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P114 Long-QT

SALSA MLPA Probemix P114 Long-QT detects copy number variations in the KCNQ1, KCNH2, KCNE1, KCNE2 and KCNJ2 genes.

Specifications

Contents: 52 MLPA probes, including 18 probes for KCNQ1, 16 probes for KCNH2, 3 probes for KCNJ2, 4 probes for KCNE1 and 2 probes for KCNE2.

Tissue: genomic DNA isolated from human peripheral whole blood.

Application: Congenital Long-QT syndrome (LQTS) type 1 and 2 and Jervell Lange-Nielsen syndrome (JLNS). Research use: LQTS type 5, 6 and 7

IVDR certified for in vitro diagnostic (IVD) use. Not all targets are for IVD use.

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Key related products

ME030 BWS/RSS

Contains probes for the KCNQ1 gene located in the 11p15 BWS/RSS locus.

P108 SCN5A

Contains probes for the SCN5A gene.

P350 CLCN1-KCNJ2

Contains five probes for KCNJ2, three of which target the same sequences as the KCNJ2 probes in P114-C1.

View all

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 P114 Long-QT is an in vitro diagnostic (IVD) or research use only (RUO) semi-quantitative manual assay for the detection of deletions or duplications in the KCNQ1 and KCNH2 genes in genomic DNA obtained from human peripheral whole blood specimens. P114 Long-QT is intended to confirm a potential cause for and clinical diagnosis of congenital Long-QT syndrome (LQTS) types 1 and 2 or Jervell Lange-Nielsen syndrome (JLNS); a recessive form of LQTS associated with homozygous or compound heterozygous mutations in KCNQ1. P114 Long-QT can also be used for molecular genetic testing of at-risk family members.

Certain probes targeting additional genes included in P114 Long-QT may only be used in a research setting. The following table summarises which probes are for IVD, and which are exclusively restricted to RUO use.

IVD targets
RUO targets
KCNQ1, KCNH2
KCNE1 , KCNE2, KCNJ2

For the full intended purpose, see the product description.

Clinical background

Congenital Long-QT Syndrome (LQTS), also referred to as Romano-Ward syndrome (RWS), is a hereditary disease that predisposes patients to cardiac arrhythmias, which can result in recurrent syncope, seizure and sudden death. LQTS patients are electrocardiographically characterized by a prolonged QT interval resulting in a predisposition to develop the ventricular tachycardia torsade de pointes. The cumulative mortality is 6-8% before the age of 40, and therefore it is a leading cause of sudden death in young people. LQTS occurs in an estimated 1:2500 live births and in 75-80% of cases it is caused by mutations in cardiac sodium or potassium channel genes which result in the prolongation of the ventricular action potential. LQTS can be diagnosed based on prolonged QT intervals and/or abnormal T-waves in an ECG.

There are presently 15 types of LQTS known, each linked to a distinct gene. Generally, LQTS is inherited in an autosomal dominant fashion but some exceptions are discussed below. Most patients have LQTS type 1 or 2 with mutations in KCNQ1 (30-35% of LQTS patients) or KCNH2 (25-30% of LQTS patients) genes, respectively. The majority of disease-causing mutations in these genes are missense, nonsense, splice site or small frameshift mutations, accounting for 97-98% of LQTS type 1 or 2 patients. CNVs in KCNQ1 and KCNH2 genes have been identified in approximately 3% of individuals with LQTS, after mutation-negative results from sequencing. KCNQ1 and KCNH2 genes have definitive evidence for disease association (Adler et al. 2020).

Jervell and Lange-Nielsen syndrome (JLNS) is an rare autosomal recessive variant of LQTS. Patients with JLNS present a much more severe phenotype. They have more extended long-QT intervals and suffer from sensorineural hearing loss. 50% of patients with this syndrome have cardiac events before the age of three and more than half of untreated children die before the age of 15. JLNS patients have biallelic mutations (homozygous or compound heterozygous) in KCNQ1 or KCNE1. 90% of JLNS cases are due to KCNQ1 mutations, the majority being missense mutations; however cases of (multi)exon deletions and insertions are rare, but have been reported. 10% of JLNS cases are due to KCNE1 mutations, and no CNVs have been reported to date.

<1% of patients have LQTS type 5 which is associated with KCNE1 gene; and ~1% have LQTS type 6, which is associated with KCNE2 gene. KCNE1 and KCNE2 genes have no validity for congenital LQTS, but have a strong susceptibility to acquired LQTS. As of yet, no exon CNVs or whole gene deletions/duplications of KCNE1 and KCNE2 have been found in LQTS patients (Williams et al. 2015).

LQTS type 7, also autosomal dominant, is associated with mutations in KCNJ2. Less than 1% of LQTS patients have this type, but there is evidence that CNVs of KCNJ2 occur in LQTS patients (Marquis-Nicholson et al. 2014). LQTS type 7 is also known as Andersen-Tawil syndrome. Besides a long-QT interval and ventricular arrhythmias, these patients experience periodic paralysis due to flaccid muscle weakness and can have a variety of congenital or developmental abnormalities including low-set ears, widely spaced eyes, small mandible, fifth-digit clinodactyly, syndactyly, short stature, scoliosis and in some cases intellectual disability.

LQTS type 3, occurring in 5-10% of LQTS patients, is associated with gain-of-function variants of the SCN5A gene. All known gain-of-function mutations are point mutations, which cannot be detected with MLPA. Because CNVs in SCN5A are not expected to cause LQTS, no probes for this gene are included in this probemix. Loss-of-function variants in SCN5A result in a different disease: Brugada syndrome, for which the SALSA MLPA Probemix P108 is available.

More information on LQTS can be found here: https://www.ncbi.nlm.nih.gov/books/NBK1129/.

Regulatory status

SALSA MLPA Probemix P114 Long-QT is CE-marked under the IVDR for in vitro diagnostic (IVD) use in Europe.

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

Product documentation

Version C1

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
P114-025R
SALSA MLPA Probemix P114 Long-QT – 25 rxn
MLPA
€ 286.00
P114-050R
SALSA MLPA Probemix P114 Long-QT – 50 rxn
MLPA
€ 560.00
P114-100R
SALSA MLPA Probemix P114 Long-QT – 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 (C1) version of this product.

KCNE1 & KCNE2

  • Coriell NA13031: Heterozygous duplication affecting the probes for KCNE1 and KCNE2.

KCNH2

  • Coriell NA01220: Heterozygous duplication affecting the probes for KCNH2.
  • Coriell NA07412: Heterozygous deletion affecting the probes for KCNH2.
  • Coriell NA08808: Heterozygous deletion affecting the probes for KCNH2.
  • Coriell NA12519: Homozygous duplication or heterozygous triplication affecting the probes for KCNH2.

KCNQ1

Resources

General MLPA resources

MLPA education

Publications

Selected publications using P114 Long-QT

  • Barc J et al. (2011). Screening for copy number variation in genes associated with the long QT syndrome: clinical relevance. J Am Coll Cardiol. 57:40-7.
  • Christiansen M et al. (2014). Mutations in Danish patients with long QT syndrome and the identification of a large founder family with p.F29L in KCNH2. BMC Med Genet. 15:31.
  • Eddy CA et al. (2008). Identification of large gene deletions and duplications in KCNQ1 and KCNH2 in patients with long QT syndrome. Heart Rhythm. 5:1275-81.
  • Gnazzo M et al. (2024). Copy Number Variants in Cardiac Channelopathies: Still a Missed Part in Routine Arrhythmic Diagnostics. Biomolecules. 14:1450.
  • Stattin EL et al. (2012). Founder mutations characterise the mutation panorama in 200 Swedish index cases referred for Long QT syndrome genetic testing. BMC Cardiovasc Disord. 12:95.
  • Tester DJ et al. (2010). Prevalence and spectrum of large deletions or duplications in the major long QT syndrome-susceptibility genes and implications for long QT syndrome genetic testing. Am J Cardiol. 106:1124-8.
  • Valente FM et al. (2019). Transcription alterations of KCNQ1 associated with imprinted methylation defects in the Beckwith-Wiedemann locus. Genet Med. 21:1808-20.
  • Williams VS et al. (2015). Multiplex ligation-dependent probe amplification copy number variant analysis in patients with acquired long QT syndrome. Europace. 17:635-41.

References

  • Adler A et al. (2020). An International, Multicentered, Evidence-Based Reappraisal of Genes Reported to Cause Congenital Long QT Syndrome. Circulation. 141:418-28.
  • Marquis-Nicholson R et al. (2014). Array comparative genomic hybridization identifies a heterozygous deletion of the entire KCNJ2 gene as a cause of sudden cardiac death. Circ Cardiovasc Genet. 7:17-22.
  • Williams VS et al. (2015). Multiplex ligation-dependent probe amplification copy number variant analysis in patients with acquired long QT syndrome. Europace. 17:635-41.
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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.