Choose your country to see the products for your location

P250 DiGeorge

SALSA MLPA Probemix P250 DiGeorge detects copy number variations in the 22q11.2, 22q11.1, 22q13.3, 4q, 8p, 9q, 10p and 17p regions.

Specifications

Contents: 48 MLPA probes, including 29 probes for the 22q11.2 region, 1 probe for the 22q11.1 region, 17 probes for the 4q, 8p, 9q, 10p, 17p regions and 2 probes for the 22q13 region.

Tissue: genomic DNA isolated from human peripheral whole blood or specified prenatal samples (see Intended Purpose)

Application: 22q11.2 deletion syndrome (22q11.2 DS), 22q11.2 duplication syndrome (22q11.2 DupS), cat eye syndrome (CES), and differential diagnosis of 22q11.2 DS (8p23 deletion syndrome, DiGeorge syndrome/velocardiofacial syndrome complex 2 or HDR).

IVDR certified and registered for in vitro diagnostic (IVD) use in selected territories. Not all targets are for IVD use.

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 P250 DiGeorge is an in vitro diagnostic (IVD) or research use only (RUO) semi-quantitative manual assay for the detection of deletions or duplications in the human 22q11 region in genomic DNA isolated from human peripheral whole blood specimens, (un)cultured amniotic fluid obtained in week 16 of the pregnancy or later and free from blood contamination, (un)cultured chorionic villi free from maternal contamination, or fetal blood. P250 DiGeorge is intended to confirm a potential cause for and clinical diagnosis of 22q11.2 deletion syndrome (including, among others, DiGeorge syndrome, velocardiofacial syndrome, and conotruncal anomaly face syndrome), 22q11.2 duplication syndrome, or cat eye syndrome (22q11 duplications), and for testing of at-risk family members. It further contains probes for the detection of deletions in the 8p23.1 and 10p14 regions for a differential diagnosis of 22q11.2 deletion syndrome.

Certain probes targeting additional genes included in P250 DiGeorge 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
22q11 region, 8p23.1 region, 10p14 region, 10p12.31 region
4q35-qter region, 9q34.3 region, 17p13.3 region, 22q13.33 region

For the full intended purpose, see the product description.

Clinical background

22q11.2 deletion syndrome

One of the most common genetic disorders causing learning disabilities and mild intellectual disability is 22q11.2 deletion syndrome (22q11.2 DS). It is now recognized that 22q11.2 DS encompasses the phenotypes previously described as DiGeorge syndrome (DGS), velocardiofacial syndrome (VCFS), conotruncal anomaly face syndrome (CTAF), some cases of autosomal dominant Opitz G/BBB syndrome, and Cayler cardiofacial syndrome (asymmetric crying facies) (GeneReviews). 22q11.22 DS is an autosomal dominant contiguous gene deletion syndrome. The overall live birth prevalence of 22q11.2 deletions appears to be approximately 1 in 3,000-6,000, with 75% of these patients having cardiac abnormalities, which represents the major cause of mortality in 22q11.2 DS. Furthermore, immunodeficiency is frequent (~75%), hypocalcemia due to hypoparathyroidism (~50% of patients) and other developmental deficiencies such as, facial dysmorphia, palatal dysfunction, and feeding difficulties are also seen in most infants with this syndrome (McDonald-McGinn et al. 2015). Presently, it is well established that 22q11.2 DS involves microdeletions of approximately 0.7–3 million base pairs in size. The chromosome 22q11.21 region contains a cluster of low copy repeats (LCRs) of high‑homology sequences, labelled A–H (LCRs A–H). These LCRs can mediate nonallelic homologous meiotic recombination leading to recurrent copy number variations with a resulting deletion or duplication of variable segments within this chromosomal region. LCR22A and LCR22D flank the most common 2.54-Mb deletion found in ~85% of patients. Two other deletions, the proximal nested 1.5-Mb (LCR22A–LCR22B) and 2-Mb (LCR22A–LCR22C), have a combined frequency 10-15% of all 22q11.2 deletions. The distal nested (LCR22B–LCR22D and LCR22C–LCR22D) and the other more distal deletions flanked by LCRs C–E; D–E; D–F; E–F; F–G are rare and in combination only explain a few percent (~2%) of cases. According to GeneReviews, 93% of all 22q11.2 DS cases occur de novo. There have been reports of asymptomatic individuals bearing central 22q11.2 deletions (Rump et al. 2014) and it is generally accepted that nested deletions in 22q11.2 are associated with reduced penetrance.

22q11.2 duplication syndrome

22q11.2 duplication syndrome (22q11.2 DupS) is a condition caused by an extra copy of a piece of chromosome 22 (~3 Mb) which contains about 30 to 40 genes. The features of this condition vary widely, even among members of the same family (intrafamilial variability). Affected individuals may have intellectual or learning disabilities, developmental delay (the two latter overlapping with 22q11.2 DS), slow growth leading to short stature, and weak muscle tone (hypotonia). Many people with the condition do not present any clinical manifestations. It is inherited in an autosomal dominant manner. 22q11.2 DupS is much rarer than 22q11.2 DS, and currently the prevalence remains undetermined. Estimation of prevalence is difficult due to the variable phenotype of the disease and the prevalence of asymptomatic patients (Draaken et al. 2010, Sedghi et al. 2015). Due to the limitations of detection techniques used in the past, duplications have been hard to identify (Lundin et al. 2010), and no established clinical image currently exists. The TBX1 gene is nonetheless generally seen as causative (Guo et al. 2017, Xu et al. 2011).

Cat eye syndrome

Cat eye syndrome (CES) presents wide clinical variability, but classic symptoms associated with the disease are ocular coloboma, anal atresia, down slanting palpebral fissures, preauricular tags and/or pits, frequent occurrence of heart and renal malformations. In general, the abnormalities associated with CES tend to involve the eyes, ears, anal region, heart, and/or kidneys, but other organs may be affected in individuals also presenting intellectual disability (thus overlapping with clinical features of 22q11.2 DS). Most CES cases are not inherited. The syndrome is very rare, and currently there are no accurate estimates of the incidence of CES in the population. The diagnosis of CES is based on the presence of extra copy of 22q11.2 which typically presents as a small extra chromosome, frequently having two centromeres. Disease management is directed toward the specific symptoms that are apparent in each individual. The treatment of CES may require the coordinated efforts of a team of medical professionals, such as pediatricians, surgeons, heart specialists (cardiologists), specialists of the digestive tract, eye specialists; health professionals who detect, evaluate, and help to manage hearing problems; physicians who diagnose and treat disorders of the skeleton, muscles, joints, and related tissues (orthopedists); and/or other health care professionals (OMIM).

8p23 deletion syndrome, DiGeorge syndrome/velocardiofacial syndrome complex 2, and HDR

There are several reports of patients presenting clinical manifestations of 22q11.2 DS in which distinct genetic aberrations are identified. Rather than the typical 22q11.2 deletion, these patients present deletions in regions 8p23 (Devriendt et al. 1999, Kumar et al. 2018, Páez et al. 2008, Wat et al. 2009) or 10p14 (Lichtner et al. 2000, Villanueva et al. 2002, Yatsenko et al. 2004), amongst others. In these rare cases, the syndrome by which the patients are affected is usually given a name eponymous to the region affected and the observed aberration type (yielding for example 8p23 duplication syndrome).

In the particular case of 10p deletion syndrome, there are different denominations which are used depending on the location affected within this region. Haploinsufficiency of the more proximal region of 10p13-10p14 (mainly affecting CUGBP2, also deletions involving GATA3, NEBL), which has been reported in a limited number of cases, is referred to as DiGeorge syndrome/velocardiofacial syndrome complex 2 (commonly referred to as DGS2). For deletions affecting the more distal region of 10p14-10pter that result in a hemizygosity of GATA3, the term hypoparathyroidism, sensorineural deafness and renal dysplasia (HDR) is used.

Nomenclature distinctions

DGS is among the syndromes which now fall under the umbrella term 22q11.2 DS. The main clinical manifestations of DGS are currently recognised as cardiac anomalies, hypoparathyroidism, and immunodeficiency, and the syndrome has over 180 features for which no single manifestation occurs in 100% of cases. As DGS and other related diseases such as VCFS, CTAF, some cases of autosomal dominant Opitz G/BBB syndrome, and Cayler cardiofacial syndrome (asymmetric crying facies) were previously used to describe variable clinical expressions of the same entity, and the association between deletions in 22q11.2 and this phenotypic spectrum strengthened, the term 22q11.2 DS became more commonly used in a clinical setting (Corsten-Janssen et al. 2013, Kozlova et al. 2014). For DGS, this grouping is somewhat limiting, as there are other regions which have been shown to be associated with the disease. In an effort to be as systematic and precise as possible, it is now recommended that patients with the classic chromosome 22q11.2 deletion be described according to their genetic nomenclature (Cillo et al. 2024, McDonald-McGinn et al. 2015). In this sense, such individuals would be referred to as 22q11.2 DS patients. Patients presenting a clinical phenotype without identifiable genetic origin, or one which differs from a 22q11.2 deletion are to be described using syndromic nomenclature. Such patients would therefore be characterised as having DGS. In practice, however, the terms DGS and 22q11.2 DS are used interchangeably.

All documentation related to SALSA MLPA Probemix P250 DiGeorge includes nomenclature usage as described in GeneReviews.

Regulatory status

SALSA MLPA Probemix P250 DiGeorge is CE-marked under the IVDR for in vitro diagnostic (IVD) use in Europe. This assay has also been registered for IVD use in Colombia and Israel.

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

Product documentation

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
P250-025R
SALSA MLPA Probemix P250 DiGeorge – 25 rxn
€ 286.00
P250-050R
SALSA MLPA Probemix P250 DiGeorge – 50 rxn
€ 560.00
P250-100R
SALSA MLPA Probemix P250 DiGeorge – 100 rxn
€ 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)
€ 348.00
EK1-Cy5
SALSA MLPA Reagent Kit – 100 rxn – Cy5 (6 vials)
€ 348.00
EK5-FAM
SALSA MLPA Reagent Kit – 500 rxn – FAM (5×6 vials)
€ 1600.00
EK5-Cy5
SALSA MLPA Reagent Kit – 500 rxn – Cy5 (5×6 vials)
€ 1600.00
EK20-FAM
SALSA MLPA Reagent Kit – 2000 rxn – FAM (5×6 vials)
€ 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.

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 (B2) version of this product.

4q

  • Coriell NA00501: Heterozygous duplication affecting the probes for SLC25A4 and KLKB1.
  • Coriell NA03013: Heterozygous deletion affecting the probes for SLC25A4 and KLKB1.
  • Coriell NA10313: Heterozygous duplication affecting the probes for SLC25A4 and KLKB1.

8p

  • Coriell NA02030: Heterozygous duplication affecting the probes for PPP1R3B, MSRA and GATA4.
  • Coriell NA03255: Heterozygous duplication affecting the probes for PPP1R3B, MSRA and GATA4.
  • Coriell NA12721: Heterozygous deletion affecting the probes for PPP1R3B, MSRA and GATA4.

9q

10p

  • Coriell NA06936: Heterozygous deletion affecting the probes for GATA3, TCEB1P3 and CELF2.

17p

  • Coriell NA06047: Heterozygous deletion affecting the probes for RPH3AL, GEMIN4 and YWHAE.
  • Coriell NA09208: Heterozygous deletion affecting the probes for RPH3AL, GEMIN4 and YWHAE.

22q

  • Coriell NA02944: Heterozygous deletion affecting the probes in the Cat Eye Syndrome region, and LCR-A to LCR-B region.
  • Coriell NA05401: Heterozygous deletion affecting the probes in the Cat Eye Syndrome region, and LCR-A to LCR-B region with the exception of the probe for DGCR8.
  • Coriell NA07106: Heterozygous duplication affecting the probes targeting chromosome 22.
  • Coriell NA07215: Heterozygous deletion affecting the probes in the LCR-A to LCR-D region.
  • Coriell NA10382: Heterozygous deletion affecting the probes in the LCR-A to LCR-D region.
  • Coriell NA13284: Heterozygous deletion affecting the probes for ARSA and SHANK3.
  • Coriell NA17942: Heterozygous deletion affecting the probes in the LCR-A to LCR-D region.

Publications

Selected publications using P250 DiGeorge

  • Delea M et al. (2018). Genetic Imbalances in Argentinean Patients with Congenital Conotruncal Heart Defects. Genes (Basel). 9:454.
  • Delea M et al. (2022). Genetic Analysis Algorithm for the Study of Patients with Multiple Congenital Anomalies and Isolated Congenital Heart Disease. Genes (Basel). 13:1172.
  • Delio M et al. (2013). Enhanced maternal origin of the 22q11.2 deletion in velocardiofacial and DiGeorge syndromes. Am J Hum Genet. 92:439-47.
  • Martin-Nalda A et al. (2019). Identification of 22q11.2 deletion syndrome via newborn screening for severe combined immunodeficiency. Two years' experience in Catalonia (Spain). Mol Genet Genomic Med. 7:e1016.
  • Michaelovsky E et al. (2012). Genotype-phenotype correlation in 22q11.2 deletion syndrome. BMC Med Genet. 13:122.
  • Miletic A et al. (2021). Genetic evaluation of newborns with critical congenital heart defects admitted to the intensive care unit. Eur J Pediatr. 180:3219-27.
  • Monteiro FP et al. (2013). Defining new guidelines for screening the 22q11.2 deletion based on a clinical and dysmorphologic evaluation of 194 individuals and review of the literature. Eur J Pediatr. 172:927-45.
  • Vieira TP et al. (2015). Clinical Features in Patients With 22q11.2 Deletion Syndrome Ascertained by Palatal Abnormalities. Cleft Palate Craniofac J. 52:411-6.
  • Wu D et al. (2013). Characteristic face: a key indicator for direct diagnosis of 22q11.2 deletions in Chinese velocardiofacial syndrome patients. PLoS One. 8:e54404.
  • Xu YJ et al. (2011). Detecting 22q11.2 deletion in Chinese children with conotruncal heart defects and single nucleotide polymorphisms in the haploid TBX1 locus. BMC Med Genet. 12:169.
  • Zodanu GKE et al. (2021). Systemic Screening for 22q11.2 Copy Number Variations in Hungarian Pediatric and Adult Patients With Congenital Heart Diseases Identified Rare Pathogenic Patterns in the Region. Front Genet. 12:635480.

References

  • Cillo F et al. (2024). Understanding the Variability of 22q11.2 Deletion Syndrome: The Role of Epigenetic Factors. Genes (Basel). 15:321.
  • Corsten-Janssen N et al. (2013). More Clinical Overlap between 22q11.2 Deletion Syndrome and CHARGE Syndrome than Often Anticipated. Mol Syndromol. 4:235-45.
  • Devriendt K et al. (1999). Delineation of the critical deletion region for congenital heart defects, on chromosome 8p23.1. Am J Hum Genet. 64:1119-26.
  • Draaken M et al. (2010). Microduplications at 22q11.21 are associated with non-syndromic classic bladder exstrophy. Eur J Med Genet. 53:55-60.
  • Guo T et al. (2017). Genome-Wide Association Study to Find Modifiers for Tetralogy of Fallot in the 22q11.2 Deletion Syndrome Identifies Variants in the GPR98 Locus on 5q14.3. Circ Cardiovasc Genet. 10:e001690.
  • Kozlova IO et al. (2014). [Genetic and clinical characteristics of 22q11.2 deletion syndrome]. Genetika. 50:602-10.
  • Kumar V et al. (2018). An Interesting and Unique Case of 8p23.3p23.1 Deletion and 8p23.1p11.1 Interstitial Duplication Syndrome. J Pediatr Genet. 7:125-9.
  • Lichtner P et al. (2000). An HDR (hypoparathyroidism, deafness, renal dysplasia) syndrome locus maps distal to the DiGeorge syndrome region on 10p13/14. J Med Genet. 37:33-7.
  • Lundin J et al. (2010). 22q11.2 microduplication in two patients with bladder exstrophy and hearing impairment. Eur J Med Genet. 53:61-5.
  • McDonald-McGinn DM et al. (2015). 22q11.2 deletion syndrome. Nat Rev Dis Primers. 1:15071.
  • Páez MT et al. (2008). Two patients with atypical interstitial deletions of 8p23.1: mapping of phenotypical traits. Am J Med Genet A. 146A:1158-65.
  • Rump P et al. (2014). Central 22q11.2 deletions. Am J Med Genet A. 164A:2707-23.
  • Sedghi M et al. (2015). Identification of Proximal and Distal 22q11.2 Microduplications among Patients with Cleft Lip and/or Palate: A Novel Inherited Atypical 0.6 Mb Duplication. Genet Res Int. 2015:398063.
  • Villanueva MP et al. (2002). Genetic and comparative mapping of genes dysregulated in mouse hearts lacking the Hand2 transcription factor gene. Genomics. 80:593-600.
  • Wat MJ et al. (2009). Chromosome 8p23.1 deletions as a cause of complex congenital heart defects and diaphragmatic hernia. Am J Med Genet A. 149A:1661-77.
  • Xu YJ et al. (2011). Detecting 22q11.2 deletion in Chinese children with conotruncal heart defects and single nucleotide polymorphisms in the haploid TBX1 locus. BMC Med Genet. 12:169.
  • Yatsenko SA et al. (2004). Interstitial deletion of 10p and atrial septal defect in DiGeorge 2 syndrome. Clin Genet. 66:128-36.

Sign in

Don't have an account? Create one

Forgot password?

Select Your Country

Choose your country to see the products for your location

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.

CO

IVD-registered in Colombia.

IL

IVD-registered in Israel.