CASK-related XLID: CASK Gene Deletion/Duplication

Condition Description

Mutations in the CASK gene (Xp11.4) have been reported to cause X-linked intellectual disability and brain malformation. The original patients characterized had severe intellectual disability, brainstem and cerebellar hypoplasia, and microcephaly. Some of these patients were female, indicating that females may be as severely affected as males.  Other symptoms included hearing loss, optic atrophy, and dysmorphic features.

Later studies identified individuals with CASK mutations who had various combinations of milder intellectual disability, microcephaly, congenital nystagmus, and dysmorphic facial features. Some individuals had nonsyndromic intellectual disability. Carrier females were variably affected, with some phenotypically normal.

An Italian family was identified in which a CASK mutation caused a form of FG syndrome (FG syndrome-4). Affected males displayed severe intellectual disability, aggressive and hyperactive behavior, macrocephaly, dysmorphic features, deafness, and severe constipation. Carrier females had mild intellectual disability and mild dysmorphic features.

In a study of 358 probable XLID families, four male probands were found to have CASK mutations. In a study of 45 probands with intellectual disability and either nystagmus or microcephaly, two individuals were found to have CASK mutation; both had nystagmus and intellectual disability.

The CASK gene codes for the calcium/calmodulin-dependent serine protein kinase. The CASK protein interacts with multiple other proteins and is thought to be involved in synaptic interaction, protein trafficking, and regulation of neural development.

For patients with suspected CASK-Related XLID, sequence analysis is recommended as the first step in mutation identification. For patients in whom mutations are not identified by full gene sequencing, deletion/duplication analysis is appropriate.

  • OMIM #300749: Mental Retardation and Microcephaly with Pontine and Cerebellar Hypoplasia.
  • OMIM #300422: FG Syndrome 4; FGS4.
  • Hackett, A. et al. CASK mutations are frequent in males and cause X-linked nystagmus and variable XLMR phenotypes. European Journal of Human Genetics 2010; 18:544-552.
  • Hsueh, Y. Calcium/calmodulin-dependent serine protein kinase and mental retardation. Annals of Neurology 2009; 66:438-443.

Genes (1)

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This test is indicated for:

  • Confirmation of a clinical diagnosis of CASK-related XLID in individuals who have tested negative for sequence analysis
  • Carrier testing in adult females with a family history of CASK-related XLID in whom sequence analysis was negative.


DNA isolated from peripheral blood is hybridized to a CGH array to detect deletions and duplications. The targeted CGH array has overlapping probes which cover the entire genomic region.


Detection is limited to duplications and deletions. The CGH array will not detect point or intronic mutations.Results of molecular analysis must be interpreted in the context of the patient's clinical and/or biochemical phenotype.

Specimen Requirements

Listed below are EGL's preferred sample criteria. For any questions, please call 470.378.2200 and ask to speak with a laboratory genetic counselor (
Submit only 1 of the following specimen types
DNA, Isolated

Isolation using the Perkin Elmer™Chemagen™ Chemagen™ Automated Extraction method or Qiagen™ Puregene kit for DNA extraction is recommended.
Collection and Shipping
Refrigerate until time of shipment in 100 ng/µL in TE buffer. Ship sample at room temperature with overnight delivery.
Whole Blood (EDTA)

EDTA (Purple Top)
Infants and Young Children (<2 years of age): 2-3 ml
Children > 2 years of age to 10 years old: 3-5 ml
Older Children & Adults: 5-10 ml
Autopsy: 2-3 ml unclotted cord or cardiac blood
Collection and Shipping
Ship sample at room temperature for receipt at EGL within 72 hours of collection. Do not freeze.

Special Instructions

Submit copies of diagnostic biochemical test results with the sample, if appropriate. Contact the laboratory if further information is needed.

Sequence analysis is required before deletion/duplication analysis by targeted CGH array. If sequencing is performed outside of EGL Genetics, please submit a copy of the sequencing report with the test requisition.

  • Sequencing analysis of the CASK gene is available and is required before deletion/duplication analysis.
  • A next-generation sequence analysis panel of 90+ XLID genes is available.
  • A CGH array-based test for deletion/duplication analysis of 90+ XLID genes is available.
  • Prenataltesting is available to individuals who are confirmed carriers ofmutations. Please contact the laboratory genetic counselor to discussappropriate testing prior to collecting a prenatal specimen.

How to Order