Genetics of Chromosome 22q11.2 Deletion Syndrome

Abstract

The 22q11.2 deletion syndrome is the most frequent deletion syndrome in humans. The genomic architecture of this chromosomal region makes it prone to anomalous meiotic rearrangements causing the loss of genetic material in the parental gamete. Gene dosage‐dependent embryonic developmental processes are subsequently disrupted and lead to multiple birth malformations, the severity of which is modulated by other unknown genetic and environmental factors. The resulting clinical picture is a heterogeneous phenotype with no correlation with the genetic lesion. Currently, genetic diagnosis is mostly performed by gene dosage quantification techniques targeting region 22q11.2, but the recent development of whole‐genome scanning methods enabling a full molecular characterisation of patients under uniform criteria and a better genotype–phenotype correlation will help to understand the pathogenesis of this disorder.

Key Concepts:

  • The 22q11.2 deletion syndrome is the most common human microdeletion syndrome.

  • It usually occurs de novo, although an estimated 10% of cases are inherited.

  • LCR22s are homologous DNA sequences that spontaneously mediate the deletion process during meiosis.

  • Parents should be studied both genomically and cytogenetically to rule out carrier status or occasional balanced rearrangements.

  • Phenotypic variability is likely to be due to genetic and environmental factors during development, and it hampers a genotype–phenotype correlation.

  • Genomic techniques will contribute to a better genotypic characterisation and understanding of the disease.

Keywords: 22q11.2 deletion syndrome; DiGeorge syndrome; velocardiofacial syndrome; microdeletion syndrome; chromosome 22

Figure 1.

Schematic representation of chromosomal region 22q11.2. (a) Relative location of genes mentioned in the text; LCR22s and some examples of typical and atypical deletions. (b) Coverage of the region with FISH and MLPA probes and aCGH probes used for genetic diagnosis. Adapted from Database of Genomic Variants (http://projects.tcag.ca/variation/) (Iafrate et al., ).

Figure 2.

Interchromosomal misalignment of LCR22s during meiotic recombination mediates deletion and duplication events in parental gametes.

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References

Adeyinka A, Stockero KJ, Flynn HC et al. (2004) Familial 22q11.2 deletions in DiGeorge/velocardiofacial syndrome are predominantly smaller than the commonly observed 3 Mb. Genetics in Medicine 6(6): 517–520.

Alkalay AA, Guo T, Montagna C et al. (2011) Genetic dosage compensation in a family with velo‐cardio‐facial/DiGeorge/22q11.2 deletion syndrome. American Journal of Medical Genetics Part A 155A(3): 548–554.

Amati F, Conti E, Novelli A et al. (1999) Atypical deletions suggest five 22q11.2 critical regions related to the DiGeorge/velo‐cardio‐facial syndrome. European Journal of Human Genetics 7(8): 903–909.

Augusseau S, Jouk S, Jalbert P and Prieur M (1986) DiGeorge syndrome and 22q11 rearrangements. Human Genetics 74(2): 206.

Babcock M, Pavlicek A, Spiteri E et al. (2003) Shuffling of genes within low‐copy repeats on 22q11 (LCR22) by Alu‐mediated recombination events during evolution. Genome Research 13(12): 2519–2532.

Babcock M, Yatsenko S, Hopkins J et al. (2007) Hominoid lineage specific amplification of low‐copy repeats on 22q11.2 (LCR22s) associated with velo‐cardio‐facial/digeorge syndrome. Human Molecular Genetics 16(21): 2560–2571.

Bartsch O, Nemecková M, Kocárek E et al. (2003) DiGeorge/velocardiofacial syndrome: FISH studies of chromosomes 22q11 and 10p14, and clinical reports on the proximal 22q11 deletion. American Journal of Medical Genetics Part A 117A(1): 1–5.

Bassett AS, Marshall CR, Lionel AC, Chow EW and Scherer SW (2008) Copy number variations and risk for schizophrenia in 22q11.2 deletion syndrome. Human Molecular Genetics 17(24): 4045–4053.

Ben‐Shachar S, Ou Z, Shaw CA et al. (2008) 22q11.2 distal deletion: a recurrent genomic disorder distinct from DiGeorge syndrome and velocardiofacial syndrome. American Journal of Human Genetics 82(1): 214–221.

Bittel DC, Yu S, Newkirk H et al. (2009) Refining the 22q11.2 deletion breakpoints in DiGeorge syndrome by aCGH. Cytogenetic and Genome Research 124(2): 113–120.

Brunet A, Armengol L, Heine D et al. (2009) BAC array CGH in patients with velocardiofacial syndrome‐like features reveals genomic aberrations on chromosome region 1q21.1. BMC Medical Genetics 10: 144.

Carelle‐Calmels N, Saugier‐Veber P, Girard‐Lemaire F et al. (2009) Genetic compensation in a human genomic disorder. New England Journal of Medicine 360(12): 1211–1216.

Cayler GG (1969) Cardiofacial syndrome. Congenital heart disease and facial weakness, a hitherto unrecognized association. Archives of Disease in Childhood 44(233): 69–75.

Costain G, Chow EW, Silversides CK and Bassett AS (2011) Sex differences in reproductive fitness contribute to preferential maternal transmission of 22q11.2 deletions. Journal of Medical Genetics 48(12): 819–824.

Daw SC, Taylor C, Kraman M et al. (1996) A common region in 10p deleted in DiGeorge and velocardiofacial syndromes. Nature Genetics 13(4): 458–460.

De la Chapelle A, Herva R, Koivisto M and Aula P (1981) A deletion in chromosome 22 can cause DiGeorge syndrome. Human Genetics 57(3): 253–256.

Devriendt K, De Mars K, De Cock P, Gewillig M and Fryns JP (1995) Terminal deletion in chromosome region 8p23.1‐8pter in a child with features of velo‐cardio‐facial syndrome. Annales de Génétique 38(4): 228–230.

DiGeorge AM (1965) Discussions on a new concept of the cellular basis of immunology. Journal of Pediatrics 67: 907.

Digilio MC, Angioni A, De Santis M et al. (2003) Spectrum of clinical variability in familial deletion 22q11.2: from full manifestation to extremely mild clinical anomalies. Clinical Genetics 63(4): 308–313.

Driscoll DA, Salvin J, Sellinger B et al. (1993) Prevalence of 22q11 microdeletions in DiGeorge and velocardiofacial syndromes: implications for genetic counselling and prenatal diagnosis. Journal of Medical Genetics 30(10): 813–817.

Edelmann L, Pandita RK and Morrow BE (1999) Low‐copy repeats mediate the common 3‐Mb deletion in patients with velo‐cardio‐facial syndrome. American Journal of Human Genetics 64(4): 1076–1086.

Fernández L, Lapunzina P, Arjona D et al. (2005b) Comparative study of three diagnostic approaches (FISH, STRs and MLPA) in 30 patients with 22q11.2 deletion syndrome. Clinical Genetics 68(4): 373–378.

Fernández L, Lapunzina P, Pajares IL et al. (2005a) Higher frequency of uncommon 1.5–2 Mb deletions found in familial cases of 22q11.2 deletion syndrome. American Journal of Medical Genetics Part A 136(1): 71–75.

Fernández L, Lapunzina P, Pajares IL et al. (2008) Unrelated chromosomal anomalies found in patients with suspected 22q11.2 deletion. American Journal of Medical Genetics Part A 146A(9): 1134–1141.

Fernández L, Nevado J, de Torres ML et al. (2012) Additional case of an uncommon 22q11.2 reciprocal rearrangement in a phenotypically normal mother of children with 22q11.2 deletion and 22q11.2 duplication syndromes. American Journal of Medical Genetics Part A 158A(11): 2963–2968.

Gothelf D, Michaelovsky E, Frisch A et al. (2007) Association of the low‐activity COMT 158Met allele with ADHD and OCD in subjects with velocardiofacial syndrome. International Journal of Neuropsychopharmacology 10(3): 301–308.

Guo T, McDonald‐McGinn D, Blonska A et al. (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.

Guris DL, Duester G, Papaioannou VE and Imamoto A (2006) Dose‐dependent interaction of Tbx1 and Crkl and locally aberrant RA signaling in a model of del22q11 syndrome. Developmental Cell 10(1): 81–92.

Halder A, Jain M, Kabra M and Gupta N (2008) Mosaic 22q11.2 microdeletion syndrome: diagnosis and clinical manifestations of two cases. Molecular Cytogenetics 1: 18.

Holmes SE, Riazi MA, Gong W et al. (1997) Disruption of the clathrin heavy chain‐like gene (CLTCL) associated with features of DGS/VCFS: a balanced (21;22)(p12;q11) translocation. Human Molecular Genetics 6(3): 357–367.

Iafrate AJ, Feuk L, Rivera MN et al. (2004) Detection of large‐scale variation in the human genome. Nature Genetics 36(9): 949–951.

Jalali GR, Vorstman JA, Errami A et al. (2007) Detailed analysis of 22q11.2 with a high density MLPA probe set. Human Mutation 29(3): 433–440.

Jensen TJ, Dzakula Z, Deciu C, van den Boom D and Ehrich M (2012) Detection of microdeletion 22q11.2 in a fetus by next‐generation sequencing of maternal plasma. Clinical Chemistry 58(7): 1148–1151.

Kelley RI, Zackai EH, Emanuel BS et al. (1982) The association of the DiGeorge anomalad with partial monosomy of chromosome 22. Journal of Pediatrics 101(2): 197–200.

Kinouchi A, Mori K, Ando M and Takao A (1976) Facial appearance of patients with conotruncal anomalies. Pediatrics of Japan 17: 84–87.

Kurahashi H, Tsuda E, Kohama R et al. (1997) Another critical region for deletion of 22q11: a study of 100 patients. American Journal of Medical Genetics 72(2): 180–185.

Li D, Tekin M, Buch M and Fan YS (2012) Co‐existence of other copy number variations with 22q11.2 deletion or duplication: a modifier for variable phenotypes of the syndrome? Molecular Cytogenetics 5(1): 18–21.

Lichtner P, Attié‐Bitach T, Schuffenhauer S et al. (2002) Expression and mutation analysis of BRUNOL3, a candidate gene for heart and thymus developmental defects associated with partial monosomy 10p. Journal of Molecular Medicine (Berlin) 80(7): 431–442.

Lindsay EA (2001) Chromosomal microdeletions: dissecting del22q11 syndrome. Nature Reviews Genetics 2(11): 858–868.

Lindsay EA, Halford S, Wadey R, Scambler PJ and Baldini A (1993) Molecular cytogenetic characterization of the DiGeorge syndrome region using fluorescence in situ hybridization. Genomics 17(2): 403–407.

Lindsay EA, Vitelli F, Su H et al. (2001) Tbx1 haploinsufficiency in the DiGeorge syndrome region causes aortic arch defects in mice. Nature 410(6824): 97–101.

Matsuoka R, Kimura M, Scambler PJ et al. (1998) Molecular and clinical study of 183 patients with conotruncal anomaly face syndrome. Human Genetics 103(1): 70–80.

McDonald‐McGinn DM, Emanuel BS and Zackai EH (2005) 22q11.2 deletion syndrome. In: Pagon RA, Bird TC, Dolan CR, Stephens K and Adam MP (eds) GeneReviews [Internet], PMID: 20301696 Seattle (WA): University of Washington, Seattle.

McDonald‐McGinn DM and Sullivan KE (2011) Chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome). Medicine 90(1): 1–18.

McDonald‐McGinn DM, Tonnesen MK, Laufer‐Cahana A et al. (2001) Phenotype of the 22q11.2 deletion in individuals identified through an affected relative: cast a wide FISHing net!. Genetics in Medicine 3(1): 23–29.

Miller DT, Adam MP, Aradhya S et al. (2010) Consensus statement: chromosomal microarray is a first‐tier clinical diagnostic test for individuals with developmental disabilities and congenital anomalies. American Journal of Human Genetics 86(5): 749–764.

Nevado J, de Torres ML, Fernández L et al. (2009) Unusual four‐generation chromosome‐22 rearrangement: when ‘normality’ masks abnormality. American Journal of Medical Genetics Part A 149A(7): 1561–1564.

Pierpont ME, Basson CT, Benson DW Jr et al. (2007) Genetic basis for congenital heart defects: current knowledge: a scientific statement from the American Heart Association Congenital Cardiac Defects Committee, Council of Cardiovascular Disease in the Young: endorsed by the American Academy of Pediatrics. Circulation 115(23): 3015–3038.

Portnoï MF (2009) Microduplication 22q11.2: a new chromosomal syndrome. European Journal of Medical Genetics 52(2–3): 88–93.

Rauch A, Zink S, Zweier C et al. (2005) Systematic assessment of atypical deletions reveals a genotype‐phenotype correlation in 22q11.2. Journal of Medical Genetics 42(11): 871–876.

Ravnan JB, Chen E, Golabi M and Lebo RV (1996) Chromosome 22q11.2 microdeletions in velocardiofacial syndrome patients with widely variable manifestations. American Journal of Medical Genetics 66(3): 250–256.

Ryan AK, Goodship JA, Wilson DI et al. (1997) Spectrum of clinical features associated with interstitial chromosome 22q11 deletions: a European collaborative study. Journal of Medical Genetics 34(10): 798–804.

Saitta SC, Harris SE, Gaeth AP et al. (2004) Aberrant interchromosomal exchanges are the predominant cause of the 22q11.2 deletion. Human Molecular Genetics 13(4): 417–428.

Schouten JP, McElgunn CJ, Waaijer R et al. (2002) Relative quantification of 40 nucleic acid sequences by multiplex ligation‐dependent probe amplification. Nucleic Acids Research 30(12): e57.

Shaikh TH, Kurahashi H, Saitta SC et al. (2000) Chromosome 22‐specific low copy repeats and the 22q11.2 deletion syndrome: genomic organization and deletion endpoint analysis. Human Molecular Genetics 9(4): 489–501.

Shaikh TH, O'Connor RJ, Pierpont ME et al. (2007) Low copy repeats mediate distal chromosome 22q11.2 deletions: sequence analysis predicts breakpoint mechanisms. Genome Research 17(4): 482–491.

Shprintzen RJ, Goldberg RB, Lewin ML et al. (1978) A new syndrome involving cleft palate, cardiac anomalies, typical facies, and learning disabilities: velo‐cardio‐facial syndrome. Cleft Palate Journal 15(1): 56–62.

Singh SM, Murphy B and O'Reilly R (2002) Monozygotic twins with chromosome 22q11 deletion and discordant phenotypes: updates with an epigenetic hypothesis. Journal of Medical Genetics 39(11): e71.

Smith A, St. Heaps L and Robson L (2002) Apparently unrelated cytogenetic abnormalities among 462 probands referred for the detection of del(22q) by FISH. American Journal of Medical Genetics 113(4): 346–350.

Stalmans I, Lambrechts D, De Smet F et al. (2003) VEGF: a modifier of the del22q11 (DiGeorge) syndrome? Nature Medicine 9(2): 173–182.

Stankiewicz P and Lupski JR (2002) Genome architecture, rearrangements and genomic disorders. Trends in Genetics 18(2): 74–82.

Strehle EM and Bantock HM (2003) The phenotype of patients with 4q‐syndrome. Genetic Counseling 14(2): 195–205.

Tan TY, Gordon CT, Amor DJ and Farlie PG (2010) Developmental perspectives on copy number abnormalities of the 22q11.2 region. Clinical Genetics 78(3): 201–218.

Tokuyasu TA, Cotter PD, Segraves R et al. (2007) Detection of single clone deletions using array CGH: identification of submicroscopic deletions in the 22q11.2 deletion syndrome as a model system. American Journal of Medical Genetics Part A 143A(9): 925–932.

Toutain J, Taine L, Morice‐Picard F et al. (2011) An unusual chromosome 22q11 deletion associated with an apparent complementary ring chromosome in a phenotypically normal woman. European Journal of Medical Genetics 54(3): 292–294.

Tsai CH, Van Dyke DL and Feldman GL (1999) Child with velocardiofacial syndrome and del (4)(q34.2): another critical region associated with a velocardiofacial syndrome‐like phenotype. American Journal of Medical Genetics 82(4): 336–339.

Vorstman JA, Jalali GR, Rappaport EF et al. (2006) MLPA: a rapid, reliable, and sensitive method for detection and analysis of abnormalities of 22q. Human Mutation 27(8): 814–821.

Wat MJ, Shchelochkov OA, Holder AM et al. (2009) Chromosome 8p23.1 deletions as a cause of complex congenital heart defects and diaphragmatic hernia. American Journal of Medical Genetics Part A 149A(8): 1661–1677.

Zweier C, Sticht H, Aydin‐Yaylagül I , Campbell CE and Rauch A (2007) Human TBX1 missense mutations cause gain of function resulting in the same phenotype as 22q11.2 deletions. American Journal of Human Genetics 80(3): 510–517.

Further Reading

Baker K and Vorstman JA (2012) Is there a core neuropsychiatric phenotype in 22q11.2 deletion syndrome? Current Opinion in Neurology 25(2): 131–137.

Bassett AS, McDonald‐McGinn DM, Devriendt K et al. (2011) Practical guidelines for managing patients with 22q11.2 deletion syndrome. Journal of Pediatrics 159(2): 332–339.

Kobrynski LJ and Sullivan KE (2007) Velocardiofacial syndrome, DiGeorge syndrome: the chromosome 22q11.2 deletion syndromes. Lancet 370(9596): 1443–1452.

Philip N and Bassett A (2011) Cognitive, behavioural and psychiatric phenotype in 22q11.2 deletion syndrome. Behavior Genetics 41(3): 403–412.

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Fernández, Luis(Jan 2013) Genetics of Chromosome 22q11.2 Deletion Syndrome. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0023881]