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
  • Clinical Features and Genetics
  • Citations
  • Methods
  • Ordering/Specimens
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Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
1826 CASK$1440.00 81479 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

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.

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Deletion/Duplication Testing via aCGH

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
600 CASK$990.00 81479 Add to Order
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Turnaround Time

The great majority of tests are completed within 20 days.

Clinical Sensitivity

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).

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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).


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). 

Testing Strategy

Testing is accomplished by amplifying each coding exon of the CASK gene and ~10 bp of adjacent noncoding sequence, then determining the nucleotide sequence using standard Sanger dideoxy sequencing methods and a capillary electrophoresis instrument. We will also sequence any single exon (Test #100) or pair of exons (Test #200) in family members of patients with known mutations or to confirm research results.

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.


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

Related Test

X-Linked Intellectual Disability Sequencing Panel with CNV Detection


Genetic Counselors
  • 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
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Bi-Directional Sanger Sequencing

Test Procedure

Nomenclature for sequence variants was from the Human Genome Variation Society (  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 10 bases of non-coding DNA flanking the exon are sequenced.

Analytical Validity

As of February 2018, we compared 26.8 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 14 years of our lab operation we have Sanger sequenced roughly 14,300 PCR amplicons. Only one error has been identified, and this was an error in analysis of sequence data.

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 10 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.

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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.
  • 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.


(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.


(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.


(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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