The SALSA MLPA probemix P189 CDKL5/ARX/FOXG1 is an in vitro diagnostic (IVD)1
or a research use only (RUO) assay for the detection of deletions or duplications in the human CDKL5
genes, in order to confirm a potential cause and clinical diagnosis for atypical Rett syndrome. This assay can also be used for the detection of deletions or duplication in the human ARX
genes, in order to confirm a potential cause and clinical diagnosis for X-linked infantile spasm syndrome, or FOXG1
syndrome, respectively. This product can also be used for molecular genetic testing of at-risk family members. This assay is for use with human DNA extracted from peripheral blood.
Deletions or duplications detected with the P189 CDKL5/ARX/FOXG1 probemix must be confirmed by another technique. In particular, deletions or duplications detected by only a single probe always require validation by another method. Most defects in CDKL5
genes are point mutations, none of which will be detected by MLPA. It is therefore recommended to use this SALSA MLPA probemix in combination with sequence analysis of the aforementioned genes. This assay is not intended to be used as a standalone assay for clinical decisions. The results of this test must be interpreted by a clinical molecular geneticist or equivalent.
Please note that this probemix is for In Vitro Diagnostic use (IVD) in the countries specified at the end of this product description. In all other countries, the product is for Research Use Only (RUO).
Rett syndrome is a dominant X-linked brain disorder characterized by microcephaly, loss of achieved psychomotor abilities, intellectual disability, and autistic behaviours. The prevalence of Rett syndrome is approximately 1 in 10.000 live female births. Rett syndrome is usually caused by mutations in the MECP2
gene, although patients with mutations in two other genes, CDKL5
, may also exhibit a Rett-like phenotype. Atypical Rett syndrome is the early onset seizure variant of Rett syndrome and is associated with an atypical presentation characterized by seizures in the first months of life with subsequent development of Rett syndrome features. It has an estimated prevalence of 1 in 45.000. Approximately 6.5-10% of patients with atypical Rett syndrome have large deletions in CDKL5
(Rett syndrome database RettBASE). Mutations in CDKL5
mainly cause X-linked early infantile epileptic encephalopathy, also called X-linked infantile spasm syndrome. Male individuals with a CDKL5
mutation typically also develop epileptic encephalopathy characterized by severe intractable seizures and intellectual disability in the absence of other signs.
Mutations in FOXG1
result in the FOXG1 syndrome, which was previously described as a congenital variant of Rett syndrome. However, Rett syndrome is diagnosed almost exclusively in females, while FOXG1 syndrome affects both males and females. Rett syndrome also involves a period of apparently normal early development that does not occur in FOXG1 syndrome.
One report described a patient with atypical Rett syndrome who presented with early onset of epileptic seizures (not infantile spasms) and a de novo
translocation in intron 6 of NTNG1
gene (Borg et al. 2005). Please note that MLPA will not detect balanced translocations.
gene mutations account for 9.5% of all cases of X-linked intellectual disability syndromes, including X-linked lissencephaly with abnormal genitalia, X-linked infantile spasm syndrome, and Partington syndrome (neurological disorder with movement problems). Since these genes are involved in multiple syndromes and are covered in multiple probemixes, Table 1 is provided to give a good overview.
More information is available at https://www.ncbi.nlm.nih.gov/books/NBK1497/
P189-C2 probemix content:
The P189-C2 CDKL5/ARX/FOXG1 probemix contains 52 probes with amplification products between 130 and 500 nt. The CDKL5/ARX/FOXG1 probemix contains probes for each exon of the CDKL5
genes. In addition, 9 reference probes are included in this probemix, detecting several different autosomal chromosomal locations. The identity of the genes detected by the reference probes is available online (www.mlpa.com
This Probemix contains nine quality control fragments generating amplification products between 64 and 105 nt: four DNA Quantity Fragments (Q-fragments), two DNA Denaturation Fragments (D-fragments), one benchmark fragment, one chromosome X and one chromosome Y-specific fragment. More information on how to interpret observations on these control fragments can be found in the MLPA General Protocol and online at www.mpla.com