CDKL5-Related Disorders Testing

CDKL5-Related Disorders (CDKL5) Sequencing and Deletion/Duplication 2004935
Method: Polymerase Chain Reaction/Sequencing/Multiplex Ligation-dependent Probe Amplification

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
CDKL5-Related Disorders (CDKL5) Sequencing 2004931
Method: Polymerase Chain Reaction/Sequencing

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

Familial Mutation, Targeted Sequencing 2001961
Method: Polymerase Chain Reaction/Sequencing

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 
  1. Archer HL, Evans J, Edwards S, Colley J, Newbury-Ecob R, O'Callaghan F, Huyton M, O'Regan M, Tolmie J, Sampson J, Clarke A, Osborne J. CDKL5 mutations cause infantile spasms, early onset seizures, and severe mental retardation in female patients. J Med Genet. 2006; 43(9): 729-34. PubMed
  2. Bahi-Buisson N, Nectoux J, Rosas-Vargas H, Milh M, Boddaert N, Girard B, Cances C, Ville D, Afenjar A, Rio M, Héron D, Morel MA, Arzimanoglou A, Philippe C, Jonveaux P, Chelly J, Bienvenu T. Key clinical features to identify girls with CDKL5 mutations. Brain. 2008; 131(Pt 10): 2647-61. PubMed
  3. Bahi-Buisson N, Bienvenu T. CDKL5-Related Disorders: From Clinical Description to Molecular Genetics. Mol Syndromol. 2012; 2(3-5): 137-152. PubMed
  4. Frullanti E, Papa FT, Grillo E, Clarke A, Ben-Zeev B, Pineda M, Bahi-Buisson N, Bienvenu T, Armstrong J, Martinez AR, Mari F, Nissenkorn A, Rizzo CL, Veneselli E, Russo S, Vignoli A, Pini G, Djuric M, Bisgaard A, Ravn K, Bosnjak VM, Hayek J, Khajuria R, Montomoli B, Cogliati F, Pintaudi M, Hadzsiev K, Craiu D, Voinova V, Djukic A, Villard L, Renieri A. Analysis of the Phenotypes in the Rett Networked Database. Int J Genomics. 2019; 2019: 6956934. PubMed
  5. National Institutes of Health. CDKL5 Deficiency Disorder. National Institutes of Health, U.S. National Library of Medicine. [Last Reviewed: Nov 2017; Accessed: Aug 2019]
  6. Hector RD, Kalscheuer VM, Hennig F, Leonard H, Downs J, Clarke A, Benke TA, Armstrong J, Pineda M, Bailey ME, Cobb SR. CDKL5 variants: Improving our understanding of a rare neurologic disorder. Neurol Genet. 2017; 3(6): e200. PubMed

Last Update: August 2019