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SALSA MLPA Probemix P158 JPS

Juvenile polyposis syndrome (JPS)

Region: BMPR1A 10q23.2; SMAD4 18q21.2; PTEN 10q23.31

MLPA | CE
Intended purpose
The SALSA MLPA Probemix P158 JPS is an in vitro diagnostic (IVD)1 or research use only (RUO) semi-quantitative assay2 for the detection of deletions or duplications in the BMPR1A and SMAD4 genes, as well as the 10q22-q23 microdeletion, which contains both BMPR1A and PTEN, in genomic DNA isolated from human peripheral whole blood specimens. P158 JPS is intended to confirm a potential cause for and clinical diagnosis of Juvenile Polyposis Syndrome (JPS) and for molecular genetic testing of at-risk family members.

Copy number variations (CNVs) detected with P158 JPS 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 BMPR1A, SMAD4 and PTEN 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, e.g from DNA extracted from formalin-fixed paraffin embedded (FFPE) or fresh tumour materials.

1Please 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).
2To be used in combination with a SALSA MLPA Reagent Kit and Coffalyser.Net analysis software.

Clinical background
Juvenile Polyposis Syndrome (JPS) is characterized by predisposition to hamartomatous polyps (non-malignant tumours, composed of tissue elements normally found at that site) in the gastrointestinal (GI) tract, specifically in the stomach, small intestine, colon, and rectum. The term "juvenile" refers to the type of polyp rather than to the age of onset of polyps. Most individuals with JPS have some polyps by the age of 20 years; some may have only four or five polyps over their lifetime, whereas others in the same family may have more than a hundred. If the polyps are left untreated, they may cause bleeding and anaemia. Most juvenile polyps are benign; however, malignant transformation can occur. Risk for GI cancers in families with JPS ranges from 9% to 50%. Most of this increased risk is attributed to colon cancer, but cancers of the stomach, upper GI tract, and pancreas have also been reported (NCBI GeneReviews: Juvenile Polyposis Syndrome).

Defects in the genes bone morphogenetic protein receptor type 1A (BMPR1A) and SMAD family member 4 (SMAD4) account for up to 60% of cases with JPS, with approximately 27% caused by defects in SMAD4 and 24% in BMPR1A (Aretz et al. 2007, Calva-Cerqueira et al. 2009, van Hattem et al. 2008). There are reports of two other genes wherein defects could cause JPS, namely endoglin (ENG) and phosphatase and tensin homolog (PTEN). However, to date, defects in ENG have only been reported in two cases and defects in PTEN are thought to underlie Cowden syndrome or Bannayan-Riley-Ruvalcaba syndrome, also associated with juvenile polyps (collectively referred to as PTEN hamartoma tumor syndrome), instead of JPS. Lastly, 10q22-q23 microdeletion, involving complete deletions of BMPR1A and PTEN have been described to underlie JPS. However, the reports on the resulting phenotype are inconsistent. In some cases it leads to a severe, early onset form of juvenile polyposis. In other cases it leads to a syndrome suggestive of Cowden syndrome or Bannayan-Riley-Ruvalcaba syndrome.

A combined syndrome of JPS and hereditary haemorrhagic telangiectasia (HHT) (termed JPS/HHT) is thought to be present in most individuals with a SMAD4 pathogenic variant. Studies have suggested that 15-22% of individuals with a pathogenic variant in SMAD4 have this combined type, however this is thought to be an underestimation. While symptoms of JPS are limited to the GI tract, HHT characteristic arterial malformations can, beside the GI tract, be found in the lungs, liver, brain and mucocutaneous tissue. Upon detection of polyps in the GI tract, the arterial malformations are sometimes overlooked by physicians.

An investigation on SMAD4 supports the presence of a pseudogene in a small percentage of individuals, which has the potential to confound the interpretation of genetic testing results, as only mutations in the native gene are clinically significant (Mancini et al. 2015; Millson et al. 2015).

Probemix content
The SALSA MLPA Probemix P158-D1 JPS contains 51 MLPA probes with amplification products between 118 and 499 nucleotides (nt). This includes 15 probes for the all 13 exons of the BMPR1A gene, with two additional probes each for exons 1 and 3, and 15 probes for all 12 exons of the SMAD4 gene, including four probes for exon 1. Furthermore, 11 probes for all nine exons of the PTEN gene are included, with two probes for exon 3 and one probe upstream of the gene. In addition, ten 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
P158-025R
SALSA MLPA Probemix P158 JPS – 25 rxn
€ 260.00
P158-050R
SALSA MLPA Probemix P158 JPS – 50 rxn
€ 510.00
P158-100R
SALSA MLPA Probemix P158 JPS – 100 rxn
€ 998.00

Required Reagents (Sold Separately)

Item no.
Description
Technology
Price
EK1-FAM
SALSA MLPA EK1 reagent kit – 100 rxn – FAM
€ 316.00
EK1-Cy5
SALSA MLPA EK1 reagent kit – 100 rxn – Cy5
€ 316.00
EK5-FAM
SALSA MLPA EK5 reagent kit – 500 rxn – FAM
€ 1455.00
EK5-Cy5
SALSA MLPA EK5 reagent kit – 500 rxn – Cy5
€ 1455.00
EK20-FAM
SALSA MLPA EK20 reagent kit – 2000 rxn – FAM
€ 5590.00

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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).