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SALSA MLPA Probemix P189 CDKL5/ARX/FOXG1

RETT syndrome, atypical; Early infantile epileptic encephalopathy; FOXG1 syndrome

Region: CDKL5 Xp22.13; NTNG1 1p13.3; ARX Xp21.3; FOXG1 14q12

MLPA | CE IL
Intended purpose
The SALSA MLPA Probemix P189 CDKL5/ARX/FOXG1 is an in vitro diagnostic (IVD)1 or research use only (RUO) semi-quantitative assay2 for the detection of deletions or duplications in the human CDKL5 and NTNG1 genes, in order to confirm a potential cause for and clinical diagnosis of atypical Rett syndrome. This assay can also be used for the detection of deletions or duplication in the human ARX and CDKL5 genes, in order to confirm a potential cause for and clinical diagnosis of early infantile epileptic encephalopathy (EIEE), and for the detection of deletions or duplications in FOXG1, in order to confirm a potential cause for and clinical diagnosis of FOXG1 syndrome, and for molecular genetic testing of at-risk family members. This assay is for use with genomic DNA isolated from human peripheral whole blood specimens.

Copy number variations (CNVs) detected with P189 CDKL5/ARX/FOXG1 should be confirmed with a different technique. In particular, CNVs detected by only a single probe always require confirmation by another method. Most defects in the CDKL5, ARX, NTNG1 and FOXG1 genes are point mutations, none of which will be detected by MLPA. It is therefore recommended to use this assay in combination with sequence analysis.

Assay results are intended to be used in conjunction with other clinical and diagnostic findings, consistent with professional standards of practice, including confirmation by alternative methods, clinical genetic evaluation, and counselling, as appropriate. The results of this test should be interpreted by a clinical molecular geneticist or equivalent.

This device is not intended to be used for standalone diagnostic purposes, pre-implantation or prenatal testing, population screening, or for the detection of, or screening for, acquired or somatic genetic aberrations.

1 Please note that this probemix is for in vitro diagnostic (IVD) use in the countries specified at the end of this product description. In all other countries, the product is for research use only (RUO).
2 To be used in combination with a SALSA MLPA Reagent Kit and Coffalyser.Net analysis software.

Clinical background
Rett syndrome (RTT) is a neurodevelopmental disorder affecting approximately 1:10,000-15,000 live female births. Classic RTT is characterized by a period of normal development during the first 6-18 months of life, followed by loss of already gained skills, such as speech and purposeful hand movement. Additional main features are acquired microcephaly, stereotypic hand movements, impaired locomotion and communication dysfunction (Hagberg et al. 1983). Patients, lacking one or more of the major features of RTT, are identified as atypical RTT cases which cluster into 5 distinct clinical subgroupings; congenital, early-onset seizure, preserved speech, late regression and forme fruste variants (Neul et al. 2010). The prevalence of atypical RTT is estimated at around 1 in 45,000 individuals (predominantly females).

Mutations in MECP2 are found in 95-97% of classic RTT individuals and in 40% of atypical RTT (GeneReviews: https://www.ncbi.nlm.nih.gov/books/NBK1497/). Involvement of other genes in atypical RTT has been reported, such as CDKL5 and NTNG1 Colak et al. 2011). Approximately 6.5-10% of patients with atypical RTT have large deletions in CDKL5 (Rett syndrome database RettBASE). 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.

Early infantile epileptic encephalopathy (EIEE) is a neurological disorder characterized by seizures. The disorder affects newborns, usually within the first three months of life (most often within the first 10 days) in the form of epileptic seizures. Most infants with the disorder show underdevelopment of part or all of the cerebral hemispheres or structural anomalies. The prevalence of EIEE is estimated at around 1 to 1.6 in 100,000 individuals. Mutations in more than 50 different genes are known to cause EIEE, including ARX and CDKL5 (Bahi-Buisson et al. 2010, Kato et al. 2004). Due to the fact that CDKL5 is located on the X chromosome, the prevalence of EIEE among women is four times higher than in men. However, the course is usually more severe among male patients.

FOXG1 syndrome is a condition characterized by impaired development and structural brain abnormalities. Affected infants are small at birth, and their heads grow more slowly than normal, leading to an unusually small head size (microcephaly) by early childhood. The condition is associated with a particular pattern of brain malformations and affects most aspects of development, and children with the condition typically have severe intellectual disability. FOXG1 syndrome affects both males and females and is caused by mutations in the FOXG1 gene (Kortüm et al. 2011, Vegas et al. 2018).

Since there are multiple genes involved in the different syndromes and since these genes are covered in multiple probemixes, Table 1 in the Product Description is provided to give an overview.

Probemix content
The SALSA MLPA Probemix P189-C2 CDKL5/ARX/FOXG1 contains 52 MLPA probes with amplification products between 130 and 500 nucleotides (nt). The CDKL5/ARX/FOXG1 probemix contains probes for each exon of the CDKL5, ARX, NTNG1 and FOXG1 genes. In addition, nine reference probes are included that detect autosomal chromosomal locations. Complete probe sequences and the identity of the genes detected by the reference probes are available online (www.mrcholland.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, and 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.mrcholland.com.

Order Items

Probemix

Item no.
Description
Technology
Price
P189-025R
SALSA MLPA Probemix P189 CDKL5/ARX/FOXG1 – 25 rxn
€ 243.00
P189-050R
SALSA MLPA Probemix P189 CDKL5/ARX/FOXG1 – 50 rxn
€ 486.00
P189-100R
SALSA MLPA Probemix P189 CDKL5/ARX/FOXG1 – 100 rxn
€ 972.00

Required Reagents (Sold Separately)

Item no.
Description
Technology
Price
EK1-FAM
SALSA MLPA EK1 reagent kit – 100 rxn – FAM
€ 300.00
EK1-Cy5
SALSA MLPA EK1 reagent kit – 100 rxn – Cy5
€ 300.00
EK5-FAM
SALSA MLPA EK5 reagent kit – 500 rxn – FAM
€ 1380.00
EK5-Cy5
SALSA MLPA EK5 reagent kit – 500 rxn – Cy5
€ 1380.00
EK20-FAM
SALSA MLPA EK20 reagent kit – 2000 rxn – FAM
€ 5295.00

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CE

CE-marked products are for In Vitro Diagnostic (IVD) use only in EU (candidate) member states and members of the European Free Trade Association (EFTA).

IL

IVD-registered in Israel.