature (Orrico et al. Clin Genet 75(6):579-581; Scheffer et al. Brain 130(Pt 1):100-109, 2007).

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Deletion/Duplication Testing via aCGH

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
600 SCN1B$690.00 81479 Add to Order
Pricing Comment

# of Genes Ordered

Total Price

1

$690

2

$730

3

$770

4-10

$840

11-30

$1,290

31-100

$1,670

Over 100

Call for quote

Turnaround Time

The great majority of tests are completed within 28 days.

Clinical Sensitivity

Thus far, no gross deletions or duplications have been reported in SCN1B (Human Gene Mutation Database).

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Clinical Features

Generalized epilepsy with febrile seizures plus (GEFS+; OMIM:604233) is a familial epilepsy syndrome characterized by  febrile seizures. GEFS+ patients usually present with fever induced seizures between the ages of 6 months and 6 years. 'Plus' refers to the persistence of seizures into adolescence when patients may also experience myoclonic, absence or focal seizures. Patients with GEFS+ usually have at least two family members with GEFS+ spectrum phenotypes and seizure-type heterogeneity is typical among family members (Scheffer et al. Brain Dev 31(5):394-400, 2009).

Dravet syndrome (DS; OMIM: 607208) is one of a group of early infantile epileptic encephalopathies (EIEE). DS is characterized by the onset of seizures within the first year of life in children with previously normal psychomotor development. Early seizures can be clonic or clonic-tonic and are usually brought on by fever. DS is characterized by the presence of multiple seizure types within a patient, including: myoclonic jerks, absence seizures, focal seizures, photosensitive seizures and prolonged seizures resulting in status epilepticus (Akiyama et al. Acta Med. Okayama 66(5):369-376, 2012). Seizures observed in DS are resistant to treatment with anti-epileptic drugs. DS patients suffer severe cognitive and motor impairments that persist throughout their lives.

Genetics

GEFS+ is inherited in an autosomal dominant manner with incomplete penetrance. Mutations in SCN1B have been identified in a small percent of GEFS+ families and show ~63% penetrance (Audenaert et al. Neurology 61(6):854-856, 2003). GEFS+ cases can also be sporadic with no family history.

Recessive mutations in SCN1B have also been reported in rare cases of Dravet syndrome (Patino et al. J Neurosci 29(34):10764-10778, 2009; Ogiwara et al. Epilepsia. 53(12):e200-e203, 2012).

SCN1B encodes a beta subunit of the voltage-gated sodium channel. SCN1B has been shown to modulate the excitability of sodium channels, mediate cell-cell adhesions and direct neurite outgrowth- all of which may contribute to the epilepsy phenotypes associated with SCN1B mutations (Patino et al., 2009).

Testing Strategy

Testing involves PCR amplification from genomic DNA and bidirectional Sanger sequencing of the coding exons and ~20bp of adjacent noncoding sequences. This testing strategy will reveal coding sequence changes, splice site mutations and small insertions or deletions in the SCN1B gene, but will not detect large deletions, insertions or rearrangements in the SCN1B locus. We will also sequence any single exon (Test#100) or pair of exons (Test#200) in family members of patients with a known mutation or to help confirm research results.

Indications for Test

Candidates for SCN1B sequencing include patients with symptoms of GEFS+ with at least two family members affected with GEFS+-spectrum disorders. SCN1B should also be considered for patients who display clinical features of Dravet syndrome, but for which no SCN1A mutation was identified. Normal development prior to seizure onset and seizures that are sensitive to elevated body temperature are two symptoms which are strong indicators for SCN1A and SCN1B testing  (Fountain-Capal et al. Pediatr Neurol 45(5):319-323, 2011).

Gene

Official Gene Symbol OMIM ID
SCN1B 600235
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Tests

Name
Brugada Syndrome Sequencing Panel
Brugada Syndrome via the SCN1B Gene
Epilepsy: Dravet Syndrome Sequencing Panel
Epilepsy: Generalized Epilepsy with Febrile Seizures Plus (GEFS+) Sequencing Panel
Familial Atrial Fibrillation Syndrome Sequencing Panel

CONTACTS

Genetic Counselors
Geneticist
Citations
  • Akiyama M. et al. 2012. Acta Medica Okayama. 66: 369-76. PubMed ID: 23093055
  • Audenaert D et al. 2003. Neurology. 61: 854-6. PubMed ID: 14504340
  • Fountain-Capal JK, Holland KD, Gilbert DL, Hallinan BE. 2011. When Should Clinicians Order Genetic Testing for Dravet Syndrome? Pediatric Neurology 45: 319–323. PubMed ID: 22000312
  • Human Gene Mutation Database (Bio-base).
  • Ogiwara I. et al. 2012. Epilepsia 53: e200–e203. PubMed ID: 23148524
  • Orrico A. et al. 2009. Clinical Genetics. 75: 579-81. PubMed ID: 19522081
  • Patino GA et al. 2009. The Journal of Neuroscience : the Official Journal of the Society For Neuroscience. 29: 10764-78. PubMed ID: 19710327
  • Scheffer IE et al. 2007. Brain : a Journal of Neurology. 130: 100-9. PubMed ID: 17020904
  • Scheffer IE. et al. 2009. Brain and Development 31: 394–400. PubMed ID: 19203856
Order Kits
TEST METHODS

Bi-Directional Sanger Sequencing

Test Procedure

Nomenclature for sequence variants was from the Human Genome Variation Society (http://www.hgvs.org).  As required, DNA is extracted from the patient specimen.  PCR is used to amplify the indicated exons plus additional flanking non-coding sequence.  After cleaning of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit.  Products are resolved by electrophoresis on an ABI 3730xl capillary sequencer.  In most cases, sequencing is performed in both forward and reverse directions; in some cases, sequencing is performed twice in either the forward or reverse directions.  In nearly all cases, the full coding region of each exon as well as 20 bases of non-coding DNA flanking the exon are sequenced.

Analytical Validity

As of March 2016, we compared 17.37 Mb of Sanger DNA sequence generated at PreventionGenetics to NextGen sequence generated in other labs. We detected only 4 errors in our Sanger sequences, and these were all due to allele dropout during PCR. For Proficiency Testing, both external and internal, in the 12 years of our lab operation we have Sanger sequenced roughly 8,800 PCR amplicons. Only one error has been identified, and this was due to sequence analysis error.

Our Sanger sequencing is capable of detecting virtually all nucleotide substitutions within the PCR amplicons. Similarly, we detect essentially all heterozygous or homozygous deletions within the amplicons. Homozygous deletions which overlap one or more PCR primer annealing sites are detectable as PCR failure. Heterozygous deletions which overlap one or more PCR primer annealing sites are usually not detected (see Analytical Limitations). All heterozygous insertions within the amplicons up to about 100 nucleotides in length appear to be detectable. Larger heterozygous insertions may not be detected. All homozygous insertions within the amplicons up to about 300 nucleotides in length appear to be detectable. Larger homozygous insertions may masquerade as homozygous deletions (PCR failure).

Analytical Limitations

In exons where our sequencing did not reveal any variation between the two alleles, we cannot be certain that we were able to PCR amplify both of the patient’s alleles. Occasionally, a patient may carry an allele which does not amplify, due for example to a deletion or a large insertion. In these cases, the report contains no information about the second allele.

Similarly, our sequencing tests have almost no power to detect duplications, triplications, etc. of the gene sequences.

In most cases, only the indicated exons and roughly 20 bp of flanking non-coding sequence on each side are analyzed. Test reports contain little or no information about other portions of the gene, including many regulatory regions.

In nearly all cases, we are unable to determine the phase of sequence variants. In particular, when we find two likely causative mutations for recessive disorders, we cannot be certain that the mutations are on different alleles.

Our ability to detect minor sequence variants, due for example to somatic mosaicism is limited. Sequence variants that are present in less than 50% of the patient’s nucleated cells may not be detected.

Runs of mononucleotide repeats (eg (A)n or (T)n) with n >8 in the reference sequence are generally not analyzed because of strand slippage during PCR and cycle sequencing.

Unless otherwise indicated, the sequence data that we report are based on DNA isolated from a specific tissue (usually leukocytes). Test reports contain no information about gene sequences in other tissues.

Deletion/Duplication Testing Via Array Comparative Genomic Hybridization

Test Procedure

Equal amounts of genomic DNA from the patient and a gender matched reference sample are amplified and labeled with Cy3 and Cy5 dyes, respectively. To prevent any sample cross contamination, a unique sample tracking control is added into each patient sample. Each labeled patient product is then purified, quantified, and combined with the same amount of reference product. The combined sample is loaded onto the designed array and hybridized for at least 22-42 hours at 65°C. Arrays are then washed and scanned immediately with 2.5 µM resolution. Only data for the gene(s) of interest for each patient are extracted and analyzed.

Analytical Validity

PreventionGenetics' high density gene-centric custom designed aCGH enables the detection of relatively small deletions and duplications within a single exon of a given gene or deletions and duplications encompassing the entire gene. PreventionGenetics has established and verified this test's accuracy and precision.

Analytical Limitations

Our dense probe coverage may allow detection of deletions/duplications down to 100 bp; however due to limitations and probe spacing this cannot be guaranteed across all exons of all genes. Therefore, some copy number changes smaller than 100-300 bp within a targeted large exon may not be detected by our array.

This array may not detect deletions and duplications present at low levels of mosaicism or those present in genes that have pseudogene copies or repeats elsewhere in the genome.

aCGH will not detect balanced translocations, inversions, or point mutations that may be responsible for the clinical phenotype.

Breakpoints, if occurring outside the targeted gene, may be hard to define.

The sensitivity of this assay may be reduced when DNA is extracted by an outside laboratory.

Order Kits

Ordering Options


myPrevent - Online Ordering
  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.
REQUISITION FORM
  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

SPECIMEN TYPES
WHOLE BLOOD

(Delivery accepted Monday - Saturday)

  • Collect 3 ml -5 ml (5 ml preferred) of whole blood in EDTA (purple top tube) or ACD (yellow top tube). For Test #500-DNA Banking only, collect 10 ml -20 ml of whole blood.
  • For small babies, we require a minimum of 1 ml of blood.
  • Only one blood tube is required for multiple tests.
  • Ship blood tubes at room temperature in an insulated container. Do not freeze blood.
  • During hot weather, include a frozen ice pack in the shipping container. Place a paper towel or other thin material between the ice pack and the blood tube.
  • In cold weather, include an unfrozen ice pack in the shipping container as insulation.
  • At room temperature, blood specimen is stable for up to 48 hours.
  • If refrigerated, blood specimen is stable for up to one week.
  • Label the tube with the patient name, date of birth and/or ID number.

DNA

(Delivery accepted Monday - Saturday)

  • Send in screw cap tube at least 5 µg -10 µg of purified DNA at a concentration of at least 20 µg/ml for NGS and Sanger tests and at least 5 µg of purified DNA at a concentration of at least 100 µg/ml for gene-centric aCGH, MLPA, and CMA tests, minimum 2 µg for limited specimens.
  • For requests requiring more than one test, send an additional 5 µg DNA per test ordered when possible.
  • DNA may be shipped at room temperature.
  • Label the tube with the composition of the solute, DNA concentration as well as the patient’s name, date of birth, and/or ID number.
  • We only accept genomic DNA for testing. We do NOT accept products of whole genome amplification reactions or other amplification reactions.

CELL CULTURE

(Delivery preferred Monday - Thursday)

  • PreventionGenetics should be notified in advance of arrival of a cell culture.
  • Culture and send at least two T25 flasks of confluent cells.
  • Some panels may require additional flasks (dependent on size of genes, amount of Sanger sequencing required, etc.). Multiple test requests may also require additional flasks. Please contact us for details.
  • Send specimens in insulated, shatterproof container overnight.
  • Cell cultures may be shipped at room temperature or refrigerated.
  • Label the flasks with the patient name, date of birth, and/or ID number.
  • We strongly recommend maintaining a local back-up culture. We do not culture cells.
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