CASK Related Disorders, Microcephaly with Pontine and Cerebellar Hypoplasia, X-linked intellectual disability with or without Nystagmus and FG Syndrome Type 4 via the CASK 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
4541 CASK 81479 81479,81479 $640 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
4541CASK81479 81479 $640 Order Options and Pricing

Pricing Comments

This test is also offered via our exome backbone with CNV detection (click here). The exome-based test may be higher priced, but permits reflex to the entire exome or to any other set of clinically relevant genes.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

Turnaround Time

18 days on average for standard orders or 14 days on average for STAT orders.

Once a specimen has started the testing process in our lab, the most accurate prediction of TAT will be displayed in the myPrevent portal as an Estimated Report Date (ERD) range. We calculate the ERD for each specimen as testing progresses; therefore the ERD range may differ from our published average TAT. View 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

Clinical Features and Genetics

Clinical Features

CASK related disorders include Microcephaly with Pontine and Cerebellar Hypoplasia (MICPCH), X-linked intellectual disability (XLID) with or without Nystagmus and FG syndrome type 4.

Microcephaly with Pontine and Cerebellar Hypoplasia (MICPCH):

Female with MICPCH: The manifestations are typically moderate to severe intellectual disability, absent language, progressive microcephaly with or without ophthalmologic anomalies, sensorineural hearing loss, axial hypotonia, hypertonia/spasticity of the extremities, and dystonia. Seizures are also common. Other behavior changes include sleep disturbances, hand stereotypies, and self-biting. MRI findings reveal pontine and cerebellar hypoplasia with diffuse mild to severe hypoplasia of the cerebellum (Najm et al. 2008; Burglen et al. 2012)

Males with MICPCH: The phenotype spectrum includes intellectual disability, postnatal microcephaly, hypotonia, profound developmental delay, and early-infantile epileptic encephalopathy. MRI findings reveal mild to severe pontocerebellar hypoplasia (Najm et al. 2008; Burglen et al. 2012; Saitsu et al. 2012; Moog et al. 2015).

X-linked intellectual disability (XLID) with or without Nystagmus:

Most affected cases are males with mild to severe X-linked intellectual disability (XLID) with or without nystagmus and additional ocular features, tremor, unsteady gait, and seizures. MRI findings show variable cerebellar hypoplasia (Takanashi et al. 2010; Moog et al. 2015).

Females are typically normal and only a few present mild intellectual disability with or without ocular features.

FG syndrome type 4:

FG syndrome was named using the initials of the first patients. FG syndrome type 4 is a syndromic X-linked intellectual disability disorder characterized by congenital hypotonia, constipation, behavioral disturbances, and dysmorphic features (Piluso et al. 2009).

Genetics

Microcephaly with Pontine and Cerebellar Hypoplasia (MICPCH) is generally caused by loss-of-function CASK pathogenic variants. It can be inherited in an X-linked dominant or recessive manner. Most affected females and males are sporadic cases due to a de novo pathogenic variants in CASK. Some loss-of-function variants could be lethal to male embryos.

X-linked intellectual disability (XLID) with or without Nystagmus and FG syndrome type 4 are generally associated with CASK pathogenic variants which cause partial loss of gene function. They are inherited in an X-linked recessive manner (Najm et al. 2008; Hackett et al. 2010; Burglen et al. 2012; Saitsu et al. 2012; Moog et al. 2015).

The CASK gene encodes a calcium/calmodulin-dependent serine protein kinase that is a member of the membrane-associated guanylate kinase (MAGUK) protein family. It has been proposed that CASK functions as a scaffolding protein that links signaling molecules, receptors, and other scaffolding proteins at intercellular and synaptic junctions, and also plays a role in regulation of postnatal brain growth (Atasoy et al. 2007; Srivastava et al. 2016). Pathogenic variants in CASK include frameshift, nonsense, splice site, and missense, as well as large deletions/duplications and inversions in the CASK locus (Human Gene Mutation Database; Moog et al. 2015). Somatic mosaicism and incomplete penetrance have also been reported (Moog et al. 2015).

Clinical Sensitivity - Sequencing with CNV PG-Select

Clinical sensitivity of CASK in a large cohort of patients with Microcephaly with Pontine and Cerebellar Hypoplasia (MICPCH), X-linked intellectual disability (XLID) with or without Nystagmus and FG syndrome type 4 relevant phenotypes is unavailable from the literature, because most studies are small or case reports.

Approximately 27% of cases of CASK related disorders in males are due to copy number variations (CNVs) on the X chromosome (Moog et al. 2015). The percentage may be even higher in females, and it is recommended that females have deletion/duplication testing first (Moog et al. 2013).

Testing Strategy

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

Indications for Test

CASK sequencing is recommended for patients suspected to have Microcephaly with Pontine and Cerebellar Hypoplasia, X-linked intellectual disability with or without Nystagmus and FG syndrome type 4.

Gene

Official Gene Symbol OMIM ID
CASK 300172
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Test

Name
Opitz G/BBB Syndrome Panel

Citations

  • Atasoy D. et al. 2007. Proceedings of the National Academy of Sciences of the United States of America. 104: 2525-30. PubMed ID: 17287346
  • Burglen L. et al. 2012. Orphanet Journal of Rare Diseases. 7: 18. PubMed ID: 22452838
  • Hackett A. et al. 2010. European Journal of Human Genetics. 18: 544-52. PubMed ID: 20029458
  • Human Gene Mutation Database (Bio-base).
  • Moog U. et al. 2013. CASK-Related Disorders. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong C-T, Smith RJ, and Stephens K, editors. GeneReviews™, Seattle (WA): University of Washington, Seattle. PubMed ID: 24278995
  • Moog U. et al. 2015. Orphanet Journal of Rare Diseases. 10: 44. PubMed ID: 25886057
  • Najm J. et al. 2008. Nature Genetics. 40: 1065-7. PubMed ID: 19165920
  • Piluso G. et al. 2009. American Journal of Human Genetics. 84: 162-77. PubMed ID: 19200522
  • Saitsu H. et al. 2012. Epilepsia. 53: 1441-9. PubMed ID: 22709267
  • Srivastava S. et al. 2016. Acta Neuropathologica Communications. 4: 30. PubMed ID: 27036546
  • Takanashi J. et al. 2010. Ajnr. American Journal of Neuroradiology. 31: 1619-22. PubMed ID: 20595373

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.

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


Specimen Types

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