CDKL5-Related Disorders Testing

Preferred initial test to confirm clinical diagnosis of a CDKL5-related disorder in individuals with:

  • Infantile seizures
  • ISSX
  • Atypical Rett syndrome and negative MECP2 result
  • Autism
  • Intellectual disability with seizure disorder

Acceptable initial test to confirm clinical diagnosis of a CDKL5-related disorder in individuals with:

  • Infantile seizures
  • ISSX
  • Atypical Rett syndrome and negative MECP2 result
  • Autism
  • Intellectual disability with seizure disorder
Related Test
  • Recommended test for a known familial sequence variant previously identified in a family member.
  • A copy of the family member’s lab report documenting the familial variant is REQUIRED.
  • Consultation with a genetic counselor is advised. 

CDKL5-related disorders are rare developmental disorders that primarily affect females. Symptoms are variable, but may include seizures, infantile spasms, and developmental delay. Clinical presentation may overlap with MECP2-related disorders, including Rett syndrome. For more information on MECP2-related disorders, see the MECP2-Related Disorders – Classic or Atypical Rett Syndrome Consult topic.

Disease Overview

Prevalence

  • Rare: >1,000 cases worldwide
  • More common in females than males (9:1)

Symptoms

Clinical phenotypes are variable; skewed X-inactivation patterns in females may account for clinical variability.

  • Features potentially overlapping with MECP2-related disorders:
    • Early-onset intractable seizures
    • Infantile spasms (females)
    • Severe developmental delay/limited developmental progression
    • Hypotonia (females)
    • Severe encephalopathy (males)
  • Features of X-linked infantile spasm syndrome (ISSX) or West syndrome:
    • Severe infantile spasms
    • Intellectual disability
    • Lack of developmental progression
    • Hypsarrhythmia
  • Hanefeld variant (early-onset seizure variant of atypical Rett syndrome in females)
    • Early onset epileptic seizures
    • Infantile spasms and Rett-like features

Genetics

Gene

CDKL5 (cyclin-dependent kinase-like 5)

Inheritance

X-linked dominant

Penetrance

100%

De novo Variants

Majority of reported cases

Structure/Function

Involved in the same molecular pathway as the MECP2 gene and exhibits similar expression patterns during development

Variants

>100 pathogenic variants reported

  • Majority are sequence variants
  • Large deletions/duplications have been reported in males and females

Test Interpretation

Sensitivity/Specificity

  • Clinical sensitivity (for sequencing combined with deletion/duplication)
    • Dependent on phenotype
    • ~17% for females with early-onset seizures  
  • Analytical sensitivity/specificity: 99%

Results

Result Findings Interpretation

Positive

Pathogenic variant detected

Diagnosis confirmed

Negative

No pathogenic variant detected

CDKL5-related disorder unlikely, but not excluded

Uncertain

Variant(s) of uncertain significance identified

Variant(s) may be disease causing or benign

Limitations

  • Diagnostic errors may occur due to rare sequence variations or repeat element insertions
  • Deep intronic variants, regulatory region variants, and breakpoints of large deletions/duplications are not detected or evaluated
  • Single exon deletions/duplications may not be detected due to probe location

References

Additional Resources