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CASK-Related Disorders

, MD, , MD, and , PhD.

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Estimated reading time: 25 minutes

Summary

Clinical characteristics.

CASK-related disorders include a spectrum of phenotypes in both females and males. The two main types of clinical presentation are:

  • Microcephaly with pontine and cerebellar hypoplasia (MICPCH), generally associated with pathogenic loss-of-function variants in CASK; and
  • X-linked intellectual disability (XLID) with or without nystagmus, generally associated with hypomorphic CASK pathogenic variants.

MICPCH is typically seen in females with moderate to severe intellectual disability, progressive microcephaly with or without ophthalmologic anomalies, and sensorineural hearing loss. To date a total of 53 females with MICPCH have been reported, the eldest of whom is 21 years old. Most are able to sit independently; 20%-25% attain the ability to walk; language is nearly absent in most. Neurologic features may include axial hypotonia, hypertonia/spasticity of the extremities, and dystonia or other movement disorders. Nearly 40% have seizures. Behaviors may include sleep disturbances, hand stereotypies, and self-biting.

To date, only seven males have been reported with the severe phenotype. The under-representation in this cohort is likely to be a consequence of early male lethality. These males typically present with intellectual disability and MICPCH, or early-infantile epileptic encephalopathy (Ohtahara syndrome, West syndrome, or early myoclonic epilepsy).

In individuals and families with milder (i.e., hypomorphic) pathogenic variants, the clinical phenotype is usually that of X-linked intellectual disability (XLID) with or without nystagmus and additional clinical features. More than 24 males and nine females have been reported. The males have mild to severe intellectual disability, with or without nystagmus and other ocular features. Females are typically normal, with some displaying mild intellectual disability with or without ocular features.

Diagnosis/testing.

The diagnosis of a CASK-related disorder is established in a female who is heterozygous for a CASK pathogenic variant and in a male who is hemizygous for a CASK pathogenic variant. Molecular genetic testing can be performed as single gene testing or as part of a multigene panel.

Management.

Treatment of manifestations: Treatment is symptomatic and includes nutritional support, treatment of hearing loss, and use of physiotherapy. Management of seizures in children with MICPCH is standard treatment and based on the specific seizure type and frequency.

Genetic counseling.

CASK-related disorders are inherited in an X-linked manner.

  • MICPCH phenotype: Most affected females and males are simplex cases (i.e., the only affected family member) resulting from a de novo CASK pathogenic variant. Because heterozygous females manifest the phenotype, a phenotypically normal mother is unlikely to have the CASK pathogenic variant. Note: It is possible (though unlikely) that one parent of an affected individual will have germline mosaicism (or germline and somatic mosaicism), which would place male and female sibs at risk (when the mother has mosaicism) or female sibs only at risk (when the father has mosaicism).
  • XLID phenotype: The father of an affected male will not have the disease or the CASK pathogenic variant. In a family with more than one affected individual, the mother of an affected male is likely to be an obligate heterozygote and may be variably affected.

For all CASK-related disorders:

  • The risk to the sibs of a proband depends on the genetic status of the mother. If the mother is heterozygous for the CASK pathogenic variant, the chance of transmitting the variant in each pregnancy is 50%; sons who inherit the pathogenic variant will be affected; daughters who inherit the pathogenic variant will be unaffected or affected to a variable degree.
  • Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the pathogenic variant in the family has been identified.

GeneReview Scope

CASK-Related Disorders: Included Phenotypes 1
  • Intellectual disability and microcephaly with pontine and cerebellar hypoplasia (MICPCH)
  • X-linked intellectual disability with or without nystagmus

For synonyms and outdated names see Nomenclature.

1.

For other genetic causes of these phenotypes see Differential Diagnosis.

Diagnosis

CASK-related disorders include a spectrum of phenotypes that differs in females and males.

  • Females typically have moderate to severe intellectual disability and progressive microcephaly with pontine and cerebellar hypoplasia (MICPCH). Possible findings are ophthalmologic anomalies and sensorineural hearing loss.
  • In males the spectrum is broad, ranging from severe (intellectual disability and MICPCH, or early-infantile epileptic encephalopathy [Ohtahara syndrome, West syndrome or early myoclonic epilepsy]) to mild (X-linked intellectual disability [XLID] with or without nystagmus and additional clinical features) [Najm et al 2008, Burglen et al 2012, Saitsu et al 2012, Takanashi et al 2012, Nakamura et al 2014].

Formal diagnostic criteria have not been established for CASK-related disorders.

A CASK-related disorder is suspected in the following:

Females with MICPCH

Clinical findings:

  • OFC at birth ranging from microcephaly (OFC < -2 SD) to normal
  • Progressive microcephaly (≤ -10 SD)
  • Moderate to severe intellectual disability
  • Absent language
  • Hypotonia, hypertonia, or a combination of both (central hypotonia and hypertonia of extremities)
  • Seizures
  • Behavioral abnormalities
  • Short stature
  • Ophthalmologic findings: optic nerve hypoplasia, retinopathy and strabismus
  • Sensorineural hearing loss
  • Facial appearance: well-drawn arched eyebrows, broad nasal bridge and tip, small or short nose, long philtrum or protruding maxilla, short chin, and large ears

MRI findings:

  • Pontine and cerebellar hypoplasia with diffuse mild to severe hypoplasia of the cerebellum [Najm et al 2008] affecting the hemispheres and vermis proportionally [Takanashi et al 2010, Moog et al 2011, Takanashi et al 2012] (Figure 1)
    • Cerebellar hemispheres can be affected asymmetrically.
    • Pontine hypoplasia may be mild to severe with relative sparing of the pontine bulging.
  • Normal or low normal-sized corpus callosum with low cerebrum/corpus callosum ratio [Takanashi et al 2010]
  • Associated MRI finding: mildly reduced number and complexity of gyri in the frontal region of the cerebral cortex
Figure 1. . MRI of the brain of a girl age 2.

Figure 1.

MRI of the brain of a girl age 2.5 years with MICPCH and a heterozygous CASK pathogenic variant a. Sagittal image showing mild pontocerebellar hypoplasia with sparing of pontine bulging. The corpus callosum is normal.

Males with MICPCH

Clinical findings:

MRI findings: mild to severe pontocerebellar hypoplasia

Males with X-linked intellectual disability (XLID) with or without nystagmus

Clinical findings:

  • Mild to severe intellectual disability
  • Seizures/epilepsy
  • Congenital nystagmus
  • Tremor and unsteady gait

MRI finding: cerebellar hypoplasia (variably present)

Females with X-linked intellectual disability (XLID) with or without nystagmus

Clinical findings in the majority:

  • Normal intelligence to mild intellectual disability
  • Normal to mild ocular findings including congenital nystagmus and strabismus
  • No additional neurologic signs to mild tremor or absence seizures

MRI finding: unknown

The diagnosis of a CASK-related disorder is established in a female who is heterozygous for a CASK pathogenic variant and in a male who is hemizygous for a CASK pathogenic variant (Table 1). The approach to molecular genetic testing of a proband can be testing of a single gene or use of a multigene panel.

Single gene testing. To confirm the diagnosis of MICPCH in a proband (male or female):

To confirm the diagnosis of XLID with or without congenital nystagmus in a male proband:

Multigene panel. Consider use of a multigene panel that includes CASK and other genes of interest (see Differential Diagnosis). Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Table 1.

Molecular Genetic Testing Used in CASK-Related Disorders

Gene 1Test MethodVariants Detected 2Variant Detection Frequency by Phenotype and Test Method 3, 4
MICPCHXLID +/- Nystagmus
CASKSequence analysis 5 of entire geneSequence variants28/58 females 6, 7, 8
6/49 males 6, 7, 8, 9, 10
7 males/505
(454 male, 51 female) 9, 11
Deletion/ duplication analysis 12(Multi)exon and whole-gene deletion/ duplication26/54 females 6, 13, 14
1/20 males 6
1 male 15

MICPCH = microcephaly with pontine and cerebellar hypoplasia

XLID = X-linked intellectual disability

1.
2.

See Molecular Genetics for information on allelic variants.

3.

The ability of the test method used to detect a variant that is present in the indicated gene

4.

Denominators are the number of individuals tested for a CASK alteration. Initially, cohorts with microcephaly and pontocerebellar hypoplasia or X-linked intellectual disability were analyzed; subsequently, only individuals with MICPCH and a CASK pathogenic variant have been reported.

5.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

6.

Mosaicism for a CASK pathogenic variant/rearrangement can occur in males and females. Mosaicism for a pathogenic variant can be difficult to detect and may produce a false negative test result.

7.

Sequence analysis of genomic DNA cannot detect a heterozygous deletion of one or more exons or the entire X-linked gene in a female.

8.

In affected females and males, de novo pathogenic loss-of-function variants are distributed throughout the gene; there are no hot-spot regions [Najm et al 2008, Moog et al 2011, Burglen et al 2012, Hayashi et al 2012, Saitsu et al 2012, Takanashi et al 2012, Nakamura et al 2014].

9.

Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation may require additional testing by deletion/duplication analysis.

10.

Somatic mosaicism for a CASK pathogenic nonsense variant has been described in one male [Burglen et al 2012].

11.

In individuals with XLID with or without nystagmus and/or additional clinical manifestations, the majority of CASK alterations are missense and splice variants [Piluso et al 2009, Tarpey et al 2009, Hackett et al 2010].

12.

Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

13.

Genomic rearrangements in females include deletions and duplications of all or part of CASK, with size ranging from 11 kb to 4.5 Mb [Froyen et al 2007, Hayashi et al 2008, Najm et al 2008, Moog et al 2011, Burglen et al 2012, Hayashi et al 2012, Saleem et al 2013]. Two females with a cytogenetically visible Xp inversion disrupting CASK are known [Najm et al 2008; K Kutsche, unpublished].

14.

Mosaicism for a CASK deletion has been described in an asymptomatic mother of a male with MICPCH and Ohtahara syndrome [Saitsu et al 2012].

15.

In males with XLID with or without congenital nystagmus, gene rearrangements have not yet been reported in the literature. However, one male with a partial CASK duplication, intellectual disability, and microcephaly is known to the authors [K Kutsche, unpublished].

Clinical Characteristics

Clinical Description

Intellectual Disability and Microcephaly with Pontine and Cerebellar Hypoplasia (MICPCH)

Females. A total of 53 females with MICPCH have been reported to date, the eldest of whom is 21 years old. The following information about the natural history is based on the recent reviews of Moog et al [2011], Burglen et al [2012], and Takanashi et al [2012] unless otherwise noted.

At birth the occipital frontal circumference (OFC) is in the normal or low-normal range in approximately two thirds of affected females; the others show microcephaly (OFC < -2 SD). Microcephaly invariably becomes severe (OFC -3.5 to -10 SD) during the first year, and usually during the first four months of life.

Affected females acquire head control and make eye contact in the range of two to 24 months. Most affected females are able to sit independently between seven and 36 months; however, only 20%-25% attain the ability to walk (between 18 and 72 months).

Language is nearly absent in most; some utter words. One individual could say two-word sentences. Intellectual development is severely impaired in nearly all affected females, with a few showing moderate intellectual disability.

Associated neurologic features include (axial) hypotonia, hypertonia of the extremities (possibly progressing to spasticity), and dystonia or other movement disorders. Seizures of various types are observed in nearly 40%; onset is between birth and age ten years.

The severity of the pontocerebellar hypoplasia observed on MRI is not of prognostic value [Moog et al 2011].

The behavioral phenotype may include sleep disturbances, hand stereotypies, and self-biting.

Mortality in affected females has not been reported.

Other findings:

  • Birth length is normal. Short stature is common by age four years [Moog et al 2011, Takanashi et al 2012].
  • Scoliosis is frequently observed.
  • Various ophthalmologic findings can be observed, in particular optic nerve hypoplasia, retinopathy, and strabismus.
  • Approximately one third of affected females have sensorineural hearing loss [Moog et al 2011, Burglen et al 2012].
  • Congenital visceral anomalies (e.g., renal/urologic or cardiac anomalies) are rarely seen; no particular anomaly occurs recurrently.
  • Recent reviews suggest a facial phenotype consisting of well-drawn arched eyebrows, a broad nasal bridge and tip, small or short nose, long philtrum or protruding maxilla, small chin, and large ears.

Males. To date, seven males ages birth to 15 years with pathogenic loss-of-function variants in CASK have been described [Najm et al 2008 (patient 5), Burglen et al 2012 (patients 12, 13), Saitsu et al 2012 (patients 1, 2), Takanashi et al 2012 (patient 16), Nakamura et al 2014]. The phenotype of affected males seems to represent the most severe end of the phenotypic spectrum of MICPCH, except for those males mosaic for a CASK pathogenic variant.

All affected males showed severe to profound developmental delay or no development at all, mild to severe microcephaly (OFC -2.7 to -6 SD), and mild to severe diffuse pontocerebellar hypoplasia.

Five of the seven had intractable seizures.

  • In two, a diagnosis of Ohtahara syndrome (early-infantile epileptic encephalopathy with suppression burst) was made [Saitsu et al 2012].
  • One showed frequent myoclonus from the first day of life (early myoclonic encephalopathy) and a suppression-burst EEG pattern during infancy [Jinnou et al 2012, Nakamura et al 2014] and another daily spasms and tonic seizures with suppression burst [Burglen et al 2012].
  • One had a diagnosis of West syndrome [Takanashi et al 2012].

Three of the seven had multiple (minor) anomalies [Burglen et al 2012, Saitsu et al 2012] and one had tetralogy of Fallot and hydronephrosis [Jinnou et al 2012, Nakamura et al 2014].

CASK pathogenic loss-of-function variants in males may also lead to perinatal or early lethality. One affected male died at age two weeks [Najm et al 2008 (patient 5)].

X-Linked Intellectual Disability (XLID) ± Nystagmus

Males. Hypomorphic CASK pathogenic variants have been described in 24 affected males from seven families with X-linked intellectual disability with or without nystagmus and/or other anomalies [Piluso et al 2003, Piluso et al 2009, Tarpey et al 2009, Hackett et al 2010]. They have mild to severe ID with or without congenital nystagmus and other eye findings, such as strabismus and mild pallor of the optic disc. Tremor and unsteady gait may be associated.

In one family with three affected males, severe ID, congenital hypotonia, constipation, hyperactive or aggressive behavior, relative macrocephaly in two of the three, and sensorineural deafness in two of the three have been reported; this family was initially reported to have FG syndrome [Piluso et al 2003, Piluso et al 2009].

OFC is usually normal. The occurrence of brain stem and cerebellar hypoplasia in males with this phenotype is unknown. MRI or CT findings were reported in three males and one heterozygous female; three had normal findings, and one male had cerebellar hypoplasia and pachygyria with severe ID, microcephaly, nystagmus, optic disc pallor, short stature, and facial dysmorphism [Hackett et al 2010 (family V, patient II-4)].

Females. Clinical information on nine heterozygous females is available. Four were unaffected; the other five showed variable clinical features: nystagmus (2), tremor (2), mild (1) or severe (1) ID, and absence seizures (1).

Genotype-Phenotype Correlations

CASK pathogenic loss-of-function variants typically result in microcephaly with pontine and cerebellar hypoplasia (MICPCH) [Moog et al 2011, Hayashi et al 2012]. CASK hypomorphic pathogenic variants typically result in X-inked intellectual disability with or without nystagmus in males [Hackett et al 2010].

In patients with microcephaly with pontine and cerebellar hypoplasia (MICPCH), no correlation exists between the clinical features and the particular type of loss-of-function variant (e.g., CASK loss-of-function variants, larger rearrangements comprising CASK and/or contiguous genes, or intragenic inactivating CASK variants) [Moog et al 2011, Hayashi et al 2012].

X-linked intellectual disability with or without nystagmus in males is caused by hypomorphic CASK pathogenic variants that are likely less deleterious than inactivating pathogenic variants. In the four families with nystagmus, all have pathogenic variants affecting the COOH-terminus of the CASK protein, suggesting a possible genotype-phenotype correlation for the presence of nystagmus [Hackett et al 2010]. Recently, the novel CASK-interacting protein FRMD7 (encoded by FRMD7) has been reported [Watkins et al 2013]. Pathogenic variants in FRMD7 are the major cause of X-linked familial idiopathic infantile nystagmus. Three of these four CASK pathogenic variants disrupt the interaction of CASK with FRMD7, supporting a correlation of nystagmus with variants affecting the CASK COOH-terminal region.

Penetrance

Penetrance for MICPCH seems to be complete in the 53 females and in the seven surviving males reported to date. The few reported males have a particularly severe phenotype (see Clinical Description), except for those with somatic mosaicism of the CASK pathogenic variant.

Penetrance for XLID with or without nystagmus is unknown. Penetrance may be complete or high in the 24 males reported to date and incomplete with high clinical variability in the nine heterozygous females reported to date.

Nomenclature

FG syndrome 4 (FGS4) has been suggested as a CASK-related disorder after report of one family with a CASK pathogenic variant segregating with an FG syndrome (FGS)-like phenotype [Piluso et al 2003, Piluso et al 2009]. However, with the exception of FGS1 caused by a recurrent MED12 pathogenic variant (OMIM 300188, 305450, 309520) (see MED12-Related Disorders), FGS is not clearly defined. OMIM lists FGS4 under the same phenotype number as MR, X-linked, with or without nystagmus (OMIM 300422). Thus, it seems more appropriate to subsume this family under MR, X-linked, with or without nystagmus.

Prevalence

The prevalence of both MICPCH and CASK-related X-linked intellectual disability with or without nystagmus is unknown.

  • MICPCH. 53 females and seven males have been reported worldwide to date; an additional six females and three males are known to the authors.
  • X-linked intellectual disability with or without nystagmus. 24 affected males and five heterozygous symptomatic females have been reported, including the family with FGS-like phenotype [Piluso et al 2009, Tarpey et al 2009, Hackett et al 2010]. The first data obtained by sequencing the coding exons of 718 genes on the X chromosome suggest that CASK pathogenic variants are likely to account for less than 1% of X-linked intellectual disability with or without nystagmus [Tarpey et al 2009].

Differential Diagnosis

Microcephaly with pontine and cerebellar hypoplasia (MICPCH). Identification of the pontocerebellar malformation is critical to the diagnosis of MICPCH.

Pontocerebellar hypoplasia (PCH) shows overlapping features with MICPCH but can be distinguished by neuroimaging and clinical findings.

In classic PCH (see Pontocerebellar Hypoplasia Type 2 and Type 4) the cerebellar hemispheres are more affected than the vermis, leading to the "dragonfly" appearance in coronal images, whereas in CASK-related disorders a "butterfly" pattern is visible that results from diffuse hypoplasia of the hemispheres and vermis. Pontine hypoplasia is more severe in individuals with PCH2/PCH4 than in females with MICPCH. The corpus callosum is often thin and hypoplastic.

PCH2 is characterized by generalized clonus ("jitteriness") with lack of voluntary motor development and later development of chorea and spasticity, impaired swallowing, and sometimes epilepsy. Individuals with PCH2 usually live into childhood.

PCH4 is characterized by polyhydramnios, contractures, severe generalized clonus, and central respiratory failure usually resulting in death in the neonatal period.

PCH2 and PCH4 are caused by biallelic pathogenic variants in TSEN54, TSEN34 or TSEN2.

Ohtahara syndrome. Ohtahara syndrome described in two males with CASK-related disorders [Saitsu et al 2012] also shows the hallmark of diffuse pontocerebellar hypoplasia. Ohtahara syndrome - early infantile epileptic encephalopathy with suppression burst - may also be caused by pathogenic variants in STXBP1 or ARX [Kato et al 2007, Saitsu et al 2008].

X-linked intellectual disability without nystagmus has a broad differential diagnosis as a multitude of genes are known to cause nonsyndromic and syndromic X-linked intellectual disability [Lubs et al 2012].

One family with X-linked intellectual disability and a CASK pathogenic variant has been reported to have a phenotype of FG syndrome (FGS) [Piluso et al 2003, Piluso et al 2009]. FGS can be a difficult clinical diagnosis because of the broadening of the phenotype since its initial description by Opitz and Kaveggia [1974]. Families with individuals with FGS have been linked to seven loci on the X chromosome (CASK is listed as FGS4, OMIM 300422). However, with the exception of FGS1 it is difficult to clearly define the phenotype. FGS1 is caused by a recurrent pathogenic variant in MED12 (OMIM 300188) (see MED12-Related Disorders).

Intellectual disability with nystagmus may be seen in the X-linked disorder Allan Herndon-Dudley syndrome caused by hemizygous pathogenic variants in SLC16A2. These individuals show severe ID, microcephaly, neurologic features (spasticity, dystonia, and ataxia), scoliosis, large ears, and other dysmorphisms. Nystagmus may also in some cases be associated with X-linked intellectual disability.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with a CASK-related disorder, the following evaluations are recommended:

  • Neurologic evaluation including EEG
  • Developmental assessment including gross motor and fine motor skills and speech and language
  • Assessment of feeding
  • Ophthalmologic evaluation
  • Audiologic evaluation
  • Orthopedic evaluation
  • Ultrasound of heart and kidneys to evaluate for rare but possible cardiac or renal/urologic anomalies
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

No specific therapy is available.

Treatment is symptomatic and includes nutritional support, treatment of hearing loss, and use of physiotherapy.

Management of seizures in children with MICPCH is standard treatment and based on the specific seizure type and frequency.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

CASK-related disorders are inherited in an X-linked manner.

Risk to Family Members – MICPCH

Parents of a female proband

  • Most females with MICPCH are simplex cases (i.e., the only affected family member) in which the CASK pathogenic variant occurs de novo and the parents do not have the pathogenic variant in leukocyte-derived DNA.
  • However, it is possible (though not likely) that the mother or the father has germline mosaicism or germline and somatic mosaicism. It is, therefore, reasonable to offer molecular genetic testing to both parents. Note: Given the rarity of mosaicism, analysis of more than one tissue is not justified.

Parents of a male proband

Sibs of a proband

  • The risk to the sibs of a proband depends on the genetic status of the parents.
  • The risk appears to be very low but greater than that of the general population because of the possibility of germline mosaicism in the mother (presenting a risk to male and female sibs) or the father (presenting a risk to female sibs).

Offspring of probands. Female and male probands with MICPCH are not likely to have offspring because of severe intellectual disability.

Risk to Family Members – X-Linked Intellectual Disability ± Nystagmus

Parents of a male proband

Sibs of a male proband

  • The risk to the sibs of a proband depends on the genetic status of the mother.
  • If the mother is heterozygous for the CASK pathogenic variant, the chance of transmitting the variant in each pregnancy is 50%. Sons who inherit the pathogenic variant will be affected. Daughters inheriting the pathogenic variant will be unaffected or affected to a variable degree.
  • If the pathogenic variant cannot be detected in the DNA of the mother of the only affected male in the family, the risk to the sibs of a proband is low but greater than that of the general population because of the possibility of germline mosaicism.

Offspring of a male proband. Theoretically, mildly affected males transmit the pathogenic variant to all of their daughters and none of their sons. However, no male with a CASK pathogenic variant has yet been reported to reproduce.

Offspring of a female proband. Women with a CASK pathogenic variant have a 50% chance of transmitting the variant to each child; sons who inherit the pathogenic variant will be affected; daughters will be unaffected or affected to a variable degree.

Other family members of a proband. If a parent of the proband also has the pathogenic variant, his or her female family members may be at risk of being heterozygous (asymptomatic or symptomatic) and his or her male family members may be at risk of being affected depending on their genetic relationship to the proband.

Heterozygote (Carrier) Detection

Carrier testing for at-risk relatives requires prior identification of the pathogenic variant in the family.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young women who are carriers (asymptomatic or symptomatic) or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the CASK pathogenic variant has been identified in an affected family member, prenatal diagnosis for a pregnancy at increased risk and preimplantation genetic diagnosis for a CASK-related disorder are possible.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • American Association on Intellectual and Developmental Disabilities (AAIDD)
    501 3rd Street Northwest
    Suite 200
    Washington DC 20001
    Phone: 202-387-1968
    Fax: 202-387-2193
    Email: sis@aaidd.org
  • Medline Plus
  • National Center on Birth Defects and Developmental Disabilities
    1600 Clifton Road
    MS E-87
    Atlanta GA 30333
    Phone: 800-232-4636 (toll-free); 888-232-6348 (TTY)
    Email: cdcinfo@cdc.gov

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

CASK-Related Disorders: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
CASKXp11​.4Peripheral plasma membrane protein CASKCASK @ LOVDCASKCASK

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for CASK-Related Disorders (View All in OMIM)

300172CALCIUM/CALMODULIN-DEPENDENT SERINE PROTEIN KINASE; CASK
300749MENTAL RETARDATION AND MICROCEPHALY WITH PONTINE AND CEREBELLAR HYPOPLASIA; MICPCH

Molecular Genetic Pathogenesis

The molecular pathogenesis of the different CASK-associated phenotypes is still largely unknown. CASK pathogenic variants in females and males with MICPCH are inactivating and represent null alleles causing a severe phenotype [Najm et al 2008, Moog et al 2011, Burglen et al 2012]. Males with hemizygous pathogenic loss-of-function variants are more severely affected than females. Early lethality may be a reason for the smaller-than-expected number of males reported.

It has been proposed that disturbances of the CASK-TBR1-RELN signaling cascade underlie the MICPCH phenotype [Najm et al 2008]. CASK forms a complex with the transcription factor TBR1 that induces the transcription of genes containing TBR1 binding sites, including RELN [Hsueh et al 2000, Hsueh 2006, Hsueh 2009]. Homozygous pathogenic variants in RELN are associated with the neuronal migration disorder, lissencephaly with severe cerebellar and hippocampal hypoplasia [Hong et al 2000].

Overlapping brain malformations in Tbr1, Reln, and Cask mutant mice suggest that Cask-Tbr1 mediated regulation of target genes is crucial for cortical development [Bulfone et al 1998, Atasoy et al 2007].

Recently, the novel CASK-interacting protein FRMD7 (encoded by FRMD7) has been described [Watkins et al 2013]. Binding of CASK to FRMD7 is important during development of the oculomotor neural network [Watkins et al 2013]. Pathogenic variants in FRMD7 are the major cause of X-linked familial idiopathic infantile nystagmus. Three of the four CASK pathogenic variants in the COOH-terminal region of the protein have been described in males with X-linked intellectual disability and nystagmus [Hackett et al 2010].

Gene structure. CASK comprises 27 exons and undergoes alternative splicing, resulting in three transcript variants encoding different isoforms.

  • Transcript variant 1 represents the longest transcript and encodes the longest protein (isoform 1).
  • Transcript variant 2 contains an alternate in-frame exon compared to variant 1. The resulting protein (isoform 2) is shorter than isoform 1.
  • Transcript variant 3 lacks two alternate in-frame exons and uses an alternate in-frame splice site compared to variant 1. The resulting protein (isoform 3) is shorter than isoform 1.

The Ensembl database lists 22 possible CASK transcript variants.

For a detailed summary of gene and protein information, see Table A, Gene.

Table 2.

CASK Transcripts and Isoforms

CASK IsoformTranscriptProteinExons# Amino AcidsTranscript Length
CASK isoform 1, variant 1NM_003688​.3NP_003679​.2279218298 bps
CASK isoform 2, variant 2NM_001126054​.2NP_001119526​.1268988229 bps
CASK isoform 3, variant 3NM_001126055​.2NP_001119527​.1258978226 bps

According to the human genome reference sequence GRCh37/hg19.

Pathogenic variants

Table 3.

Selected CASK Pathogenic Variants Discussed in This GeneReview

PhenotypeDNA Nucleotide ChangePredicted Protein ChangeReference Sequences
MICPCHc.316C>Tp.Arg106TerNM_003688​.3
NP_003679​.2
c.2074C>Tp.Gln692Ter
X-linked intellectual
disability ± nystagmus
c.83G>Tp.Arg28LeuNM_001126055​.2
NP_001119527​.1
c.802T>Cp.Tyr268HisENST00000378163​.1
ENSP00000367405
c.1186C>Tp.Pro396Ser
c.2129A>Gp.Asp710Gly
c.2183A>Gp.Tyr728Cys
c.2521-2A>T
c.2755T>Cp.Trp919Arg

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. CASK encodes the calcium/calmodulin-dependent serine protein kinase, which belongs to the membrane associated guanylate kinase (MAGUK) family of proteins [Zheng et al 2011]. The gene product has at least three isoforms that result from alternative splicing and is expressed in a wide variety of tissues. However, CASK is predominantly expressed in the brain. The longest isoform of CASK consists of 921 amino acids and has the following domains: calmodulin-dependent kinase-like domain (CaMK); LIN-2 and LIN-7 interaction (L27); PSD-95-Dlg-ZO1 (PDZ); Src homologous 3 (SH3); protein 4.1 interaction (4.1); guanylate kinase (GK).

CASK plays a critical role in brain development and synaptic function [Hsueh 2006, Hsueh 2009] by:

  • Presynaptic organization and regulation of neurotransmitter release;
  • Regulation of ion channels at postsynaptic sites and maintenance of spine morphology;
  • Entering the nucleus of neurons and regulating the expression of target genes such as Reln and Grin2b, involved in neuronal development.

Abnormal gene product

  • MICPCH is caused by pathogenic loss-of-function variants and rearrangements of CASK. It is currently not known how pathogenic variants in CASK identified in humans affect CASK function. However, pathogenic variants likely result in complete loss of CASK protein or lead to truncated CASK proteins not fulfilling their normal function.
  • X-linked intellectual disability with or without nystagmus. Missense variants and in-frame deletions likely result in expression of CASK proteins with some residual function. Some protein-protein interactions (e.g., between CASK and liprin-α) may be disturbed [Wei et al 2011].
    Recently, the novel CASK-interacting protein FRMD7 (encoded by FRMD7) has been described [Watkins et al 2013]. Pathogenic variants in FRMD7 are the major cause of X-linked familial idiopathic infantile nystagmus. Four CASK pathogenic variants affecting the COOH-terminal region of the protein have been described in males with X-linked intellectual disability and nystagmus. Three of these variants disrupt the interaction of CASK with FRMD7, supporting a model in which binding of CASK to FRMD7 is important during development of the oculomotor neural network [Watkins et al 2013].

References

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Chapter Notes

Author Notes

We are interested in determining the phenotypic spectrum and molecular pathogenesis of CASK-related disorders.

Acknowledgments

We thank the families with individuals affected by MICPCH participating in our research programs.

Revision History

  • 26 November 2013 (me) Review posted live
  • 28 February 2013 (kk) Original submission
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