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

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).

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).

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.