• Test Code:
    2404
  • Department:
    Molecular Genetics
  • Test Synonyms:
    Atypical RETT SyndromeEarly Infantile 2 (EIEE2)Epileptic EncephalopathyInfantile Spasm Syndrome X-linked (ISSX2)Rett Syndrome Variant with Infantile Spasms
  • CPT Code(s):
    81406
Background:

Aytpical Rett syndrome (also known as Epileptic Encephalopathy, Early Infantile, 2 (EIEE2);  Infantile Spasm Syndrome, X-Linked (ISSX2); and Rett Syndrome, Variant, with Infantile Spasms) is an X-linked, severe progressive neurodevelopmental disorder that generally presents in infancy with early onset seizures during the first weeks to months of life.  Infantile spasms and myoclonic jerks are the cardinal feature of this disorder, (with a unique EEG pattern) most frequently marked by hypotonia, poor eye contact, severe mental retardation and profound global developmental delay.  Usually there is no period of regression which is often seen in Rett syndrome, the hand movements are less notable but grasp is affected.   In the majority, growth is normal except head circumference is variably affected and autonomic disturbances are not noted. This presentation is far more frequent in females than in males although males can be affected. Variable clinical   presentation may occur with milder psychosocial phenotypes resembling autistic features and tactile hypersensitivities.  Atypical Rett syndrome presenting with early onset seizures may be associated with mutations and this would be a clear indication to consider CDKL5 testing.  Approximately 10% of patients with encephalopathy and early onset seizures carry an identified mutation in the CDKL5 gene, cyclin dependent kinase-like 5 gene (CDKL5) on chromosome Xp22.1.  

Reasons for Referral:

  • Confirmation of clinical diagnosis in patients with atypical Rett, or suspicion based on infantile spasms AND with a negative MECP2 mutation screen.
  • Carrier testing of family members of Atypical Rett patients, given previous CDKL5 mutation identified.
  • Prenatal diagnosis, given previous CDKL5 mutation identified.

Methodology:

Next generation sequencing will analyze the exons or coding regions of the CDKL5 gene using Illumina NextSeq 500 technology.  Samples are prepared using hybridization probes to enrich exonic regions.  Promoter, intronic, etc. regions are not assessed on our assay, but may contain variants that impact gene function.

OR

All 21 coding exons, and exon/intron boundaries, of CDKL5 are amplified by PCR.  All amplicons are sequenced in both forward and reverse directions using Sanger sequencing.

Clinical sensitivity is unknown; however, it is estimated that ~10% of patients with encephalopathy and early onset seizures have a mutation in the CDKL5 gene.

Test reporting follows the American College of Medical Genetics guidelines.

Specimen Requirements:

Blood: EDTA (purple-top) or ACD (yellow-top Solution A or B) tube

  • Adult: 5 mL
  • Child: 5 mL
  • Infant: 2-3 mL

Saliva: 2 ORAgene Saliva Kit(s) (OGR-500)
Skin Fibroblast: Punch Biopsy, or 2 T-25 confluent flasks
Prenatal:

  • Direct Amniotic Fluid (10-20mL)
  • Direct CVS
  • Cultured Amnio or CVS (2-T25 flasks)

DNA: 1-2µg at a minimum of 50-100ng/µL (DNA must be extracted in a CLIA-certified laboratory or a laboratory meeting equivalent requirements as determined by the CAP and/or CMS)

Notice Regarding Molecular Genetic Testing on CVS or Amniotic Fluid Specimens:

  • Maternal cell rule-out testing will be performed on all prenatal specimens received.Please provide maternal blood in addition to the fetal specimen.Additional charges apply for the maternal cell rule-out test.
  • All genetic testing performed on Direct CVS or Direct Amniotic Fluid specimens will be confirmed on cell cultures prepared by Knight Diagnostic Laboratories.Cell cultures will be prepared from the specimen received.Additional charges apply for confirmatory testing. 

For routine testing of blood, saliva and buccal swabs, KDL does NOT accept samples from patients within two (2) weeks of a packed cell/platelet transfusion or within four (4) weeks of a whole blood transfusion.  For extraordinary circumstances, where testing must be performed outside of the above windows, please contact our lab.

A REQUISITION FORM MUST ACCOMPANY ALL SAMPLES.  Please include detailed clinical information, including ethnicity, clinical history, and family history.

Test Performed (Days):

Weekly

Turn Around Time:

14 - 21 Days

Shipment Sensitivity Requirements:

  • Package and ship specimen to remain cold, but not frozen. 
  • Ship via overnight express, using the FedEx priority overnight label provided. 
  • Contact Client Services for shipping kits and instructions at (855) 535-1522.

References:

Additional Info: