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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).

IVDR 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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This product has recently been CE-marked for in vitro diagnostic (IVD) use under the In Vitro Diagnostic Regulation (IVDR; EU 2017/746), which replaces the former CE-marking under the IVD Directive (IVDD; Directive 98/79/EC). This update was accompanied by a change in the intended purpose and a change in format of the product description. Some information can now be found in a different location (more information).

Intended purpose

The SALSA MLPA Probemix P093 HHT/HPAH is an in vitro diagnostic (IVD) or research use only (RUO) semi-quantitative manual assay for the detection of deletions in the ACVRL1 gene and deletions or duplications in the BMPR2 and ENG genes in genomic DNA isolated from human peripheral whole blood specimens. P093 HHT/HPAH is intended to confirm a potential cause for or clinical diagnosis of Hereditary Hemorrhagic Telangiectasia (HHT) (deletions in ACVRL1, and deletions and duplications in ENG), and to confirm a potential cause for and clinical diagnosis of Heritable Pulmonary Arterial Hypertension (HPAH) (deletions and duplications in BMPR2). This assay is additionally intended 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) (Mutize et al. 2020, Torring et al. 2014)(GeneReviews). It occurs in one out of every 5,000 individuals (Faughnan et al. 2020). Depending on the genetic cause of HHT, this disease is divided into different subtypes. HHT type 1 stems from pathogenic variations in the ENG gene and HHT type 2 is caused by pathogenic alterations in the ACVLR1 gene (MedlinePlus). Mutations in the ENG and ACVLR1 genes cause approximately 96% of HHT cases (44% and 52%, respectively)(GeneReviews).

Disruptive ENG variants compromise endoglin function predominantly through loss of function associated with haploinsufficiency (GeneReviews)(McDonald et al. 2015). Copy number variations (CNVs) are part of the mutation spectrum associated with HHT type 1, explaining 4% - 5% of the disease (GeneReviews).

Heterozygous pathogenic variants in ACVRL1 result in reduced levels or function of the Activin-Receptor Like kinase 1 (ALK1) receptor, leading to loss of function associated with haploinsufficiency and impaired signalling through the TGF β/BMP pathway (GeneReviews)(McDonald et al. 2015) (Faughnan et al. 2020)). CNVs represent part of the ACVRL1 mutational spectrum in HHT type 2, explaining 5% - 6% of the disease (GeneReviews). Large deletions, including complete loss of the ACVRL1 gene, have been documented for HHT (ClinVar ACVRL1). Apart from CNVs, the mutation spectrum associated with the ACVRL1 and ENG genes in HHT includes a range of sequence level pathogenic variants, including nonsense, frameshift, missense, and indel mutations (ClinVar ACVRL1, ClinVar ENG)(McDonald et al. 2015).

Heritable Pulmonary Arterial Hypertension (HPAH) is inherited in an autosomal dominant manner (GeneReviews)(Austin and Loyd 2014) and is characterised by elevated pulmonary arterial pressure. This disease encompasses familial Pulmonary Arterial Hypertension (PAH) and simplex PAH (GeneReviews). PAH is estimated to affect 48-55 adults per million (Humbert et al. 2023).

The BMPR2 gene encodes the cell surface receptor BMPR2, which is part of the TGF-β/BMP signalling pathway (Handa et al. 2014, Machado et al. 2015). BMPR2 mutations diminish receptor expression or function, leading to defective BMP signalling (West et al. 2014). Mutations in BMPR2 account for disease in approximately 75% of patients with HPAH (GeneReviews). According to literature, 5% - 20% of HPAH is caused by deletions/duplications in BMPR2 (Aldred et al. 2006, Graf et al. 2018, Machado et al. 2009). Apart from CNVs, the mutation spectrum associated with the BMPR2 gene in HPAH includes a range of sequence level pathogenic variants, including nonsense, missense, splice site and small intragenic deletions and duplications mutations (GeneReviews, ClinVar BMPR2)(Machado et al. 2006).

Regulatory status

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

Translations and Summary of Safety and Performance

Translations of the product description in selected European languages are available upon request. Please contact us or one of our local sales partners. Translations of the MLPA General Protocol in selected languages are available here.

The Summary of Safety and Performance (SSP) is also available upon request.

List prices

Product

Item no.
Description
Technology
Price
P093-025R
SALSA MLPA Probemix P093 HHT/HPAH – 25 rxn
MLPA
€ 296.00
P093-050R
SALSA MLPA Probemix P093 HHT/HPAH – 50 rxn
MLPA
€ 580.00
P093-100R
SALSA MLPA Probemix P093 HHT/HPAH – 100 rxn
MLPA
€ 1135.00

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
€ 361.00
EK1-CY5
SALSA MLPA Reagent Kit – 100 rxn – Cy5 (6 vials)
MLPA MS-MLPA
€ 361.00
EK5-FAM
SALSA MLPA Reagent Kit – 500 rxn – FAM (5×6 vials)
MLPA MS-MLPA
€ 1658.00
EK5-CY5
SALSA MLPA Reagent Kit – 500 rxn – Cy5 (5×6 vials)
MLPA MS-MLPA
€ 1658.00
EK20-FAM
SALSA MLPA Reagent Kit – 2000 rxn – FAM (5×6 vials)
MLPA MS-MLPA
€ 6373.00

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.
  • Austin ED et al. (2014). The genetics of pulmonary arterial hypertension. Circ Res. 115:189-202.
  • Faughnan ME et al. (2020). Second International Guidelines for the Diagnosis and Management of Hereditary Hemorrhagic Telangiectasia. Ann Intern Med. 173:989-1001.
  • Gräf S et al. (2018). Identification of rare sequence variation underlying heritable pulmonary arterial hypertension. Nat Commun. 9:1416.
  • Handa T et al. (2014). BMPR2 gene mutation in pulmonary arteriovenous malformation and pulmonary hypertension: a case report. Respir Investig. 52:195-8.
  • Humbert M et al. (2023). 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J. 61:2200879.
  • Machado RD et al. (2006). Mutations of the TGF-beta type II receptor BMPR2 in pulmonary arterial hypertension. Hum Mutat. 27:121-32.
  • Machado RD et al. (2009). Genetics and genomics of pulmonary arterial hypertension. J Am Coll Cardiol. 54:S32-S43.
  • Machado RD et al. (2015). Pulmonary Arterial Hypertension: A Current Perspective on Established and Emerging Molecular Genetic Defects. Hum Mutat. 36:1113-27.
  • McDonald J et al. (2015). Hereditary hemorrhagic telangiectasia: genetics and molecular diagnostics in a new era. Front Genet. 6:1.
  • 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.
  • Tørring PM et al. (2014). National mutation study among Danish patients with hereditary haemorrhagic telangiectasia. Clin Genet. 86:123-33.
  • West J et al. (2014). Rescuing the BMPR2 signaling axis in pulmonary arterial hypertension. Drug Discov Today. 19:1241-5.
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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.

CE2797

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.