What is 22q11.2 Deletion Syndrome?
22q11.2 deletion syndrome (DS) has an extremely variable symptoms (1) and is estimated to in occur 1/4,000-6,000 live births (2). The symptoms are so variable, in fact, that 22q11.2 DS was originally broken up into five different syndromes including: DiGeorge syndrome, velocardiofacial syndrome/Sphrintzen syndrome, conotruncal anomaly face syndrome, autosomal dominant Opitz G/BBB syndrome, and Cayler cardiofacial syndrome (2). These syndromes remained separate until it was discovered that they had the same genetic cause. The syndromes were then unified under a single name, 22q11.2 DS, named after the genetic anomaly (3,4). Clinically, the term 22q11.2 DS is used when patients are known to have that deletion whereas the specific syndrome names, such as DiGeorge syndrome, is used when a diagnosis relies on clinical features (5).
Characteristics of 22q11.2 DS (2)
Other than being extremely variable, 22q11.2 DS most commonly presents with:
1. Congenital heart defect (74% of patients)
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Hypocalcaemia (50%), renal anomalies (31%), autism spectrum disorders (20%), psychiatric illnesses (25%), feeding and swallowing problems (36%), hearing loss, laryngotracheoesophageal anomalies, growth hormone deficiency, autoimmune disorders, seizers, center nervous system anomalies, skeletal abnormalities, ophthalmologic abnormalities, enamel hypoplasia, and malignancies are also associated with 22q11.2 DS (2).
The role of Tbx1
A majority of patients with the clinical features of 22q11.2 DS have a deletion on the 22 chromosome that can be identified by Fluorescent in situ hybridization (FISH) (5). The two most common deletions are a 3 mega base (Mb) and 1.5 Mb that contains that 30-40 genes (3,5).
Transcription Box-1 (Tbx1) is one of the genes located in this deleted region and has been proven to be a successful candidate gene for 22q11.2 DS for two main reasons (7):
1. In mice, when both copies of Tbx1 are not functioning, the mice phenotypically resembles a severe case of 22q11.2 DS.
2. Tbx1 is expressed in the tissue that forms the pharyngeal apparatus that will later become the heart and face of the organism.
1. In mice, when both copies of Tbx1 are not functioning, the mice phenotypically resembles a severe case of 22q11.2 DS.
2. Tbx1 is expressed in the tissue that forms the pharyngeal apparatus that will later become the heart and face of the organism.
Transcription FactorsTbx1 is a transcription factor. In references to Figure 3, transcription factors play a role in transcription and is the first step in the central dogma. The central dogma is simply DNA makes RNA makes proteins. Transcription factors are one way of regulating gene expression by controlling the rate at which RNA is made (9).
As you could imagine, when one whole copy of the Tbx1 gene is gone, like in 22q11.2 DS, there is half the amount to the Tbx1 transcription factor in the cell. Since Tbx1 is so important in development, the organism will not be able to develop or function normally. This is thought to be creating the symptoms associated with 22q11.2 DS.
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InheritanceIn most cases, the deletion of this region is a random (de novo) event that is not inherited from parents, however, in 8%-28% of cases are inherited in an autosomal dominant pattern (3,10).
As seen in Figure 4, a parent who has 22q11.2 DS has a 50% chance of having a child also with the syndrome. It has been noted that the second generation with 22q11.2 DS has a more severe phenotype than the first generation (10). |
Treatment
This is no cure for 22q11.2 DS, however, it can be managed fairly well through multidisciplinary medical care. Patients with 22q11.2 deletion syndrome need to be monitored in a "system by system" basis (2) and are treated by many types of doctors and other healthcare professionals. Patients often see specialists in (4):
References:
1. Guo, T., McGinn, D. M., Blonska, A., Shanske, A., Bassett, A., Chow, E., … Morrow, B., the International Chromosome 22q11.2 Consortium. (2011). Genotype and cardiovascular phenotype correlations with TBX1 in 1,022 velo-cardio- facial/DiGeorge/22q11.2 deletion syndrome patients. Human Mutation,32(11), 1278–1289. doi:10.1002/humu.21568
2. McDonald-McGinn DM, Emanuel BS, Zackai EH. 22q11.2 Deletion Syndrome. 1999 Sep 23 [Updated 2013 Feb 28]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2015. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1523/
3. Genetics Home Reference. (2013). http://ghr.nlm.nih.gov/condition/22q112-deletion-syndrome. Retrieved February 16, 2015.
4. The International 22q11.2 Foundation Inc. http://www.22q.org/index.php/what-is-22q/overview. Retrieved January 23, 2015.
5. Kobrynski, Lisa J et al. (2007). Velocardiofacial syndrome, DiGeorge syndrome: the chromosome 22q11.2 deletion syndromes. The Lancet, Volume 370, Issue 9596, 1443-1452.
6. Grassi, M. S., Jacob, C. M. A., Kulikowski, L. D., Pastorino, A. C., Dutra, R. L., Miura, N., … Carneiro-Sampaio, M. (2014). Congenital Heart Disease as a Warning Sign for the Diagnosis of the 22q11.2 Deletion. Arquivos Brasileiros de Cardiologia, 103(5), 382–390. doi:10.5935/abc.20140145
7. Gao, S., Li, X., & Amendt, B. A. (2013). Understanding the Role of Tbx1 as a Candidate Gene for 22q11.2 Deletion Syndrome. Current Allergy and Asthma Reports, 13(6), 10.1007/s11882–013–0384–6. doi:10.1007/s11882-013-0384-6
8. Digilio, M., Marino, B., Capolino, R., & Dallapiccola, B. (2005). Clinical manifestations of Deletion 22q11.2 syndrome (DiGeorge/Velo-Cardio-Facial syndrome). Images in Paediatric Cardiology, 7(2), 23–34.
9. Genetic Home Reference. (2015). http://ghr.nlm.nih.gov/glossary=transcriptionfactor. Retrieved May 17, 2015.
10. Cirillo, E., Giardino, G., Gallo, V., Puliafito, P., Azzari, C., Bacchetta, R., … Pignata, C. (2014). Intergenerational and intrafamilial phenotypic variability in 22q11.2 Deletion syndrome subjects. BMC Medical Genetics, 15, 1. doi:10.1186/1471-2350-15-1
Images:
Header Image: http://www.research.chop.edu/blog/tag/22q11-2-deletion-syndrome/
Figure 3: Kobrynski, Lisa J et al. (2007). Velocardiofacial syndrome, DiGeorge syndrome: the chromosome 22q11.2 deletion syndromes. The Lancet, Volume 370, Issue 9596, 1443-1452.
Figure 1:
TOF http://commons.wikimedia.org/wiki/File:Tetralogy_of_Fallot.svg
Cleft lip/palate http://www.tour2india4health.com/cleft-palate-surgery-india.htm
Facial features www.ncbi.nlm.nih.gov/pmc/articles/PMC3232571/
Body form http://www.learnalberta.ca/content/ssock/html/images/kid_outline.jpg
Umbrella http://dreamatico.com/umbrella.html
1. Guo, T., McGinn, D. M., Blonska, A., Shanske, A., Bassett, A., Chow, E., … Morrow, B., the International Chromosome 22q11.2 Consortium. (2011). Genotype and cardiovascular phenotype correlations with TBX1 in 1,022 velo-cardio- facial/DiGeorge/22q11.2 deletion syndrome patients. Human Mutation,32(11), 1278–1289. doi:10.1002/humu.21568
2. McDonald-McGinn DM, Emanuel BS, Zackai EH. 22q11.2 Deletion Syndrome. 1999 Sep 23 [Updated 2013 Feb 28]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2015. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1523/
3. Genetics Home Reference. (2013). http://ghr.nlm.nih.gov/condition/22q112-deletion-syndrome. Retrieved February 16, 2015.
4. The International 22q11.2 Foundation Inc. http://www.22q.org/index.php/what-is-22q/overview. Retrieved January 23, 2015.
5. Kobrynski, Lisa J et al. (2007). Velocardiofacial syndrome, DiGeorge syndrome: the chromosome 22q11.2 deletion syndromes. The Lancet, Volume 370, Issue 9596, 1443-1452.
6. Grassi, M. S., Jacob, C. M. A., Kulikowski, L. D., Pastorino, A. C., Dutra, R. L., Miura, N., … Carneiro-Sampaio, M. (2014). Congenital Heart Disease as a Warning Sign for the Diagnosis of the 22q11.2 Deletion. Arquivos Brasileiros de Cardiologia, 103(5), 382–390. doi:10.5935/abc.20140145
7. Gao, S., Li, X., & Amendt, B. A. (2013). Understanding the Role of Tbx1 as a Candidate Gene for 22q11.2 Deletion Syndrome. Current Allergy and Asthma Reports, 13(6), 10.1007/s11882–013–0384–6. doi:10.1007/s11882-013-0384-6
8. Digilio, M., Marino, B., Capolino, R., & Dallapiccola, B. (2005). Clinical manifestations of Deletion 22q11.2 syndrome (DiGeorge/Velo-Cardio-Facial syndrome). Images in Paediatric Cardiology, 7(2), 23–34.
9. Genetic Home Reference. (2015). http://ghr.nlm.nih.gov/glossary=transcriptionfactor. Retrieved May 17, 2015.
10. Cirillo, E., Giardino, G., Gallo, V., Puliafito, P., Azzari, C., Bacchetta, R., … Pignata, C. (2014). Intergenerational and intrafamilial phenotypic variability in 22q11.2 Deletion syndrome subjects. BMC Medical Genetics, 15, 1. doi:10.1186/1471-2350-15-1
Images:
Header Image: http://www.research.chop.edu/blog/tag/22q11-2-deletion-syndrome/
Figure 3: Kobrynski, Lisa J et al. (2007). Velocardiofacial syndrome, DiGeorge syndrome: the chromosome 22q11.2 deletion syndromes. The Lancet, Volume 370, Issue 9596, 1443-1452.
Figure 1:
TOF http://commons.wikimedia.org/wiki/File:Tetralogy_of_Fallot.svg
Cleft lip/palate http://www.tour2india4health.com/cleft-palate-surgery-india.htm
Facial features www.ncbi.nlm.nih.gov/pmc/articles/PMC3232571/
Body form http://www.learnalberta.ca/content/ssock/html/images/kid_outline.jpg
Umbrella http://dreamatico.com/umbrella.html
Jaclyn Kotlarek
[email protected]
Last Updated:May 17, 2015
[email protected]
Last Updated:May 17, 2015