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P093 HHT/HPAH

SALSA MLPA Probemix P093 HHT/HPAH detects copy number variations in the ENG, ACVRL1 and BMPR2 genes.

Specifications

Contents: 51 MLPA probes, including 14 probes for BMPR2, 11 probes for ACVRL1 and 18 probes for ENG.

Tissue: genomic DNA isolated from human peripheral whole blood.

Application: hereditary hemorrhagic telangiectasia (HHT), and heritable pulmonary arterial hypertension (HPAH).

IVDD certified and registered for in vitro diagnostic (IVD) use in selected territories.

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Key related products

P093 HHT/HPAH

Targets SMAD4, BMPR1A, and PTEN.

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Intended purpose

The SALSA MLPA Probemix P093 HHT/HPAH is an in vitro diagnostic (IVD) or research use only (RUO) semi-quantitative assay for the detection of deletions or duplications in the ENG, ACVRL1 and BMPR2 genes in genomic DNA isolated from human peripheral whole blood specimens. P093 HHT/HPAH is intended to confirm a potential cause for and clinical diagnosis of Hereditary Hemorrhagic Telangiectasia (HHT) or Heritable Pulmonary Arterial Hypertension (HPAH) and for molecular genetic testing of at-risk family members.

For the full intended purpose, see the product description.

Clinical background

Hereditary Hemorrhagic Telangiectasia (HHT) is a disease with an autosomal dominant inheritance pattern and is characterized by the presence of multiple arteriovenous malformations (AVMs). In AVMs, arteries connect directly to veins instead of through intervening capillaries, resulting in high blood pressure. AVMs occur on the skin, but also in the brain, lungs, liver and intestines. Depending on the location, rupture of these malformations can have catastrophic consequences for the patient. Diagnosis is based on the presence of multiple AVMs in the skin, mucus membranes, or visceral organs. Recurrent nosebleeds are also a common finding in HHT patients. Molecular genetic testing is performed to confirm or establish a diagnosis in a proband. HHT is primarily caused by pathogenic variations in the genes endoglin (ENG/HHT1) and activin A receptor like type 1 (ACVRL1/HHT2). Both genes encode endothelial cell surface receptors that are part of a TGF-β/BMP signalling cascade, a pathway involved in angiogenesis, among multiple other developmental processes. Approximately 10% of pathogenic variation consists of large deletions/duplications. More information is available at: https://www.ncbi.nlm.nih.gov/books/NBK1351/.

Heritable Pulmonary Arterial Hypertension (HPAH) is inherited in an autosomal dominant manner. This disease is caused by loss or obstruction of the smallest pulmonary arteries, resulting in high blood pressure in the arteries of the lung. Diagnosis is based on the presence of pulmonary hypertension as confirmed through right heart catheterization, and subsequently by identification of a heterozygous pathogenic variant in a known associated gene (simplex cases) and/or confirmation of Pulmonary Arterial Hypertension (PAH) in one or more of the proband's family members. Approximately 75% of HPAH is caused by variation in the bone morphogenetic protein receptor type 2 (BMPR2) gene. 7-43% of identified BMPR2 mutations in individuals with HPAH are large duplications/deletions (Aldred et al. 2006, Cogan et al. 2006, Liu et al. 2012, Sztrymf et al. 2008), equivalent to 5-32% of all mutations in HPAH patients. Similar to ENG and ACVRL1, the BMPR2 gene also encodes a cell surface receptor that is part of the TGF-β/BMP signalling pathway. Sporadically, PAH is observed as a symptom of HHT. The biological similarities between the causative genes suggests a similar aetiology between HPAH and HHT. This is supported by rare observations of mutations in ACVRL1, and even more infrequent in ENG, causing HPAH. In the literature, a patient has been described with a combined PAH and HHT phenotype carrying a deletion of exons 6 and 7 in BMPR2 (Handa et al. 2014). In very rare cases, HPAH can be caused by mutations in the KCNK3, SMAD9 or CAV1 gene. To the best of our knowledge, no HPAH causing deletions or duplications have been reported in these genes. More information is available at: https://www.ncbi.nlm.nih.gov/books/NBK1485/.

Regulatory status

SALSA MLPA Probemix P093 HHT/HPAH is CE-marked under the IVDD for in vitro diagnostic (IVD) use in Europe. This assay has also been registered for IVD use in Israel.

This assay is for research use only (RUO) in all other territories.

Product documentation

Version C2

Other versions

Contact us for earlier versions.

List prices

Product

Item no.
Description
Technology
Price
P093-025R
SALSA MLPA Probemix P093 HHT/HPAH – 25 rxn
MLPA
€ 286.00
P093-050R
SALSA MLPA Probemix P093 HHT/HPAH – 50 rxn
MLPA
€ 560.00
P093-100R
SALSA MLPA Probemix P093 HHT/HPAH – 100 rxn
MLPA
€ 1096.00

Required reagents

A general SALSA MLPA Reagent Kit is required for MLPA experiments (to be ordered separately).

Item no.
Description
Technology
Price
EK1-FAM
SALSA MLPA Reagent Kit – 100 rxn – FAM (6 vials)
MLPA MS-MLPA
€ 348.00
EK1-Cy5
SALSA MLPA Reagent Kit – 100 rxn – Cy5 (6 vials)
MLPA MS-MLPA
€ 348.00
EK5-FAM
SALSA MLPA Reagent Kit – 500 rxn – FAM (5×6 vials)
MLPA MS-MLPA
€ 1600.00
EK5-Cy5
SALSA MLPA Reagent Kit – 500 rxn – Cy5 (5×6 vials)
MLPA MS-MLPA
€ 1600.00
EK20-FAM
SALSA MLPA Reagent Kit – 2000 rxn – FAM (5×6 vials)
MLPA MS-MLPA
€ 6152.00

Price details & ordering

The prices above are list prices for direct orders from MRC Holland. Contact us for a quote that takes discounts and additional costs (such as shipping costs) into account. Different prices apply for orders through one of our sales partners; contact your local supplier for a quote.

More information about ordering & prices

Positive samples

Inclusion of a positive sample is usually not required, but can be useful for the analysis of your experiments. MRC Holland has very limited access to positive samples and cannot supply such samples. We recommend using positive samples from your own collection. Alternatively, you can use positive samples from an online biorepository, such as the Coriell Institute.

The commercially available positive samples below can be used with the current (C2) version of this product.

  • Coriell NA01229: Heterozygous duplication affecting the probes for BMPR2 on chromosome 2q.
  • Coriell NA11213: Heterozygous deletion affecting the probes for BMPR2 on chromosome 2q.
  • Coriell NA10186: Heterozygous duplication affecting the probe for ENG on chromosome 9q and the reference probe at 290 nt.

Resources

General MLPA resources

MLPA education

Publications

Selected publications using P093 HHT/HPAH

  • Eichstaedt CA et al. (2022). Gene panel diagnostics reveals new pathogenic variants in pulmonary arterial hypertension. Respir Res. 23:74.
  • Eyries M et al. (2019). Widening the landscape of heritable pulmonary hypertension mutations in paediatric and adult cases. Eur Respir J. 53:1801371.
  • Gamou S et al. (2018). Genetics in pulmonary arterial hypertension in a large homogeneous Japanese population. Clin Genet. 94:70-80.
  • Girerd B et al. (2016). Genetic counselling in a national referral centre for pulmonary hypertension. Eur Respir J. 47:541-52.
  • Kitayama K et al. (2021). Mutational and clinical spectrum of Japanese patients with hereditary hemorrhagic telangiectasia. BMC Med Genomics. 14:288.
  • Liang K-W et al. (2022). Whole Exome Sequencing of Patients With Heritable and Idiopathic Pulmonary Arterial Hypertension in Central Taiwan. Front Cardiovasc Med. 9:911649.
  • Momose Y et al. (2015). De novo mutations in the BMPR2 gene in patients with heritable pulmonary arterial hypertension. Ann Hum Genet. 79:85-91.
  • Mutize TT et al. (2020). The clinical and genetic features of hereditary haemorrhagic telangiectasia (HHT) in central South Africa-three novel pathogenic variants. Mol Biol Rep. 47:9967-72.
  • Van der Bruggen CE et al. (2016). Bone Morphogenetic Protein Receptor Type 2 Mutation in Pulmonary Arterial Hypertension: A View on the Right Ventricle. Circulation. 133:1747-60.
  • Xi Q et al. (2016). High Frequency of Pulmonary Hypertension-Causing Gene Mutation in Chinese Patients with Chronic Thromboembolic Pulmonary Hypertension. PLoS One. 11:e0147396.

References

  • Aldred MA et al. (2006). BMPR2 gene rearrangements account for a significant proportion of mutations in familial and idiopathic pulmonary arterial hypertension. Hum Mutat. 27:212-3.
  • Cogan JD et al. (2006). High frequency of BMPR2 exonic deletions/duplications in familial pulmonary arterial hypertension. Am J Respir Crit Care Med. 174:590-8.
  • Handa T et al. (2014). BMPR2 gene mutation in pulmonary arteriovenous malformation and pulmonary hypertension: a case report. Respir Investig. 52:195-8.
  • Liu D et al. (2012). Molecular genetics and clinical features of Chinese idiopathic and heritable pulmonary arterial hypertension patients. Eur Respir J. 39:597-603.
  • Sztrymf B et al. (2008). Clinical outcomes of pulmonary arterial hypertension in carriers of BMPR2 mutation. Am J Respir Crit Care Med. 177:1377-83.
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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), and the UK.

IL

IVD-registered in Israel.