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Malignant Migrating Partial Seizures of Infancy and Autosomal Dominant Nocturnal Frontal Lobe Epilepsy via the KCNT1 Gene

Summary and Pricing

Test Method

Sequencing and CNV Detection via NextGen Sequencing using PG-Select Capture Probes
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
KCNT1 81479 81479,81479 $990
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
3111KCNT181479 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.

EMAIL CONTACTS

Genetic Counselors

Geneticist

  • Eric Bend, PhD

Clinical Features and Genetics

Clinical Features

Malignant migrating partial seizures of infancy (MMPSI) is a type of early epileptic encephalopathy (EIEE14) characterized by seizure onset in developmentally normal infants within the first 6 months of life. Infants present with focal motor seizures which move between hemispheres during the same ictal event; these seizures commonly affect the eyes and limbs (Barcia et al. 2012). Interictal EEG recordings show multi-focal spikes whereas ictal EEG shows shifting foci of ictal onset. MMPSI patients develop multiple seizure types as they age including: tonic, clonic, myoclonic and infantile spasms (McTague et al. 2013). Other features of MMPSI include acquired microcephaly, hypotonia, motor impairment, profound intellectual disability and delayed myelination. Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE-5) is a focal epilepsy disorder characterized by seizures that occur during non-REM sleep. Seizures in ADNFLE patients can present as repetitive limb movements, dystonic posturing or sleep walking (Kurahashi and Hirose 2012). Frontal origin of ADNFLE seizures is revealed by ictal EEG recordings; interictal EEGs are normal. ADNFLE is not generally associated with cognitive deficits, however mutations in the KCNT1 gene result in a more severe form of ADNFLE that includes intellectual disability (Heron et al. 2012). It can be difficult to clinically distinguish ADNFLE from other non-epileptic paroxysmal sleep disorders, therefore a video-polysomnography recording brain/eye/muscle activity during sleep is considered essential for diagnosis.

Genetics

Dominant missense mutations in the KCNT1 gene can cause either MMPSI or ADNFLE. Reported MMPSI cases are sporadic and result from de novo missense mutations in the KCNT1 gene (Barcia et al. 2012; Ishii et al. 2013). ADNFLE can also be caused by missense mutations in the KCNT1 gene and is inherited in an autosomal dominant manner. A sporadic NFLE case resulting from a de novo mutation in KCNT1 has also been reported (Heron et al. 2012). KCNT1 variants result in a more severe ADNFLE phenotype and have a higher genetic penetrance (nearly 100%) than other genetic causes of ADNFLE (CHRNA4, CHRNB2). KCNT1 encodes a subunit of the sodium-activated potassium channel. KCNT1 is highly expressed in the brain and is present in neurons of the frontal cortex (Heron et al. 2012). KCNT1 binds the protein KCNT2 to form a heterotetrameric ion channel. Most reported pathogenic KCNT1 variants are contained within the intracellular C-terminal domain and are believed to alter channel activity or impair signal transduction (Barcia et al. 2012).

Clinical Sensitivity - Sequencing with CNV PG-Select

KCNT1 is believed to be a significant cause of MMPSI. Studies have identified pathogenic KCNT1 variants in 14% (2 of 14) and 50% (6 of 12) of patients with sporadic MMPSI (McTague et al. 2013; Barcia et al. 2012). Pathogenic variants in KCNT1 were identified in 2.8% (3 of 108) of patients with ADNFLE or sporadic NFLE (Heron et al. 2012).

Testing Strategy

This test provides full coverage of all coding exons of the KCNT1 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.

Indications for Test

Candidates for KCNT1 testing include patients with infantile onset focal seizures and delayed myelination (Barcia et al. 2012). KCNT1 sequencing should also be considered for ADNFLE or sporadic NFLE cases, particularly cases in which patients also present with intellectual disability (Heron et al. 2012).

Gene

Official Gene Symbol OMIM ID
KCNT1 608167
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Citations

  • Barcia G, Fleming MR, Deligniere A, Gazula V-R, Brown MR, Langouet M, Chen H, Kronengold J, Abhyankar A, Cilio R, Nitschke P, Kaminska A, et al. 2012. De novo gain-of-function KCNT1 channel mutations cause malignant migrating partial seizures of infancy. Nature Genetics 44: 12551259. PubMed ID: 23086397
  • Heron SE, Smith KR, Bahlo M, Nobili L, Kahana E, Licchetta L, Oliver KL, Mazarib A, Afawi Z, Korczyn A, Plazzi G, Petrou S, et al. 2012. Missense mutations in the sodium-gated potassium channel gene KCNT1 cause severe autosomal dominant nocturnal frontal lobe epilepsy. Nature Genetics 44: 11881190. PubMed ID: 23086396
  • Ishii A, Shioda M, Okumura A, Kidokoro H, Sakauchi M, Shimada S, Shimizu T, Osawa M, Hirose S, Yamamoto T. 2013. A recurrent KCNT1 mutation in two sporadic cases with malignant migrating partial seizures in infancy. Gene 531: 467471. PubMed ID: 24029078
  • Kurahashi H, Hirose S. 2012. Autosomal Dominant Nocturnal Frontal Lobe Epilepsy. In: Pagon RA, Adam MP, Ardinger HH, Bird TD, Dolan CR, Fong C-T, Smith RJ, and Stephens K, editors. GeneReviews(), Seattle (WA): University of Washington, Seattle. PubMed ID: 20301348
  • McTague A, Appleton R, Avula S, Cross JH, King MD, Jacques TS, Bhate S, Cronin A, Curran A, Desurkar A, Farrell MA, Hughes E, et al. 2013. Migrating partial seizures of infancy: expansion of the electroclinical, radiological and pathological disease spectrum. Brain 136: 15781591. PubMed ID: 23599387

Ordering/Specimens

Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

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.
  • PGnome sequencing panels can be ordered via the myPrevent portal only at this time.

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.

For Requisition Forms, visit our Forms page

If ordering a Duo or Trio test, the proband and all comparator samples are required to initiate testing. If we do not receive all required samples for the test ordered within 21 days, we will convert the order to the most effective testing strategy with the samples available. Prior authorization and/or billing in place may be impacted by a change in test code.


Specimen Types

Specimen Requirements and Shipping Details

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Note: acceptable specimen types are whole blood and DNA from whole blood only.
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