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Molecular Genetics Laboratory

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Mental Retardation and Microcephaly with Pontine and Cerebellar Hypoplasia (CASK)

  • LIS Mnemonic: MBCASKSEQ


    Collect whole blood in a purple top (EDTA) tube (preferred). Extracted DNA is also acceptable.

    Volume Required

    5 ml whole blood or 8 ug extracted DNA

    Minimum Required

    3 ml whole blood


    Refrigerate sample until shipment. Send the sample at room temperature with overnight delivery for receipt Monday through Friday within 24 hours of collection.


    Whole blood can be refrigerated until shipment.

    Unacceptable conditions

    Heparinized specimens, severely hemolyzed specimens, frozen, clotted or possibly commingled specimens, blood in non-sterile or leaky containers, mislabeled or inappropriately labeled specimens.

    Specimen Handling

    Do not heat, freeze or centrifuge blood before shipment. Refrigerate sample until shipment.

Days Performed

Mon - Fri 9:00am to 4:00pm


Sequence Analysis- 3-4 weeks; Known Point Mutation- 1-2 weeks


Sequence Analysis- 81479; Known Point Mutation- 81479

Disease Information

Clinical Features:

Mutations in the CASK gene result in a distinctive phenotype in females that is characterized by severe mental retardation, microcephaly, and disproportionate pontine and cerebellar hypoplasia (MIC-PHC). These mutations are likely to be in lethal in males. However, there is a milder phenotype in males that is associated with mild to moderate mental retardation and congenital nystagmus. Carrier females demonstrate variable phenotypes. Finally, a missense mutation in CASK has also been identified in a family with FG syndrome.

Molecular Genetics:

Calcium/calmodulin-dependent serine protein kinase (CASK) belongs to the membrane-associated guanylate kinase protein family. CASK encodes a multi domain scaffolding protein that interacts with several different proteins and is thought to play an important role in embryonic brain development and synaptic functions. Nonsense, splice site, missense and gross deletions have been identified previously in affected patients. Loss of function mutations are generally identified only in females, while the milder (hypomorphic) mutations are thought to be more commonly associated with the mild to moderate MR phenotype in males.

Test Methods:

Analysis for mutations in the open reading frame of the CASK gene involves PCR amplification of the coding region followed by direct sequencing. Assay development involved designing primer pairs for all exons optimizing PCR conditions, amplification and sequencing of a negative control. Sequencing was performed using a commercially available kit (ABI). Sequences were analyzed on an automated DNA sequencer (ABI) and compared with control sequences.

Detection Rate:

Mutations were detected in 5 out of 46 individuals with MIC-PHC (10%). Of these 5 patients, 4 patients were females with heterozygous loss of function mutations and one patient was a male with a splice mutation. Mutations in the CASK gene were identified in 4/358 families with XLMR (1%). Finally, 2/45 probands with nystagmus and/or microcephaly MR had mutations in the CASK gene (4%).


Test results with interpretation will be mailed and/or faxed to the referring physician or send out lab following completion of the test. Additional reports will be provided as requested.


The clinical utility of the assay is to support a clinical diagnosis of the disease, facilitate genetic counseling, and assess the risk to other first degree relatives and to facilitate testing of at - risk family members.

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