Test Code: 3659

CASK-related XLID: CASK Gene Sequencing
Test Code: 3659
Turnaround time: 5 weeks


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.


This test is indicated for:

  • Confirmation of a clinical diagnosis of CASK-related XLID
  • Carrier testing in adult females with a family history of CASK-related XLID


Next Generation Sequencing: In-solution hybridization of all coding exons is performed on the patient’s genomic DNA. Although some deep intronic regions may also be analyzed, this assay is not mean to interrogate most promoter regions, deep intronic regions, or other regulatory elements, and does not detect single or multi-exon deletions or duplications. Direct sequencing of the captured regions is performed using next generation sequencing. The patient’s gene sequences are then compared to a standard reference sequence. Potentially causative variants and areas of low coverage are Sanger-sequenced. Sequence variations are classified as pathogenic, likely pathogenic, benign, likely benign, or variants of unknown significance. Variants of unknown significance may require further studies of the patient and/or family members.


Clinical Sensitivity: Unknown. Mutations in the promoter region, some mutations in the introns and other regulatory element mutations cannot be detected by this analysis. Large deletions will not be detected by this analysis. Results of molecular analysis should be interpreted in the context of the patient’s biochemical phenotype.

Analytical Sensitivity: ~99%


Submit only 1 of the following specimen types
* Preferred specimen type: Whole Blood

Type: Whole Blood
Specimen Requirements:
In EDTA (purple top) or ACD (yellow top) tube: Infants (2 years): 3-5 ml
Older Children & Adults: 5-10 ml

Specimen Collection and Shipping: Refrigerate until time of shipment. Ship sample within 5 days of collection at room temperature with overnight delivery.

Type: Saliva
Specimen Requirements:
OrageneTM Saliva Collection kit (available through CEN4GEN) used according to manufacturer instructions.

Specimen Collection and Shipping: Store sample at room temperature. Ship sample within 5 days of collection at room temperature with overnight delivery.

Submit copies of diagnostic biochemical test results with the sample, if appropriate.
Sequence analysis is required before deletion/duplication analysis by targeted CGH array. If sequencing is performed by another third party provider, please submit a copy of the sequencing report with the test requisition.

• Deletion/duplication analysis of the CASK gene by CGH array is available for those individuals in whom sequence analysis is negative (test code: 7219).
• 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.
• Custom diagnostic mutation analysis (test code: 6875) is available to family members if mutations are identified by targeted mutation testing or sequencing analysis.