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Division of Genetics and Metabolism Department of Pediatrics in the College of Medicine
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CASK-Related Disorders

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Vol. XXXVIII No. 1
Editor: Heather J. Stalker, M.Sc.
Director: Megan Boothe, M.D
By: Colleen Martin, BS Genetic Counseling Student, University of South Florida

Introduction

CASK-related disorders are a spectrum of X-linked neurodevelopmental conditions associated with intellectual disability, developmental delay, and neurologic abnormalities.1-3 These conditions are considered ultra-rare, having less than 200 cases reported in the literature as of 2025.2 The clinical presentation was first reported in 1998, but it was not until 2008 that pathogenic variants in the CASK gene were described as the underlying cause.4-6 While the spectrum of symptoms varies widely, there are two main presentations of CASK-related neurodevelopmental disorders: microcephaly with pontine and cerebellar hypoplasia (MICPCH) and a second, milder presentation of X-linked intellectual disability (XLID).1-3,7

Clinical Presentations

MICPCH

Affected females with the MICPCH phenotype show severe, progressive microcephaly within their first year of life.3,9 As indicated by its name, hypoplasia of the pons and cerebellum is a hallmark feature of this phenotype.1,3,9 All individuals have intellectual disability and developmental delay, with most patients not developing speech and only 20-25% developing the ability to walk.3 Other features of varying frequency include tone abnormalities, movement disorder, seizures, scoliosis, ophthalmologic abnormalities, and sensorineural hearing loss.1-3,7-10

The MICPCH phenotype is less common in males but is typically more severe than in females.3 In addition to progressive microcephaly, pontine and cerebellar hypoplasia, developmental delay, and intellectual disability, affected males can experience severe epileptic encephalopathy and mortality within the first few months of life.3,10

XLID

Individuals with the XLID phenotype typically do not show the same structural abnormalities of the brain as those with the MICPCH phenotype.3,10 Both males and females can show mild-to-severe intellectual disability and nystagmus, whereas developmental delay and epilepsy are more commonly reported in males.3,10 This phenotype is more common in male patients.3

Molecular Etiology

The CASK gene, located on Xp11.4, encodes calcium-/calmodulin-dependent serine protein kinase (CASK), a protein that is highly expressed in the nervous system.11,12 CASK plays an important role in several processes essential to neurological development and function, including synaptic trafficking and transcription regulation of genes involved in brain formation.11,12 Typically, complete loss-of-function variants are associated with the more severe MICPCH phenotype, whereas hypomorphic variants are associated with the less severe XLID phenotype since some protein function is retained.3,6,9

Inheritance

CASK-related disorders are X-linked conditions, with most cases arising from de novo pathogenic variants.2,7-10 Maternally inherited variants have also been reported, with skewed X-inactivation and mosaicism present in seemingly unaffected mothers.7 Penetrance appears to be complete in males, while females with hypomorphic variants may demonstrate incomplete penetrance, with some being asymptomatic.3

Diagnosis

Genetic testing is required to establish a diagnosis of a CASK-related disorder.3 A diagnosis is established in females with a heterozygous pathogenic variant in CASK and in males with a hemizygous pathogenic variant. The diagnosis may be classified as MICPCH or XLID based on the individual’s clinical presentation. Due to the overlapping features of CASK-related disorders with other neurodevelopmental conditions, it is recommended to pursue broader testing if a CASK-related disorder is suspected, such as whole exome sequencing or whole genome sequencing.3

Clinical Management

There is currently no cure for CASK-related disorders. Management of these conditions focuses on a multidisciplinary approach to alleviate symptoms and support development. Recommended specialties include:

  • Neurology
  • Orthopedics
  • Gastroenterology
  • Ophthalmology
  • Audiology
  • Cardiology
  • Nephrology
  • Genetics

Early intervention programs including physical, speech, and occupational therapies are recommended.3

Patient and Family Resources

References

  1. Hayashi S, Okamoto N, Chinen Y, Takanashi J ichi, Makita Y, Hata A, et al. Novel intragenic duplications and mutations of CASK in patients with mental retardation and microcephaly with pontine and cerebellar hypoplasia (MICPCH). Hum Genet. 2012 Jan 1;131(1):99–110. doi:10.1007/s00439-011-1047-0
  2. Martin J, Mavrogalou-Foti A, Eck J, Hattersley L, Baker K. The neurodevelopmental spectrum of CASK-related disorder. J Neurodev Disord. 2025 Oct 2;17:60. doi:10.1186/s11689-025-09643-3 
  3. Moog U, Kutsche K. CASK Disorders. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from: ncbi.nlm.nih.gov/books/NBK169825
  4. Hayashi S, Mizuno S, Migita O, Okuyama T, Makita Y, Hata A, et al. The CASK gene harbored in a deletion detected by array-CGH as a potential candidate for a gene causative of X-linked dominant mental retardation. American Journal of Medical Genetics Part A. 2008;146A(16):2145–51. doi: 10.1002/ajmg.a.32433