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SALSA MLPA Probemix P163 GJB-WFS1-POU3F4

SALSA® MLPA® Probemix P163 GJB-WFS1-POU3F4 detects copy number variations in the GJB2, GJB3, GJB6, WFS1 and POU3F4 genes, and microdeletions in the upstream region of POU3F4.

Specifications

Contents: 51 MLPA probes, including 3 probes for GJB2, 5 probes for GJB6, 4 probes for GJB3, 9 probes for the POU3F4 region, 9 probes for WFS1 and 6 probes for the c.313del14, c.235delC, c.167delT, c.101T>C, c.35delG and IVS1+1G>A mutations in GJB2.

Tissue: genomic DNA isolated from human peripheral whole blood.

Application: hereditary hearing loss and Wolfram Syndrome type 1 (WS1).

CE-marked for in vitro diagnostic (IVD) use.

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List Prices Documentation

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Intended purpose

The SALSA MLPA Probemix P163 GJB-WFS1-POU3F4 is an in vitro diagnostic (IVD) or research use only (RUO) semi-quantitative assay for the detection of deletions or duplications in the GJB2, GJB3, GJB6, WFS1, and POU3F4 genes, microdeletions upstream of POU3F4, and the presence of six specific mutations in the GJB2 gene in genomic DNA isolated from human peripheral whole blood specimens. P163 GJB-WFS1-POU3F4 is intended to confirm a potential cause for and clinical diagnosis of hereditary hearing loss and Wolfram Syndrome type 1. This assay can also be used for molecular genetic testing of at-risk family members.

For the full intended purpose, see the product description.

Clinical background

Hearing loss is a common congenital defect. The estimated incidence of permanent hearing loss at birth, defined as a sensorineural loss of ≥35 dB, is 1 in 500-1000 newborns, and approximately 50 to 60% of all hearing loss cases have been attributed to inherited or genetic factors. Inheritance of hearing loss can be autosomal recessive (75-85%), autosomal dominant (15-24%), X-linked (1-2%) or mitochondrial. More than 70% of hereditary hearing loss is nonsyndromic; the remaining 30% is accompanied by additional clinical findings and is considered syndromic.

In many populations, up to 50% of all cases of autosomal recessive nonsyndromic hearing loss are caused by mutations in the DFNB1 (Deafness, Nonsyndromic, autosomal recessive 1) locus on 13q12 (https://www.ncbi.nlm.nih.gov/books/NBK1272/). This locus contains the GJB2 and GJB6 genes, encoding connexin 26 and 30 protein, respectively. In Caucasians, the GJB2 c.35delG is the most frequent mutation, comprising 70% of mutated DFNB1 alleles with a carrier rate of 2–4% in the northern European population. The c.235delC mutation is the most common variant in the Japanese population (carrier rate of 1-2%). With a carrier rate of ~7.5%, the c.167delT mutation is the most frequently occurring mutation in the Ashkenazi Jewish population. The c.101T>C mutation is associated with mild hearing loss and has a minor allele frequency of 1-2%. The IVS1+1G>A and c.313del14 mutations have been found with relatively high frequency among various populations, mainly in eastern Europe, Russia, the Middle East and Asia. Six large deletions in GJB2 and/or GJB6 have been shown to contribute to DFNB1 hearing loss and account for 1–10% of all the mutated DFNB1 alleles. The most common deletions of 309 kilobases (kb) [del(GJB6-D13S1830)] and 232 kb [del(GJB6-D13S1854)] truncate GJB6 and the upstream CRYL1 gene.

GJB3 is located on 1p34, which is the DFNA2B (Deafness, Nonsyndromic, autosomal dominant 2B) locus. Mutations in GJB3 can cause nonsyndromic hearing loss, as well as the skin disorder erythrokeratodermia variabilis (https://www.ncbi.nlm.nih.gov/books/NBK1434/).

The GJB2 and GJB6 genes are also involved in DFNA3 (Deafness, Nonsyndromic, autosomal dominant 3). DFNA3 is caused by a heterozygous pathogenic mutation in one of the two genes. The relative prevalence of DFNA3 as a cause of autosomal dominant nonsyndromic hearing loss is not known, but it is extremely rare; only 14 pathogenic variants have been described worldwide. The majority of these pathogenic variants are described only in single families or simplex cases. Copy number changes in GJB2 and GJB6 related to DFNA3 have not been described (https://www.ncbi.nlm.nih.gov/books/NBK1536/).

About half of all X-linked hearing loss cases are caused by pathogenic mutations in the POU3F4 gene and upstream region of the gene. Several X-linked hearing loss patients and families possess deletions that do not affect the transcribed region of POU3F4, but instead remove different portions of DNA upstream of POU3F4 where putative regulatory elements reside. POU3F4 is located on the X chromosome, in a 3-Mb gene desert region enriched for highly conserved non-coding regions (HCNRs). Multiple enhancers, important for POU3F4 expression, are defined within these HCNRs at 970, 920, 170 and 12 kb upstream of POU3F4 (Naranjo et al. 2010, Song et al. 2010, Vore et al. 2005).

Wolfram Syndrome is a progressive neurodegenerative disorder characterised by the onset of diabetes mellitus and optic atrophy before the age of 15 and is typically associated with sensorineural hearing loss, progressive neurologic abnormalities, and other endocrine abnormalities. The estimated prevalence of Wolfram Syndrome type 1 is 1 in 500,000 people worldwide. Mutations in WFS1 cause more than 90% of Wolfram Syndrome type 1 cases (https://www.ncbi.nlm.nih.gov/books/NBK4144/).

Regulatory status

SALSA MLPA Probemix P163 GJB-WFS1-POU3F4 is CE-marked for in vitro diagnostic (IVD) use.

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

Product documentation

Version E1

Other versions

Contact us for earlier versions.

List prices

Product

Item no.
Description
Technology
Price
P163-025R
SALSA MLPA Probemix P163 GJB-WFS1-POU3F4 – 25 rxn
MLPA
€ 281.00
P163-050R
SALSA MLPA Probemix P163 GJB-WFS1-POU3F4 – 50 rxn
MLPA
€ 550.00
P163-100R
SALSA MLPA Probemix P163 GJB-WFS1-POU3F4 – 100 rxn
MLPA
€ 1075.00

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
€ 341.00
EK1-Cy5
SALSA MLPA Reagent Kit – 100 rxn – Cy5 (6 vials)
MLPA MS-MLPA
€ 341.00
EK5-FAM
SALSA MLPA Reagent Kit – 500 rxn – FAM (5×6 vials)
MLPA MS-MLPA
€ 1571.00
EK5-Cy5
SALSA MLPA Reagent Kit – 500 rxn – Cy5 (5×6 vials)
MLPA MS-MLPA
€ 1571.00
EK20-FAM
SALSA MLPA Reagent Kit – 2000 rxn – FAM (5×6 vials)
MLPA MS-MLPA
€ 6037.00

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 have been tested with the current (E1) version of this product and have been shown to produce useful results.

  • Coriell HG00478 (m): Heterozygous positive for the GJB2 c.235delC mutation.
  • Coriell NA12606 (m): Large heterozygous duplication (42 Mb) affecting the probes for GJB2, GJB6, CRYL1 and flanking probes.
  • Coriell NA22601 (m): Heterozygous deletion affecting the probes for WFS1.
  • Coriell NA23835 (m): Heterozygous positive for the GJB2 35delG and the 101T>C mutations.

Resources

General MLPA resources

MLPA education

Publications

References

  • Naranjo S et al. (2010). Multiple enhancers located in a 1-Mb region upstream of POU3F4 promote expression during inner ear development and may be required for hearing. Hum Genet. 128:411-9.
  • Song MH et al. (2010). Clinical evaluation of DFN3 patients with deletions in the POU3F4 locus and detection of carrier female using MLPA. Clin Genet. 78:524-32.
  • Vore AP et al. (2005). Deletion of and novel missense mutation in POU3F4 in 2 families segregating X-linked nonsyndromic deafness. Arch Otolaryngol Head Neck Surg. 131:1057-63.
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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.