SALSA MLPA P066 Marfan Syndrome-2 probemixCE

application: Marfan syndrome
region: FBN1 15q21.1
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version: C1
sold since: 2017-09-18

item no. description price
P066-025R SALSA MLPA P066 Marfan Syndrome-2 probemix – 25 rxn € 237
P066-050R SALSA MLPA P066 Marfan Syndrome-2 probemix – 50 rxn € 474
P066-100R SALSA MLPA P066 Marfan Syndrome-2 probemix – 100 rxn € 948
EK1-FAM SALSA MLPA EK1 reagent kit – 100 rxn - FAM € 294
EK1-Cy5 SALSA MLPA EK1 reagent kit – 100 rxn - Cy5 € 294
EK5-FAM SALSA MLPA EK5 reagent kit – 500 rxn - FAM € 1355
EK5-Cy5 SALSA MLPA EK5 reagent kit – 500 rxn - Cy5 € 1355

Please note that both a probemix and reagent kit are needed to perform MLPA.

description
Intended use: The SALSA MLPA probemixes P065 and P066 are in vitro diagnostic (IVD)1 or research use only (RUO) assays for the detection of deletions or duplications in the human FBN1 and TGFBR2 genes, in order to confirm a potential cause of Marfan syndrome and other FBN1- or TGFBR2-related disorders. These assays are optimised for use with human DNA derived from peripheral blood.

Deletions or duplications detected with the P065/P066 Marfan Syndrome probemixes should be verified by another technique. In particular, deletions or duplications detected by only a single probe always require validation by another method. Most defects in the FBN1 and TGFBR2 genes are point mutations, none of which are detected by MLPA. It is therefore recommended to use these SALSA MLPA probemixes in combination with sequence analysis of these genes. These probemixes require in depth knowledge of the Marfan syndrome and related disorders and are not intended to be used as a standalone assay for clinical decisions. The results of these tests should be interpreted by a clinical molecular geneticist or equivalent.

1Please 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).

Clinical background: Marfan syndrome is a rare, autosomal-dominant disorder that in a majority of cases is caused by mutations in the FBN1 gene. The FBN1 gene encodes fibrillin-1, which is a large, extracellular matrix glycoprotein that serves as a structural component of calcium-binding microfibrils. Marfan syndrome is a systemic disorder of connective tissue, which mainly affects the ocular, skeletal and cardiovascular system. There is a high degree of clinical variability between and in families, where FBN1 mutations can lead to isolated features of Marfan syndrome or a neonatal presentation of severe and progressive disease in multi-organ systems. The disorders of the cardiovascular system are often the major cause of morbidity and mortality (Lerner-Ellis et al. 2014). If proper management is executed, the life expectancy of a patient with Marfan syndrome approximates that of the general population.
The diagnosis of Marfan syndrome is based on fulfilling international Ghent criteria, which includes family history and the observation of characteristic findings in multiple organ systems. An FBN1 mutation is part of the criteria, however, not in all Marfan patients an FBN1 mutation has been detected. In addition, although patients with an FBN1 mutation will eventually show clinical features of Marfan, it is possible they do not fulfil the international criteria for Marfan syndrome throughout life. Patients with Marfan syndrome with an FBN1 mutation will receive the same treatment as patients without an FBN1 mutation (Arslan-Kirchner et al. 2010).

There are other Marfan-related disorders caused by FBN1 mutations, such as MASS phenotype (mitral valve, aortic, skin and skeletal features), mitral valve prolapse syndrome and ectopia lentis syndrome. In addition, several Marfan-like appearance disorders are caused by other genes, such as TGFBR2. The TGFBR2 gene encodes a member of the Serine/Threonine protein kinase family and the TGFB receptor subfamily. TGFBR2 is one of the genes in which pathogenic variants can result in Loeys-Dietz syndrome. This disorder is characterized by vascular findings (cerebral, thoracic, and abdominal arterial aneurysms and/or dissections) and skeletal manifestations. Moreover, mutations in both FBN1 and TGFBR2, beside other genes, have been reported to cause familial thoracic aortic aneurysms and aortic dissections (TAAD). This shows the complicated clinical variability of these genes and the phenotypic overlap of the disorders (Lerner-Ellis et al. 2014). Of note, although a whole gene deletion of TGFBR2 has been described, no clear features of Loeys-Dietz syndrome or arterial or cardiac abnormalities were (yet) detected (Campbell et al. 2011). In addition, no deletions or duplications in TGFBR2 have been reported in Loeys-Dietz patients.
More information is available at: https://www.ncbi.nlm.nih.gov/books/NBK1335/ and https://www.ncbi.nlm.nih.gov/books/NBK1133/.

P065-C1 and P066-C1 probemix content: The P065-C1 and the P066-C1 probemixes contain 34 probes and 36 probes for the FBN1 gene, respectively. Together, these probemixes cover each exon of the FBN1 gene by at least one probe, exon 2 and exon 65 are covered by two probes and one probe upstream of the FBN1 gene is present. In addition, P065-C1 includes nine probes for TGFBR2. Each exon of TGFBR2 is covered by at least one probe, with the exception of exon 1, which is covered by two probes.

The P065-C1 probemix contains 52 probes with amplification products between 130 and 503 nt in length including nine reference probes. The P066-C1 probemix contains 49 probes with amplification products between 130 and 490 nt in length, 13 of which are reference probes. The identity of the genes detected by the reference probes is available online (www.mlpa.com).

These probemixes contain nine quality control fragments generating amplification products between 64 and 105 nt: four DNA Quantity Fragments (Q-fragments), three DNA Denaturation Fragments (D-fragments), and one chromosome X and one chromosome Y-specific fragment (Table 1). The Q-fragments are only visible when less than 100 ng sample DNA is used. Low signal of the 88 and 96 nt fragments indicates incomplete DNA denaturation. More information on how to interpret observations on these control fragments can be found in the MLPA General Protocol.

related products
SALSA MLPA P148 TGFBR1-TGFBR2 probemix
Contains probes for TGFBR1 and TGFBR2, involved in the aortic aneurysm syndrome.

product history
version C1: Two FBN1 probes have been replaced and one probe for the FBN1 promoter has been added. Also, five reference probes have been replaced.
version B2: One reference probe has been removed and two probes have been adjusted.
version B1: four new FBN1 probes have been added, eight FBN1 probes have been replaced, and all reference probes have been replaced.
version A3: The 88 and 96 nt control fragments have been replaced (QDX2).
version A2: As compared to previous lots 0207, 1205, 0904, DNA control fragments (D-fragments) and X- and Y- specific control fragments have been added.

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