22q11.2 deletion syndrome

Article metrics

Abstract

22q11.2 deletion syndrome (22q11.2DS) is the most common chromosomal microdeletion disorder, estimated to result mainly from de novo non-homologous meiotic recombination events occurring in approximately 1 in every 1,000 fetuses. The first description in the English language of the constellation of findings now known to be due to this chromosomal difference was made in the 1960s in children with DiGeorge syndrome, who presented with the clinical triad of immunodeficiency, hypoparathyroidism and congenital heart disease. The syndrome is now known to have a heterogeneous presentation that includes multiple additional congenital anomalies and later-onset conditions, such as palatal, gastrointestinal and renal abnormalities, autoimmune disease, variable cognitive delays, behavioural phenotypes and psychiatric illness — all far extending the original description of DiGeorge syndrome. Management requires a multidisciplinary approach involving paediatrics, general medicine, surgery, psychiatry, psychology, interventional therapies (physical, occupational, speech, language and behavioural) and genetic counselling. Although common, lack of recognition of the condition and/or lack of familiarity with genetic testing methods, together with the wide variability of clinical presentation, delays diagnosis. Early diagnosis, preferably prenatally or neonatally, could improve outcomes, thus stressing the importance of universal screening. Equally important, 22q11.2DS has become a model for understanding rare and frequent congenital anomalies, medical conditions, psychiatric and developmental disorders, and may provide a platform to better understand these disorders while affording opportunities for translational strategies across the lifespan for both patients with 22q11.2DS and those with these associated features in the general population.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Chromosome 22 idiogram.
Figure 2: Low copy repeats and genes within the 22q11.2 deletion.
Figure 3: 22q11.2 non-allelic homologous recombination.
Figure 4: Development of the cardiovascular and pharyngeal structures affected in 22q11.2 deletion syndrome.
Figure 5: Organ and system involvement in 22q11.2 deletion syndrome.
Figure 6: Craniofacial features associated with 22q11.2 deletion syndrome.
Figure 7: Developmental trajectory.
Figure 8: Associated autosomal recessive conditions on 22q11.2.

References

  1. 1

    DiGeorge, A. Discussion on a new concept of the cellular immunology. J. Pediatr. 67, 907–908 (1965).

  2. 2

    Takao, A., Ando, M., Cho, K., Kinouchi, A. & Murakami, Y. in Etiology and Morphogenesis of Congenital Heart Disease (eds Van Praagh, R. & Takao, A. ) 253–269 (Futura Pub. Co., 1980).

  3. 3

    Digilio, M. C., Marino, B., Formigari, R. & Giannotti, A. Maternal diabetes causing DiGeorge anomaly and renal agenesis. Am. J. Med. Genet. 55, 513–514 (1995).

  4. 4

    Sulik, K. K., Johnston, M. C., Daft, P. A., Russell, W. E. & Dehart, D. B. Fetal alcohol syndrome and DiGeorge anomaly: critical ethanol exposure periods for craniofacial malformations as illustrated in an animal model. Am. J. Med. Genet. Suppl. 2, 97–112 (1986).

  5. 5

    Coberly, S., Lammer, E. & Alashari, M. Retinoic acid embryopathy: case report and review of literature. Pediatr. Pathol. Lab. Med. 16, 823–836 (1996).

  6. 6

    Sanlaville, D. et al. Phenotypic spectrum of CHARGE syndrome in fetuses with CHD7 truncating mutations correlates with expression during human development. J. Med. Genet. 43, 211–217 (2006).

  7. 7

    Jyonouchi, S., McDonald-McGinn, D. M., Bale, S., Zackai, E. H. & Sullivan, K. E. CHARGE (coloboma, heart defect, atresia choanae, retarded growth and development, genital hypoplasia, ear anomalies/deafness) syndrome and chromosome 22q11.2 deletion syndrome: a comparison of immunologic and nonimmunologic phenotypic features. Pediatrics 123, e871–e877 (2009).

  8. 8

    Yagi, H. et al. Role of TBX1 in human del22q11.2 syndrome. Lancet 362, 1366–1373 (2003). Mutations were identified in TBX1 in two unrelated patients who do not have a 22q11.2 deletion but have some of the medical findings. This finding implicates TBX1 as a causative gene for 22q11.2DS.

  9. 9

    Zweier, C., Sticht, H., Aydin-Yaylagul, I., Campbell, C. E. & Rauch, A. Human TBX1 missense mutations cause gain of function resulting in the same phenotype as 22q11.2 deletions. Am. J. Hum. Genet. 80, 510–517 (2007).

  10. 10

    Daw, S. C. et al. A common region of 10p deleted in DiGeorge and velocardiofacial syndromes. Nat. Genet. 13, 458–460 (1996). This paper demonstrates that pathogenetic copy number variations elsewhere in the genome can cause similar phenotypes as in 22q11.2DS.

  11. 11

    Grossfeld P. D. et al. The 11q terminal deletion disorder: a prospective study of 110 cases. Am. J. Med. Genet. A 129A 51–61 (2004).

  12. 12

    de la Chapelle, A., Herva, R., Koivisto, M. & Aula, P. A deletion in chromosome 22 can cause DiGeorge syndrome. Hum. Genet. 57, 253–256 (1981).

  13. 13

    Kelley, R. I. et al. The association of the DiGeorge anomalad with partial monosomy of chromosome 22. J. Pediatr. 101, 197–200 (1982). This paper and reference 12 were seminal in elucidating the association of 22q11.2DS with the clinical features of DiGeorge syndrome.

  14. 14

    Scambler, P. J. et al. Microdeletions within 22q11 associated with sporadic and familial DiGeorge syndrome. Genomics 10, 201–206 (1991). The development of FISH probes, as described in this seminal paper and in reference 15, changed our understanding of both the prevalence and the breadth of clinical variability for 22q11.2DS.

  15. 15

    Driscoll, D. A. et al. Prevalence of 22q11 microdeletions in DiGeorge and velocardiofacial syndromes: implications for genetic counselling and prenatal diagnosis. J. Med. Genet. 30, 813–817 (1993).

  16. 16

    Burn, J. et al. Conotruncal anomaly face syndrome is associated with a deletion within chromosome 22q11. J. Med. Genet. 30, 822–824 (1993).

  17. 17

    Matsuoka, R. et al. Confirmation that the conotruncal anomaly face syndrome is associated with a deletion within 22q11.2. Am. J. Med. Genet. 53, 285–289 (1994).

  18. 18

    McDonald-McGinn, D. M. et al. Autosomal dominant ‘Opitz’ GBBB syndrome due to a 22q11.2 deletion. Am. J. Med. Genet. 59, 103–113 (1995).

  19. 19

    Giannotti, A., Digilio, M. C., Marino, B., Mingarelli, R. & Dallapiccola, B. Cayler cardiofacial syndrome and del 22q11: part of the CATCH22 phenotype. Am. J. Med. Genet. 53, 303–304 (1994).

  20. 20

    McDonald-McGinn, D. M. et al. The 22q11.2 deletion: screening, diagnostic workup, and outcome of results; report on 181 patients. Genet. Test. 1, 99–108 (1997).

  21. 21

    McDonald-McGinn, D. M., Zackai, E. H. & Low, D. What's in a name? The 22q11.2 deletion. Am. J. Med. Genet. 72, 247–249 (1997).

  22. 22

    Bassett, A. S. et al. Practical guidelines for managing patients with 22q11.2 deletion syndrome. J. Pediatr. 159, 332–339.e331 (2011).

  23. 23

    McDonald-McGinn, D. M. & Sullivan, K. Chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome). Medicine 90, 1–18 (2011).

  24. 24

    Botto, L. D. et al. A population-based study of the 22q11.2 deletion: phenotype, incidence, and contribution to major birth defects in the population. Pediatrics 112, 101–107 (2003).

  25. 25

    Devriendt, K., Fryns, J. P., Mortier, G., van Thienen, M. N. & Keymolen, K. The annual incidence of DiGeorge/velocardiofacial syndrome. J. Med. Genet. 35, 789–790 (1998).

  26. 26

    Goodship, J., Cross, I., LiLing, J. & Wren, C. A population study of chromosome 22q11 deletions in infancy. Arch. Dis. Child. 79, 348–351 (1998).

  27. 27

    Oskarsdottir, S., Vujic, M. & Fasth, A. Incidence and prevalence of the 22q11 deletion syndrome: a population-based study in Western Sweden. Arch. Dis. Child. 89, 148–151 (2004).

  28. 28

    Té zenas Du Montcel, S., Mendizabai, H., Ayme, S., Levy, A. & Philip, N. Prevalence of 22q11 microdeletion. J. Med. Genet. 33, 719 (1996).

  29. 29

    McDonald-McGinn, D. M. et al. Phenotype of the 22q11.2 deletion in individuals identified through an affected relative: cast a wide FISHing net! Genet. Med. 3, 23–29 (2001).

  30. 30

    Costain, G., Chow, E. W., Silversides, C. K. & Bassett, A. S. Sex differences in reproductive fitness contribute to preferential maternal transmission of 22q11.2 deletions. J. Med. Genet. 48, 819–824 (2011).

  31. 31

    Repetto, G. M. et al. Case fatality rate and associated factors in patients with 22q11 microdeletion syndrome: a retrospective cohort study. BMJ Open 4, e005041 (2014).

  32. 32

    McDonald-McGinn, D. M. et al. The perplexing prevalence of familial nested 22q11.2 deletions. ASGH [online], (2014).

  33. 33

    Wapner, R. J. et al. Chromosomal microarray versus karyotyping for prenatal diagnosis. N. Engl. J. Med. 367, 2175–2184 (2012).

  34. 34

    Grati, F. R. et al. Prevalence of recurrent pathogenic microdeletions and microduplications in over 9500 pregnancies. Prenat. Diagn. 35, 801–809 (2015).

  35. 35

    Tomita-Mitchell A. et al. Multiplexed quantitative real-time PCR to detect 22q11.2 deletion in patients with congenital heart disease. Physiol. Genomics 42A 52–60 (2010).

  36. 36

    Chien, Y. H. et al. Incidence of severe combined immunodeficiency through newborn screening in a Chinese population. J. Formos. Med. Assoc. 114, 12–16 (2015).

  37. 37

    Kaminsky, E. B. et al. An evidence-based approach to establish the functional and clinical significance of copy number variants in intellectual and developmental disabilities. Genet. Med. 13, 777–784 (2011).

  38. 38

    Schwinger, E., Devriendt, K., Rauch, A. & Philip, N. Clinical utility gene card for: DiGeorge syndrome, velocardiofacial syndrome, Shprintzen syndrome, chromosome 22q11.2 deletion syndrome (22q11.2, TBX1). Eur. J. Hum. Genet. http://dx.doi.org/10.1038/ejhg.2010.5 (2010).

  39. 39

    McDonald-McGinn, D. M. et al. The Philadelphia story: the 22q11.2 deletion: report on 250 patients. Genet. Couns. 10, 11–24 (1999). This paper and references 20 and 29 were the first to outline the broad scope and breadth of features associated with 22q11.2DS, both in a large cohort of patients as well as in affected family members.

  40. 40

    Delio, M. et al. Enhanced maternal origin of the 22q11.2 deletion in velocardiofacial and DiGeorge syndromes. Am. J. Hum. Genet. 92, 439–447 (2013).

  41. 41

    McDonald-McGinn, D. M. et al. The 22q11.2 deletion in African-American patients: an underdiagnosed population? Am. J. Med. Genet. A 134, 242–246 (2005).

  42. 42

    Liu, A. P. et al. Under-recognition of 22q11.2 deletion in adult Chinese patients with conotruncal anomalies: implications in transitional care. Eur. J. Med. Genet. 57, 306–311 (2014).

  43. 43

    Goldmuntz, E. et al. Microdeletions of chromosomal region 22q11 in patients with congenital conotruncal cardiac defects. J. Med. Genet. 30, 807–812 (1993).

  44. 44

    Peyvandi, S. et al. 22q11.2 deletions in patients with conotruncal defects: data from 1,610 consecutive cases. Pediatr. Cardiol. 34, 1687–1694 (2013).

  45. 45

    Zori, R. T. et al. Prevalence of 22q11 region deletions in patients with velopharyngeal insufficiency. Am. J. Med. Genet. 77, 8–11 (1998).

  46. 46

    Boorman, J. G., Varma, S. & Mackie Ogilvie, C. Velopharyngeal incompetence and chromosome 22q11 deletion. Lancet 357, 774 (2001).

  47. 47

    Ruiter, E. M., Bongers, E. M., Smeets, D., Kuijpers-Jagtman, A. M. & Hamel, B. C. No justification of routine screening for 22q11 deletions in patients with overt cleft palate. Clin. Genet. 64, 216–219 (2003).

  48. 48

    Rauch, A. et al. Diagnostic yield of various genetic approaches in patients with unexplained developmental delay or mental retardation. Am. J. Med. Genet. 140, 2063–2074 (2006).

  49. 49

    Bassett, A. S. et al. Clinically detectable copy number variations in a Canadian catchment population of schizophrenia. J. Psychiatr. Res. 44, 1005–1009 (2010).

  50. 50

    Horowitz, A., Shifman, S., Rivlin, N., Pisante, A. & Darvasi, A. A survey of the 22q11 microdeletion in a large cohort of schizophrenia patients. Schizophr. Res. 73, 263–267 (2005).

  51. 51

    Bassett, A. S. et al. Premature death in adults with 22q11.2 deletion syndrome. J. Med. Genet. 46, 324–330 (2009). This paper was the first to systematically study mortality in adults with 22q11.2DS, identifying shortened longevity as an issue.

  52. 52

    Edelmann, L., Pandita, R. K. & Morrow, B. E. Low-copy repeats mediate the common 3-Mb deletion in patients with velo-cardio-facial syndrome. Am. J. Hum. Genet. 64, 1076–1086 (1999). The molecular mechanism responsible for chromosome rearrangements leading to the 22q11.2 deletion was identified. The de novo deletion is caused by non-allelic recombination events between flanking LCRs during meiosis.

  53. 53

    Shaikh, T. H. et al. Chromosome 22-specific low copy repeats and the 22q11.2 deletion syndrome: genomic organization and deletion endpoint analysis. Hum. Mol. Genet. 9, 489–501 (2000).

  54. 54

    Saitta, S. C. et al. Aberrant interchromosomal exchanges are the predominant cause of the 22q11.2 deletion. Hum. Mol. Genet. 13, 417–428 (2004).

  55. 55

    Bailey, J. A. et al. Human-specific duplication and mosaic transcripts: the recent paralogous structure of chromosome 22. Am. J. Hum. Genet. 70, 83–100 (2002).

  56. 56

    Babcock, M. et al. Shuffling of genes within low-copy repeats on 22q11 (LCR22) by Alu-mediated recombination events during evolution. Genome Res. 13, 2519–2532 (2003).

  57. 57

    Morrow, B. et al. Molecular definition of the 22q11 deletions in velo-cardio-facial syndrome. Am. J. Hum. Genet. 56, 1391–1403 (1995).

  58. 58

    Rump, P. et al. Central 22q11.2 deletions. Am. J. Med. Genet. A 164A, 2707–2723 (2014). Importantly, this paper reports cases of nested deletions of LCR22B–LCR22D, LCR22C–LCR22D and beyond, demonstrating that genes within the LCR22B–LCR22D regions result in features typically associated with the full LCR22A–LCR22D deletion.

  59. 59

    Steinberg, K. M. et al. Single haplotype assembly of the human genome from a hydatidiform mole. Genome Res. 24, 2066–2076 (2014).

  60. 60

    Chaisson, M. J. et al. Resolving the complexity of the human genome using single-molecule sequencing. Nature 517, 608–611 (2015).

  61. 61

    Ellegood, J. et al. Neuroanatomical phenotypes in a mouse model of the 22q11.2 microdeletion. Mol. Psychiatry 19, 99–107 (2014).

  62. 62

    Mukai, J. et al. Molecular substrates of altered axonal growth and brain connectivity in a mouse model of schizophrenia. Neuron 86, 680–695 (2015).

  63. 63

    Earls, L. R. & Zakharenko, S. S. A synaptic function approach to investigating complex psychiatric diseases. Neuroscientist 20, 257–271 (2013).

  64. 64

    Karpinski, B. A. et al. Dysphagia and disrupted cranial nerve development in a mouse model of DiGeorge (22q11) deletion syndrome. Dis. Model. Mech. 7, 245–257 (2014).

  65. 65

    Meechan, D. W., Maynard, T. M., Tucker, E. S. & Lamantia, A. S. Three phases of DiGeorge/22q11 deletion syndrome pathogenesis during brain development: patterning, proliferation, and mitochondrial functions of 22q11 genes. Int. J. Dev. Neurosci. 29, 283–294 (2011).

  66. 66

    Zhang, Z. & Baldini, A. In vivo response to high-resolution variation of Tbx1 mRNA dosage. Hum. Mol. Genet. 17, 150–157 (2008). In this article, mouse models were used to demonstrate that Tbx1 function in individual tissues during embryonic development is sensitive to altered gene dosage.

  67. 67

    Meechan, D. W., Maynard, T. M., Gopalakrishna, D., Wu, Y. & LaMantia, A. S. When half is not enough: gene expression and dosage in the 22q11 deletion syndrome. Gene Expr. 13, 299–310 (2007). This review paper discusses the importance of gene dosage and 22q11.2DS.

  68. 68

    McDonald-McGinn, D. M. et al. Hemizygous mutations in SNAP29 unmask autosomal recessive conditions and contribute to atypical findings in patients with 22q11.2DS. J. Med. Genet. 50, 80–90 (2013).

  69. 69

    Amati, F. et al. Dynamic changes in gene expression profiles of 22q11 and related orthologous genes during mouse development. Gene 391, 91–102 (2007).

  70. 70

    Guris, D. L., Duester, G., Papaioannou, V. E. & Imamoto, A. Dose-dependent interaction of Tbx1 and Crkl and locally aberrant RA signaling in a model of del22q11 syndrome. Dev. Cell 10, 81–92 (2006). This article shows that both Tbx1 and Crkl genetically interact in mouse models during cardiac, thymus and parathyroid gland development.

  71. 71

    Earls, L. R. et al. Age-dependent microRNA control of synaptic plasticity in 22q11 deletion syndrome and schizophrenia. J. Neurosci. 32, 14132–14144 (2012).

  72. 72

    Brzustowicz, L. M. & Bassett, A. S. miRNA-mediated risk for schizophrenia in 22q11.2 deletion syndrome. Front. Genet. 3, 291 (2012).

  73. 73

    Zhao, D. et al. MicroRNA profiling of neurons generated using induced pluripotent stem cells derived from patients with schizophrenia and schizoaffective disorder, and 22q11.2 del. PLoS ONE 10, e0132387 (2015).

  74. 74

    Bassett, A. S., Marshall, C. R., Lionel, A. C., Chow, E. W. & Scherer, S. W. Copy number variations and risk for schizophrenia in 22q11.2 deletion syndrome. Hum. Mol. Genet. 17, 4045–4053 (2008).

  75. 75

    Swillen, A. et al. The behavioural phenotype in velo-cardio-facial syndrome (VCFS): from infancy to adolescence. Genet. Couns. 10, 79–88 (1999).

  76. 76

    Arnold, J. S. et al. Inactivation of Tbx1 in the pharyngeal endoderm results in 22q11DS malformations. Development 133, 977–987 (2006).

  77. 77

    Pane, L. S. et al. Tbx1 is a negative modulator of Mef2c. Hum. Mol. Genet. 21, 2485–2496 (2012).

  78. 78

    Diogo, R. et al. A new heart for a new head in vertebrate cardiopharyngeal evolution. Nature 520, 466–473 (2015).

  79. 79

    Meechan, D. W. et al. Modeling a model: mouse genetics, 22q11.2 deletion syndrome, and disorders of cortical circuit development. Prog. Neurobiol. 130, 1–28 (2015).

  80. 80

    Sivagnanasundaram, S. et al. Differential gene expression in the hippocampus of the Df1/+ mice: a model for 22q11.2 deletion syndrome and schizophrenia. Brain Res. 1139, 48–59 (2007).

  81. 81

    Xu, B., Hsu, P. K., Stark, K. L., Karayiorgou, M. & Gogos, J. A. Derepression of a neuronal inhibitor due to miRNA dysregulation in a schizophrenia-related microdeletion. Cell 152, 262–275 (2013).

  82. 82

    Xu, B., Karayiorgou, M. & Gogos, J. A. MicroRNAs in psychiatric and neurodevelopmental disorders. Brain Res. 1338, 78–88 (2010).

  83. 83

    Zou, D. et al. Patterning of the third pharyngeal pouch into thymus/parathyroid by Six and Eya1. Dev. Biol. 293, 499–512 (2006).

  84. 84

    Kelly, R. G., Buckingham, M. E. & Moorman, A. F. Heart fields and cardiac morphogenesis. Cold Spring Harb. Perspect. Med. 4, a015750 (2014). The heart fields are crucial to form the aortic arch and conotruncal region of the heart, which are affected in 22q11.2DS. This paper explains the importance of the second heart field.

  85. 85

    Milgrom-Hoffman, M., Michailovici, I., Ferrara, N., Zelzer, E. & Tzahor, E. Endothelial cells regulate neural crest and second heart field morphogenesis. Biol. Open 3, 679–688 (2014).

  86. 86

    Keyte, A. L., Alonzo-Johnsen, M. & Hutson, M. R. Evolutionary and developmental origins of the cardiac neural crest: building a divided outflow tract. Birth Defects Res. C Embryo Today 102, 309–323 (2014).

  87. 87

    Neeb, Z., Lajiness, J. D., Bolanis, E. & Conway, S. J. Cardiac outflow tract anomalies. Wiley Interdiscip. Rev. Dev. Biol. 2, 499–530 (2013).

  88. 88

    Lewin, M. B. et al. A genetic etiology for interruption of the aortic arch type B. Am. J. Cardiol. 80, 493–497 (1997).

  89. 89

    Guna, A., Butcher, N. J. & Bassett, A. S. Comparative mapping of the 22q11.2 deletion region and the potential of simple model organisms. J. Neurodev. Disord. 7, 18 (2015).

  90. 90

    Jerome, L. A. & Papaioannou, V. E. DiGeorge syndrome phenotype in mice mutant for the T-box gene, Tbx1. Nat. Genet. 27, 286–291 (2001). By using mouse model approaches, Tbx1 was found to be required for craniofacial, thymus and parathyroid gland as well as cardiac development. This is a seminal paper in the field.

  91. 91

    Merscher, S. et al. TBX1 is responsible for cardiovascular defects in velo-cardio-facial/DiGeorge syndrome. Cell 104, 619–629 (2001).

  92. 92

    Lindsay, E. A. et al. Tbx1 haploinsufficieny in the DiGeorge syndrome region causes aortic arch defects in mice. Nature 410, 97–101 (2001).

  93. 93

    Zhang, Z. et al. Tbx1 expression in pharyngeal epithelia is necessary for pharyngeal arch artery development. Development 132, 5307–5315 (2005).

  94. 94

    Zhang, Z., Huynh, T. & Baldini, A. Mesodermal expression of Tbx1 is necessary and sufficient for pharyngeal arch and cardiac outflow tract development. Development 133, 3587–3595 (2006).

  95. 95

    Papangeli, I. & Scambler, P. The 22q11 deletion: DiGeorge and velocardiofacial syndromes and the role of TBX1. Wiley Interdiscip. Rev. Dev. Biol. 2, 393–403 (2013).

  96. 96

    Calmont, A. et al. Tbx1 controls cardiac neural crest cell migration during arch artery development by regulating Gbx2 expression in the pharyngeal ectoderm. Development 136, 3173–3183 (2009). In mice, the gastrulation brain homeobox 2 (Gbx2) gene was found to be crucial in the pharyngeal ectoderm to signal to adjacent neural crest cells, which was required to form the aortic arch and branching vessels.

  97. 97

    Vitelli, F., Morishima, M., Taddei, I., Lindsay, E. A. & Baldini, A. Tbx1 mutation causes multiple cardiovascular defects and disrupts neural crest and cranial nerve migratory pathways. Hum. Mol. Genet. 11, 915–922 (2002).

  98. 98

    Caprio, C. & Baldini, A. p53 suppression partially rescues the mutant phenotype in mouse models of DiGeorge syndrome. Proc. Natl Acad. Sci. USA 111, 13385–13390 (2014). Genetic rescue is the gold standard for future therapeutics for 22q11.2DS. This is the first paper demonstrating that genetic rescue can take place by reducing the levels of p53.

  99. 99

    Cioffi, S. et al. Tbx1 regulates brain vascularization. Hum. Mol. Genet. 23, 78–89 (2014).

  100. 100

    Paylor, R. et al. Tbx1 haploinsufficiency is linked to behavioral disorders in mice and humans: implications for 22q11 deletion syndrome. Proc. Natl Acad. Sci. USA 103, 7729–7734 (2006).

  101. 101

    Stark, K. L. et al. Altered brain microRNA biogenesis contributes to phenotypic deficits in a 22q11-deletion mouse model. Nat. Genet. 40, 751–760 (2008).

  102. 102

    Chapnik, E., Sasson, V., Blelloch, R. & Hornstein, E. Dgcr8 controls neural crest cells survival in cardiovascular development. Dev. Biol. 362, 50–56 (2012).

  103. 103

    Petri, R., Malmevik, J., Fasching, L., Akerblom, M. & Jakobsson, J. miRNAs in brain development. Exp. Cell Res. 321, 84–89 (2014).

  104. 104

    Beveridge, N. J., Gardiner, E., Carroll, A. P., Tooney, P. A. & Cairns, M. J. Schizophrenia is associated with an increase in cortical microRNA biogenesis. Mol. Psychiatry 15, 1176–1189 (2010).

  105. 105

    Merico, D. et al. MicroRNA dysregulation, gene networks, and risk for schizophrenia in 22q11.2 deletion syndrome. Front. Neurol. 5, 238 (2014).

  106. 106

    Sellier, C. et al. Decreased DGCR8 expression and miRNA dysregulation in individuals with 22q11.2 deletion syndrome. PLoS ONE 9, e103884 (2014).

  107. 107

    Guris, D. L., Fantes, J., Tara, D., Druker, B. J. & Imamoto, A. Mice lacking the homologue of the human 22q11.2 gene CRKL phenocopy neurocristopathies of DiGeorge syndrome. Nat. Genet. 27, 293–298 (2001). This paper shows that, in addition to Tbx1, inactivation of Crkl on 22q11.2 can result in physical malformations observed in 22q11.2DS.

  108. 108

    Racedo, S. E. et al. Mouse and human CRKL is dosage sensitive for cardiac outflow tract formation. Am. J. Hum. Genet. 96, 235–244 (2015). The combination of human and mouse genetics has shed new light on the function of CRKL in the formation of the cardiac outflow tract.

  109. 109

    Zheng, P. et al. Molecular mechanisms of functional natural killer deficiency in patients with partial DiGeorge syndrome. J. Allergy Clin. Immunol. 135, 1293–1302 (2015).

  110. 110

    Bedeschi, M. F. et al. Unmasking of a recessive SCARF2 mutation by a 22q11.12 de novo deletion in a patient with Van den Ende–Gupta syndrome. Mol. Syndromol. 1, 239–245 (2010).

  111. 111

    Bassett, A. S., Caluseriu, O., Weksberg, R., Young, D. A. & Chow, E. W. Catechol-O-methyl transferase and expression of schizophrenia in 73 adults with 22q11 deletion syndrome. Biol. Psychiatry 61, 1135–1140 (2007).

  112. 112

    Murphy, K. C., Jones, L. A. & Owen, M. J. High rates of schizophrenia in adults with velo-cardio-facial syndrome. Arch. Gen. Psychiatry 56, 940–945 (1999).

  113. 113

    Gothelf, D. et al. Risk factors and the evolution of psychosis in 22q11.2 deletion syndrome: a longitudinal 2-site study. J. Am. Acad. Child Adolesc. Psychiatry 52, 1192–1203.e3 (2013).

  114. 114

    Philip, N. & Bassett, A. S. Cognitive, behavioural and psychiatric phenotype in 22q11.2 deletion syndrome. Behav. Genet. 41, 403–412 (2011).

  115. 115

    Goodman, B. K., Rutberg, J., Lin, W. W., Pulver, A. E. & Thomas, G. H. Hyperprolinaemia in patients with deletion (22)(q11.2) syndrome. J. Inherit. Metab. Dis. 23, 847–848 (2000).

  116. 116

    Magnée, M. J., Lamme, V. A., de Sain-van der Velden, M. G., Vorstman, J. A. & Kemner, C. Proline and COMT status affect visual connectivity in children with 22q11.2 deletion syndrome. PLoS ONE 6, e25882 (2011).

  117. 117

    Paronett, E. M., Meechan, D. W., Karpinski, B. A., LaMantia, A.-S. & Maynard, T. M. Ranbp1, deleted in DiGeorge/22q11.2 deletion syndrome, is a microcephaly gene that selectively disrupts layer 2/3 cortical projection neuron generation. Cereb. Cortex 25, 3977–3993 (2014).

  118. 118

    Raux, G. et al. Involvement of hyperprolinemia in cognitive and psychiatric features of the 22q11 deletion syndrome. Hum. Mol. Genet. 16, 83–91 (2007).

  119. 119

    Vorstman, J. A. S. et al. Proline affects brain function in 22q11DS children with the low activity COMT158 allele. Neuropsychopharmacology 34, 739–746 (2008).

  120. 120

    Newbern, J. et al. Mouse and human phenotypes indicate a critical conserved role for ERK2 signaling in neural crest development. Proc. Natl Acad. Sci. USA 105, 17115–17120 (2008).

  121. 121

    Dykes, I. M. et al. HIC2 is a novel dosage-dependent regulator of cardiac development located within the distal 22q11 deletion syndrome region. Circ. Res. 115, 23–31 (2014).

  122. 122

    Toritsuka, M. et al. Deficits in microRNA-mediated Cxcr4/Cxcl12 signaling in neurodevelopmental deficits in a 22q11 deletion syndrome mouse model. Proc. Natl Acad. Sci. USA 110, 17552–17557 (2013).

  123. 123

    Swaby, J. A. et al. Complex congenital heart disease in unaffected relatives of adults with 22q11.2 deletion syndrome. Am. J. Cardiol. 107, 466–471 (2011).

  124. 124

    Merico, D. et al. Whole-genome sequencing suggests schizophrenia risk mechanisms in humans with 22q11.2 deletion syndrome. G3 (Bethesda) 5, 2453–2461 (2015).

  125. 125

    Swillen, A. & McDonald-McGinn, D. Developmental trajectories in 22q11.2 deletion syndrome. Am. J. Med. Genet. C Semin. Med. Genet. 169, 172–181 (2015). This paper provides a current state of the art perspective on developmental trajectories with appropriate interventions.

  126. 126

    Fung, W. L. et al. Practical guidelines for managing adults with 22q11.2 deletion syndrome. Genet. Med. 17, 599–609 (2015). This paper (for adults) and reference 22 (for children) provide a comprehensive overview of all domains to be covered in the multidisciplinary management of patients with 22q11.2DS.

  127. 127

    Vergaelen, E. et al. 3 generation pedigree with paternal transmission of the 22q11.2 deletion syndrome: intrafamilial phenotypic variability. Eur. J. Med. Genet. 58, 244–248 (2015).

  128. 128

    McElhinney, D. B., McDonald-McGinn, D., Zackai, E. H. & Goldmuntz, E. Cardiovascular anomalies in patients diagnosed with a chromosome 22q11 deletion beyond 6 months of age. Pediatrics 108, E104 (2001).

  129. 129

    John, A. S., McDonald-McGinn, D. M., Zackai, E. H. & Goldmuntz, E. Aortic root dilation in patients with 22q11.2 deletion syndrome. Am. J. Med. Genet. A 149A, 939–942 (2009).

  130. 130

    Piliero, L. M., Sanford, A. N., McDonald-McGinn, D. M., Zackai, E. H. & Sullivan, K. E. T-cell homeostasis in humans with thymic hypoplasia due to chromosome 22q11.2 deletion syndrome. Blood 103, 1020–11025 (2004). The consequences of thymic hypoplasia were elucidated in this paper. It highlights the dynamic nature of immunodeficiency over time in this syndrome.

  131. 131

    Sullivan, K. E. et al. Lack of correlation between impaired T cell production, immunodeficiency, and other phenotypic features in chromosome 22q11.2 deletion syndromes. Clin. Immunol. Immunopathol. 86, 141–146 (1998).

  132. 132

    Sullivan, K. E., McDonald-McGinn, D. & Zackai, E. H. CD4+CD25+ T-cell production in healthy humans and in patients with thymic hypoplasia. Clin. Diagn. Lab. Immunol. 9, 1129–1131 (2002).

  133. 133

    Sullivan, K. E. et al. Longitudinal analysis of lymphocyte function and numbers in the first year of life in chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome). Clin. Diagn. Lab. Immunol. 6, 906–911 (1999).

  134. 134

    Jawad, A. F. et al. A prospective study of influenza vaccination and a comparison of immunologic parameters in children and adults with chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome). J. Clin. Immunol. 31, 927–935 (2011).

  135. 135

    Perez, E. E., Bokszczanin, A., McDonald-McGinn, D., Zackai, E. H. & Sullivan, K. E. Safety of live viral vaccines in patients with chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome). Pediatrics 112, e325 (2003).

  136. 136

    Smith, C. A. et al. Increased prevalence of immunoglobulin A deficiency in patients with the chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome). Clin. Diagn. Lab. Immunol. 5, 415–417 (1998).

  137. 137

    Staple, L., Andrews, T., McDonald-McGinn, D., Zackai, E. & Sullivan, K. E. Allergies in patients with chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome) and patients with chronic granulomatous disease. Pediatr. Allergy Immunol. 16, 226–230 (2005).

  138. 138

    Zemble, R. et al. Secondary immunologic consequences in chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome). Clin. Immunol. 136, 409–418 (2010).

  139. 139

    Sullivan, K. E. et al. Juvenile rheumatoid arthritis-like polyarthritis in chromosome 22q11.2 deletion syndrome (DiGeorge anomalad/velocardiofacial syndrome/conotruncal anomaly face syndrome). Arthritis Rheum. 40, 430–436 (1997).

  140. 140

    Lawrence, S., McDonald-McGinn, D. M., Zackai, E. & Sullivan, K. E. Thrombocytopenia in patients with chromosome 22q11.2 deletion syndrome. J. Pediatr. 143, 277–278 (2003).

  141. 141

    Kratz, C. P. et al. Evans syndrome in a patient with chromosome 22q11.2 deletion syndrome: a case report. Pediatr. Hematol. Oncol. 20, 167–172 (2003).

  142. 142

    Kawame, H. et al. Graves' disease in patients with 22q11.2 deletion. J. Pediatr. 139, 892–895 (2001).

  143. 143

    Bale, P. M. & Sotelo-Avila, C. Maldescent of the thymus: 34 necropsy and 10 surgical cases, including 7 thymuses medial to the mandible. Pediatr. Pathol. 13, 181–190 (1993).

  144. 144

    Chinen, J., Rosenblatt, H. M., Smith, E. O., Shearer, W. T. & Noroski, L. M. Long-term assessment of T-cell populations in DiGeorge syndrome. J. Allergy Clin. Immunol. 111, 573–579 (2003).

  145. 145

    Dyce, O. et al. Otolaryngologic manifestations of the 22q11.2 deletion syndrome. Arch. Otolaryngol. Head Neck Surg. 128, 1408–1412 (2002).

  146. 146

    Hamilton, S., Husein, M. & Dworschak-Stokan, A. Velopharyngeal insufficiency clinic: the first 18 months. J. Otolaryngol. Head Neck Surg. 37, 586–590 (2008).

  147. 147

    Solot, C. B. et al. Communication issues in 22q11.2 deletion syndrome: children at risk. Genet. Med. 3, 67–71 (2001).

  148. 148

    Ruotolo, R. A. et al. Velopharyngeal anatomy in 22q11.2 deletion syndrome: a three-dimensional cephalometric analysis. Cleft Palate Craniofac. J. 43, 446–456 (2006).

  149. 149

    Widdershoven, J. C. et al. A candidate gene approach to identify modifiers of the palatal phenotype in 22q11.2 deletion syndrome patients. Int. J. Pediatr. Otorhinolaryngol. 77, 123–127 (2013).

  150. 150

    Stransky, C. et al. Perioperative risk factors in patients with 22q11.2 deletion syndrome requiring surgery for velopharyngeal dysfunction. Cleft Palate Craniofac. J. 52, 183–191 (2015).

  151. 151

    Forbes, B. J. et al. Ocular findings in the chromosome 22q11.2 deletion syndrome. J. AAPOS 11, 179–182 (2007).

  152. 152

    Cheung, E. N. et al. Prevalence of hypocalcemia and its associated features in 22q11.2 deletion syndrome. Clin. Endocrinol. 81, 190–196 (2014).

  153. 153

    Bassett, A. S. et al. Clinical features of 78 adults with 22q11 deletion syndrome. Am. J. Med. Genet. A 138, 307–313 (2005).

  154. 154

    Weinzimer, S. A. Endocrine aspects of the 22q11.2 deletion syndrome. Genet. Med. 3, 19–22 (2001).

  155. 155

    Digilio, M. C. et al. Auxological evaluation in patients with DiGeorge/velocardiofacial syndrome (deletion 22q11.2 syndrome). Genet. Med. 3, 30–33 (2001).

  156. 156

    Habel, A., McGinn, M.-J. 2nd, Zackai, E. H., Unanue, N. & McDonald-McGinn, D. M. Syndrome-specific growth charts for 22q11.2 deletion syndrome in Caucasian children. Am. J. Med. Genet. A 158A, 2665–2671 (2012).

  157. 157

    Van, L. et al. Fetal growth and gestational factors as predictors of schizophrenia in 22q11.2 deletion syndrome. Genet. Med. http://dx.doi.org/10.1038/gim.2015.84 (2015).

  158. 158

    Eicher, P. S. et al. Dysphagia in children with a 22q11.2 deletion: unusual pattern found on modified barium swallow. J. Pediatr. 137, 158–164 (2000).

  159. 159

    Digilio, M. C., Marino, B., Bagolan, P., Giannotti, A. & Dallapiccola, B. Microdeletion 22q11 and oesophageal atresia. J. Med. Genet. 36, 137–139 (1999).

  160. 160

    Oskarsdottir, S., Belfrage, M., Sandstedt, E., Viggedal, G. & Uvebrant, P. Disabilities and cognition in children and adolescents with 22q11 deletion syndrome. Dev. Med. Child Neurol. 47, 177–184 (2005).

  161. 161

    Wu, H.-Y. et al. Genitourinary malformations in chromosome 22q11.2 deletion. J. Urol. 168, 2564–2565 (2002).

  162. 162

    Devriendt, K., Swillen, A., Fryns, J. P., Proesmans, W. & Gewillig, M. Renal and urological tract malformations caused by a 22q11 deletion. J. Med. Genet. 33, 349 (1996).

  163. 163

    Sundaram, U. T. et al. Primary amenorrhea and absent uterus in the 22q11.2 deletion syndrome. Am. J. Med. Genet. A 143A, 2016–2018 (2007).

  164. 164

    Barnett, C., Langer, J. C., Hinek, A., Bradley, T. J. & Chitayat, D. Looking past the lump: genetic aspects of inguinal hernia in children. J. Pediatr. Surg. 44, 1423–1431 (2009).

  165. 165

    Binenbaum, G. et al. Sclerocornea associated with the chromosome 22q11.2 deletion syndrome. Am. J. Med. Genet. A 146A, 904–909 (2008).

  166. 166

    Bingham, P. M., Lynch, D., McDonald-McGinn, D. & Zackai, E. Polymicrogyria in chromosome 22 delection syndrome. Neurology 51, 1500–1502 (1998).

  167. 167

    Ming, J. E. et al. Skeletal anomalies and deformities in patients with deletions of 22q11. Am. J. Med. Genet. 72, 210–215 (1997).

  168. 168

    Ricchetti, E. T. et al. Radiographic study of the upper cervical spine in the 22q11.2 deletion syndrome. J. Bone Joint Surg. Am. 86, 1751–1760 (2004).

  169. 169

    McDonald-McGinn, D. M. et al. Malignancy in chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome). Am. J. Med. Genet. A 140, 906–909 (2006).

  170. 170

    Butcher, N. et al. Association between early-onset Parkinson disease and 22q11.2 deletion syndrome: identification of a novel genetic form of Parkinson disease and its clinical implications. JAMA Neurol. 70, 1359–1366 (2013).

  171. 171

    Swillen, A. et al. Early motor development in young children with 22q.11 deletion syndrome and a conotruncal heart defect. Dev. Med. Child Neurol. 47, 797–802 (2005).

  172. 172

    Solot, C. B. et al. Communication disorders in the 22Q11.2 microdeletion syndrome. J. Commun. Disord. 33, 187–203 (2000).

  173. 173

    Swillen, A. et al. Intelligence and psychosocial adjustment in velocardiofacial syndrome: a study of 37 children and adolescents with VCFS. J. Med. Genet. 34, 453–458 (1997).

  174. 174

    De Smedt, B. et al. Intellectual abilities in a large sample of children with velo-cardio-facial syndrome: an update. J. Intellect. Disabil. Res. 51, 666–670 (2007).

  175. 175

    De Smedt, B., Swillen, A., Verschaffel, L. & Ghesquiere, P. Mathematical learning disabilities in children with 22q11.2 deletion syndrome: a review. Dev. Disabil. Res. Rev. 15, 4–10 (2009).

  176. 176

    Wang, P. P., Woodin, M. F., Kreps-Falk, R. & Moss, E. M. Research on behavioral phenotypes: velocardiofacial syndrome (deletion 22q11.2). Dev. Med. Child Neurol. 42, 422–427 (2000).

  177. 177

    Glaser, B. et al. Language skills in children with velocardiofacial syndrome (deletion 22q11.2). J. Pediatr. 140, 753–758 (2002).

  178. 178

    Evers, L. J. et al. Psychopathology in adults with 22q11 deletion syndrome and moderate and severe intellectual disability. J. Intellect. Disabil. Res. 58, 915–925 (2014).

  179. 179

    Cheung, E. N. et al. Neonatal hypocalcemia, neonatal seizures, and intellectual disability in 22q11.2 deletion syndrome. Genet. Med. 16, 40–44 (2014).

  180. 180

    Duijff, S. N. et al. Cognitive development in children with 22q11.2 deletion syndrome. Br. J. Psychiatry 200, 462–468 (2012). This paper presents a longitudinal data study on cognitive development in a large cohort of children.

  181. 181

    Vorstman, J. A. et al. Cognitive decline preceding the onset of psychosis in patients with 22q11.2 deletion syndrome. JAMA Psychiatry 72, 377–385 (2015). Using data from a large collaborative effort (The International 22q11.2 Brain and Behavior Consortium), this paper shows the association of cognitive decline as an antecedent to the onset of psychosis. Drawing from this same consortium, reference 182, reports on the psychiatric disorders observed in this population.

  182. 182

    Schneider, M. et al. Psychiatric disorders from childhood to adulthood in 22q11.2 deletion syndrome: results from the International Consortium on Brain and Behavior in 22q11.2 deletion syndrome. Am. J. Psychiatry 171, 627–639 (2014).

  183. 183

    Fung, W. L. et al. Elevated prevalence of generalized anxiety disorder in adults with 22q11.2 deletion syndrome. Am. J. Psychiatry 167, 998 (2010).

  184. 184

    Bassett, A. S. & Chow, E. W. 22q11 deletion syndrome: a genetic subtype of schizophrenia. Biol. Psychiatry 46, 882–891 (1999).

  185. 185

    Amelsvoort, T. V. et al. Cognitive deficits associated with schizophrenia in velo-cardio-facial syndrome. Schizophr. Res. 70, 223–232 (2004).

  186. 186

    Bassett, A. S. et al. The schizophrenia phenotype in 22q11 deletion syndrome. Am. J. Psychiatry 160, 1580–1586 (2003).

  187. 187

    Chow, E. W., Watson, M., Young, D. A. & Bassett, A. S. Neurocognitive profile in 22q11 deletion syndrome and schizophrenia. Schizophr. Res. 87, 270–278 (2006).

  188. 188

    Stoddard, J., Niendam, T., Hendren, R., Carter, C. & Simon, T. J. Attenuated positive symptoms of psychosis in adolescents with chromosome 22q11.2 deletion syndrome. Schizophr. Res. 118, 118–121 (2010).

  189. 189

    Butcher, N. J. et al. Response to clozapine in a clinically identifiable subtype of schizophrenia. Br. J. Psychiatry 206, 484–491 (2015). This paper is notable as it is the first report on the functional outcome of a large group (>100 subjects) of adults with 22q11.2 DS.

  190. 190

    Baker, K. & Vorstman, J. A. S. Is there a core neuropsychiatric phenotype in 22q11.2 deletion syndrome? Curr. Opin. Neurol. 25, 131–137 (2012).

  191. 191

    Chan, C., Costain, G., Chow, E. W. C. & Bassett, A. S. Reproductive health issues for adults with a common genomic disorder. J. Genet. Couns. 24, 810–821 (2015).

  192. 192

    Balci, A. et al. Prospective validation and assessment of cardiovascular and offspring risk models for pregnant women with congenital heart disease. Heart 100, 1373–1381 (2014).

  193. 193

    Grewal, J., Silversides, C. K. & Colman, J. M. Pregnancy in women with heart disease: risk assessment and management of heart failure. Heart Fail. Clin. 10, 117–129 (2014).

  194. 194

    Sorensen, K. M. et al. Detecting 22q11.2 deletions by use of multiplex ligation-dependent probe amplification on DNA from neonatal dried blood spot samples. J. Mol. Diagn. 12, 147–151 (2010).

  195. 195

    Vorstman, J. A. et al. MLPA: a rapid, reliable, and sensitive method for detection and analysis of abnormalities of 22q. Hum. Mut. 27, 814–821 (2006).

  196. 196

    Sandrin-Garcia, P. et al. Recurrent 22q11.2 deletion in a sibship suggestive of parental germline mosaicism in velocardiofacial syndrome. Clin. Genet. 61, 380–383 (2002).

  197. 197

    Gross, S. J. et al. Clinical experience with single-nucleotide polymorphism-based noninvasive prenatal screening for 22q11.2 deletion syndrome. Ultrasound Obstet. Gynecol. http://dx.doi.org/10.1002/uog.15754 (2015).

  198. 198

    Bretelle, F. et al. Prenatal and postnatal diagnosis of 22q11.2 deletion syndrome. Eur. J. Med. Genet. 53, 367–370 (2010).

  199. 199

    Carotti, A. et al. Cardiac defects and results of cardiac surgery in 22q11.2 deletion syndrome. Dev. Disabil. Res. Rev. 14, 35–42 (2008).

  200. 200

    Michielon, G. et al. Impact of DEL22q11, trisomy 21, and other genetic syndromes on surgical outcome of conotruncal heart defects. J. Thorac. Cardiovasc. Surg. 138, 565–570.e2 (2009).

  201. 201

    Mercer-Rosa, L., Pinto, N., Yang, W., Tanel, R. & Goldmuntz, E. 22q11.2 deletion syndrome is associated with perioperative outcome in tetralogy of Fallot. J. Thorac. Cardiovasc. Surg. 146, 868–873 (2013).

  202. 202

    O'Byrne, M. L. et al. 22q11.2 deletion syndrome is associated with increased perioperative events and more complicated postoperative course in infants undergoing infant operative correction of truncus arteriosus communis or interrupted aortic arch. J. Thorac. Cardiovasc. Surg. 148, 1597–1605 (2014).

  203. 203

    Warnes, C. A. et al. ACC/AHA 2008 guidelines for the management of adults with congenital heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J. Am. College Cardiol. 52, e143–e263 (2008).

  204. 204

    Lin, A. E. et al. Adults with genetic syndromes and cardiovascular abnormalities: clinical history and management. Genet. Med. 10, 469–494 (2008).

  205. 205

    Butcher, N. et al. Functional outcomes of adults with 22q11.2 deletion syndrome. Genet. Med. 14, 836–843 (2012).

  206. 206

    Hofstetter, A. M. et al. Live vaccine use and safety in DiGeorge syndrome. Pediatrics 133, e946–e954 (2014).

  207. 207

    Moylett, E. H., Wasan, A. N., Noroski, L. M. & Shearer, W. T. Live viral vaccines in patients with partial DiGeorge syndrome: clinical experience and cellular immunity. Clin. Immunol. 112, 106–112 (2004). This paper and reference 135 were the first to define the safety of live viral vaccines in this syndrome.

  208. 208

    Bjork, A. H., Oskarsdottir, S., Andersson, B. A. & Friman, V. Antibody deficiency in adults with 22q11.2 deletion syndrome. Am. J. Med. Genet. A 158A, 1934–1940 (2012).

  209. 209

    Gennery, A. R. et al. Antibody deficiency and autoimmunity in 22q11.2 deletion syndrome. Arch. Dis. Child. 86, 422–425 (2002).

  210. 210

    Maggadottir, S. M. & Sullivan, K. E. The diverse clinical features of chromosome 22q11.2 deletion syndrome (DiGeorge syndrome). J. Allergy Clin. Immunol. Pract. 1, 589–594 (2013).

  211. 211

    Basta, M. N. et al. A 35-year experience with syndromic cleft palate repair: operative outcomes and long-term speech function. Ann. Plast. Surg. 73, S130–S135 (2014).

  212. 212

    Kennedy, W. P. et al. 22q11.2 deletion syndrome and obstructive sleep apnea. Int. J. Pediatr. Otorhinolaryngol. 78, 1360–1364 (2014).

  213. 213

    Sobin, C., Monk, S. H., Kiley-Brabeck, K., Khuri, J. & Karayiorgou, M. Neuromotor deficits in children with the 22q11 deletion syndrome. Mov. Disord. 21, 2082–2089 (2006).

  214. 214

    Van Aken, K., Caeyenberghs, K., Smits-Engelsman, B. & Swillen, A. The motor profile of primary school-age children with a 22q11.2 deletion syndrome (22q11.2DS) and an age- and IQ-matched control group. Child Neuropsychol. 15, 532–542 (2009).

  215. 215

    Vorstman, J. A. S. et al. The 22q11.2 deletion in children: high rate of autistic disorders and early onset of psychotic symptoms. J. Am. Acad. Child Adolesc. Psychiatry 45, 1104–1113 (2006).

  216. 216

    Dori, N., Green, T., Weizman, A. & Gothelf, D. The effectiveness and safety of antipsychotic and antidepressant medications in individuals with 22q11.2 deletion syndrome. J. Child Adolesc. Psychopharmacol. http://dx.doi.org/10.1089/cap.2014.0075 (2015).

  217. 217

    Gothelf, D. et al. Obsessive–compulsive disorder in patients with velocardiofacial (22q11 deletion) syndrome. Am. J. Med. Genet. B Neuropsychiatr. Genet. 126B, 99–105 (2004).

  218. 218

    Gothelf, D. et al. Methylphenidate treatment for attention-deficit/hyperactivity disorder in children and adolescents with velocardiofacial syndrome: an open-label study. J. Clin. Psychiatry 64, 1163–1169 (2003).

  219. 219

    Karas, D. J., Costain, G., Chow, E. W. & Bassett, A. S. Perceived burden and neuropsychiatric morbidities in adults with 22q11.2 deletion syndrome. J. Intellect. Disabil. Res. 58, 198–210 (2014).

  220. 220

    Mercer-Rosa, L. et al. 22q11.2 deletion status and disease burden in children and adolescents with tetralogy of Fallot. Circ. Cardiovasc. Genet. 8, 74–81 (2015).

  221. 221

    Briegel, W., Schneider, M. & Schwab, K. O. 22q11.2 deletion: handicap-related problems and coping strategies of primary caregivers. Z. Kinder Jugendpsychiatr. Psychother. 37, 535–540 (in German) (2009).

  222. 222

    Looman, W. S., Thurmes, A. K. & O'Conner-Von, S. K. Quality of life among children with velocardiofacial syndrome. Cleft Palate Craniofac. J. 47, 273–283 (2010).

  223. 223

    Mahle, W. T. et al. Deletion of chromosome 22q11.2 and outcome in patients with pulmonary atresia and ventricular septal defect. Ann. Thorac. Surg. 76, 567–571 (2003).

  224. 224

    Woodin, M. et al. Neuropsychological profile of children and adolescents with the 22q11.2 microdeletion. Genet. Med. 3, 34–39 (2001).

  225. 225

    Jacobson, C. et al. Core neuropsychological characteristics of children and adolescents with 22q11.2 deletion. J. Intellectual Disabil. Res. 54, 701–713 (2010).

  226. 226

    Driscoll, D. A. Molecular and genetic aspects of DiGeorge/velocardiofacial syndrome. Methods Mol. Med. 126, 43–55 (2006).

  227. 227

    Mlynarski, E. E. et al. Copy-number variation of the glucose transporter gene SLC2A3 and congenital heart defects in the 22q11.2 deletion syndrome. Am. J. Hum. Genet. 96, 753–764 (2015).

  228. 228

    Chung, J. H. et al. Whole-genome sequencing and integrative genomic analysis approach on two 22q11.2 deletion syndrome family trios for genotype to phenotype correlations. Hum. Mut. 36, 797–807 (2015).

  229. 229

    Guo, T. et al. Genotype and cardiovascular phenotype correlations with TBXn 1,022 velo-cardio-facial/DiGeorge/22q11.2 deletion syndrome patients. Hum. Mut. 32, 1278–1289 (2011).

  230. 230

    Budarf, M. L. et al. Identification of a patient with Bernard–Soulier syndrome and a deletion in the DiGeorge/velo-cardio-facial chromosomal region in 22q11.2. Hum. Mol. Genet. 4, 763–766 (1995). This paper and reference 68 highlight the possibility of unmasking an autosomal recessive condition to explain atypical phenotypes and to identify important genes associated with 22q11.2DS beyond TBX1.

  231. 231

    Insel, T. R. Rethinking schizophrenia. Nature 468, 187–193 (2010).

  232. 232

    Wapner, R. J. et al. Expanding the scope of noninvasive prenatal testing: detection of fetal microdeletion syndromes. Am. J. Obstet. Gynecol. 212, 332.e1–332.e9 (2015).

  233. 233

    Vialard, F. et al. Prenatal BACs-on-BeadsTM: the prospective experience of five prenatal diagnosis laboratories. Prenat. Diagn. 32, 329–335 (2012).

  234. 234

    Koontz, D., Baecher, K., Kobrynski, L., Nikolova, S. & Gallagher, M. A pyrosequencing-based assay for the rapid detection of the 22q11.2 deletion in DNA from buccal and dried blood spot samples. J. Mol. Diagn. 16, 533–540 (2014).

  235. 235

    Pretto, D., Maar, D., Yrigollen, C. M., Regan, J. & Tassone, F. Screening newborn blood spots for 22q11.2 deletion syndrome using multiplex droplet digital PCR. Clin. Chem. 61, 182–190 (2015).

Download references

Acknowledgements

The authors acknowledge grants from the National Institute of Mental Health (consortium grants U01MH101723, U01MH101720 and U01MH101719-01 to D.M.M.-M., N.P., A.S., J.A.S.V., B.S.E., J.R.V., B.E.M. and A.S.B., and grant U01MH087636 to D.M.M.-M.); NIH grant P01-HD070454 to D.M.M.-M., B.S.E. and B.E.M.; the Immune Deficiency Foundation, Baxalta and Janssen (to K.S.); Brain and Behavior Research Foundation (formerly NARSAD) 2010 Young Investigator Award (to J.A.S.V.); and the Canadian Institutes of Health Research (CIHR; MOP 97800 and MOP 111238), the Canada Research Chair in Schizophrenia Genetics and Genomic Disorders, and the Dalglish Chair in 22q11.2 Deletion Syndrome (to A.S.B.). The authors thank L. DiCairano, L. Lunny, A. Melchiorre, K. Schlechtweg, M. Torsan and G. Wong for assistance with manuscript formatting.

Author information

Introduction (D.M.M.-M., K.E.S. and A.S.B.); Epidemiology (D.M.M.-M., K.E.S., B.M. and A.S.B.); Mechanisms/pathophysiology (D.M.M.-M., K.E.S., B.M., J.A.S.V., J.R.V., B.E.M., P.J.S. and A.S.B.); Diagnosis, screening and prevention (D.M.M.-M., K.E.S., B.M., N.P., A.S., J.A.S.V., E.H.Z., B.S.E. and A.S.B.); Management (D.M.M.-M., K.E.S., B.M., N.P., A.S., J.A.S.V., E.H.Z. and A.S.B.); Quality of life (D.M.M.-M., K.E.S., B.M., A.S., J.A.S.V. and A.S.B.); Outlook (D.M.M.-M., K.E.S., B.E.M, P.J.S., J.R.V. and A.S.B.); Overview of the Primer (D.M.M.-M.).

Correspondence to Donna M. McDonald-McGinn.

Ethics declarations

Competing interests

D.M.M.-M. has presented lectures on 22q11.2 deletion syndrome for Natera. All other authors declare no competing interests.

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

McDonald-McGinn, D., Sullivan, K., Marino, B. et al. 22q11.2 deletion syndrome. Nat Rev Dis Primers 1, 15071 (2015) doi:10.1038/nrdp.2015.71

Download citation

Further reading