Human Genetics

, Volume 138, Issue 1, pp 93–103 | Cite as

Downregulation of genes outside the deleted region in individuals with 22q11.2 deletion syndrome

  • Anelisa Gollo Dantas
  • Marcos Leite Santoro
  • Natalia Nunes
  • Claudia Berlim de Mello
  • Larissa Salustiano Evangelista Pimenta
  • Vera Ayres Meloni
  • Diogo Cordeiro Queiroz Soares
  • Sintia Nogueira Belangero
  • Gianna Carvalheira
  • Chong Ae Kim
  • Maria Isabel MelaragnoEmail author
Original Investigation


The 22q11.2 deletion syndrome (22q11.2DS) is caused by recurrent hemizygous deletions of chromosome 22q11.2. The phenotype of the syndrome is complex and varies widely among individuals. Little is known about the role of the different genes located in 22q11.2, and we hypothesized that genetic risk factors lying elsewhere in the genome might contribute to the phenotype. Here, we present the whole-genome gene expression data of 11 patients with approximately 3 Mb deletions. Apart from the hemizygous genes mapped to the 22q11.2 region, the TUBA8 and GNAZ genes, neighboring the deleted interval but in normal copy number, showed altered expression. When genes mapped to other chromosomes were considered in the gene expression analysis, a genome-wide dysregulation was observed, with increased or decreased expression levels. The enriched pathways of these genes were related to immune response, a deficiency that is frequently observed in 22q11.2DS patients. We also used the hypothesis-free weighted gene co-expression network analysis (WGCNA), which revealed the co-expression gene network modules with clear connection to mechanisms associated with 22q11.2DS such as immune response and schizophrenia. These findings, combined with the traditional gene expression profile, can be used for the identification of potential pathways and genes not previously considered to be related to the 22q11.2 deletion syndrome.



This work was supported by the Fundação de Amparo à Pesquisa do Estado de São Paulo (Grant Nos. 2014/11572-8, 2014/26768-5).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

439_2018_1967_MOESM1_ESM.pptx (4.9 mb)
Supplementary material 1 (PPTX 5067 KB)
439_2018_1967_MOESM2_ESM.pptx (41 kb)
Supplementary material 2 (PPTX 41 KB)
439_2018_1967_MOESM3_ESM.xlsx (22 kb)
Supplementary material 3 (XLSX 22 KB)
439_2018_1967_MOESM4_ESM.xlsx (25 kb)
Supplementary material 4 (XLSX 24 KB)
439_2018_1967_MOESM5_ESM.xlsx (10.3 mb)
Supplementary material 5 (XLSX 10524 KB)
439_2018_1967_MOESM6_ESM.xlsx (63 kb)
Supplementary material 6 (XLSX 62 KB)


  1. Abdollahi MR et al (2009) Mutation of the variant alpha-tubulin TUBA8 results in polymicrogyria with optic nerve hypoplasia. Am J Hum Genet 85:737–744. Google Scholar
  2. Bailey JA et al (2002) Human-specific duplication and mosaic transcripts: the recent paralogous structure of chromosome 22. Am J Hum Genet 70:83–100. Google Scholar
  3. Bassett AS, Chow EW (2008) Schizophrenia and 22q11.2 deletion syndrome. Curr Psychiatry Rep 10:148–157Google Scholar
  4. Bassett AS, Chow EW, Husted J, Weksberg R, Caluseriu O, Webb GD, Gatzoulis MA (2005) Clinical features of 78 adults with 22q11 Deletion Syndrome. Am J Med Genet A 138:307–313. Google Scholar
  5. Bertini V, Azzara A, Legitimo A, Milone R, Battini R, Consolini R, Valetto A (2017) Deletion extents are not the cause of clinical variability in 22q11.2 deletion syndrome: does the interaction between DGCR8 and miRNA-CNVs play a major role? Front Genet 8:47. Google Scholar
  6. Bi W, Park SS, Shaw CJ, Withers MA, Patel PI, Lupski JR (2003) Reciprocal crossovers and a positional preference for strand exchange in recombination events resulting in deletion or duplication of chromosome 17p11.2. Am J Hum Genet 73:1302–1315. Google Scholar
  7. Bittel DC, Yu S, Newkirk H, Kibiryeva N, Holt A III, Butler MG, Cooley LD (2009) Refining the 22q11.2 deletion breakpoints in DiGeorge syndrome by aCGH. Cytogenet Genome Res 124:113–120. Google Scholar
  8. Burn J, Goodship J (1996) Developmental genetics of the heart. Curr Opin Genet Dev 6:322–325Google Scholar
  9. Chen EY et al (2013) Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool. BMC Bioinform 14:128. Google Scholar
  10. Cramer SC, Schaefer PW, Krishnamoorthy KS (1996) Microgyria in the distribution of the middle cerebral artery in a patient with DiGeorge syndrome. J Child Neurol 11:494–497. Google Scholar
  11. Diggle CP et al (2017) A tubulin alpha 8 mouse knockout model indicates a likely role in spermatogenesis but not in brain development. PLoS One 12:e0174264. Google Scholar
  12. Dykes IM et al (2014) HIC2 is a novel dosage-dependent regulator of cardiac development located within the distal 22q11 deletion syndrome region. Circ Res 115:23–31. Google Scholar
  13. Edelmann L, Pandita RK, Morrow BE (1999) Low-copy repeats mediate the common 3-Mb deletion in patients with velo-cardio-facial syndrome. Am J Hum Genet 64:1076–1086Google Scholar
  14. Fong HK, Yoshimoto KK, Eversole-Cire P, Simon MI (1988) Identification of a GTP-binding protein alpha subunit that lacks an apparent ADP-ribosylation site for pertussis toxin. Proc Natl Acad Sci USA 85:3066–3070Google Scholar
  15. Gao W et al (2015) DGCR6 at the proximal part of the DiGeorge critical region is involved in conotruncal heart defects. Hum Genome Var 2:15004. Google Scholar
  16. Ghazalpour A et al (2006) Integrating genetic and network analysis to characterize genes related to mouse weight. PLoS Genet 2:e130. Google Scholar
  17. Gross SJ et al (2016) Clinical experience with single-nucleotide polymorphism-based non-invasive prenatal screening for 22q11.2 deletion syndrome. Ultrasound Obstet Gynecol 47:177–183. Google Scholar
  18. Guris DL, Fantes J, Tara D, Druker BJ, Imamoto A (2001) Mice lacking the homologue of the human 22q11.2 gene CRKL phenocopy neurocristopathies of DiGeorge syndrome. Nat Genet 27:293–298. Google Scholar
  19. Harewood L et al (2010) The effect of translocation-induced nuclear reorganization on gene expression. Genome Res 20:554–564. Google Scholar
  20. Iascone MR, Vittorini S, Sacchelli M, Spadoni I, Simi P, Giusti S (2002) Molecular characterization of 22q11 deletion in a three-generation family with maternal transmission. Am J Med Genet 108:319–321. Google Scholar
  21. Jalbrzikowski M et al (2015) Transcriptome profiling of peripheral blood in 22q11.2 deletion syndrome reveals functional pathways related to psychosis and autism spectrum disorder. PLoS One 10:e0132542. Google Scholar
  22. Jawad AF, McDonald-Mcginn DM, Zackai E, Sullivan KE (2001) Immunologic features of chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome. J Pediatr 139:715–723. Google Scholar
  23. Jerome LA, Papaioannou VE (2001) DiGeorge syndrome phenotype in mice mutant for the T-box gene, Tbx1. Nat Genet 27:286–291. Google Scholar
  24. Kawame H et al (2001) Graves’ disease in patients with 22q11.2 deletion. J Pediatr 139:892–895. Google Scholar
  25. Kobrynski LJ, Sullivan KE (2007) Velocardiofacial syndrome, DiGeorge syndrome: the chromosome 22q11.2 deletion syndromes. Lancet 370:1443–1452. Google Scholar
  26. Kuleshov MV et al (2016) Enrichr: a comprehensive gene set enrichment analysis web server 2016 update. Nucleic Acids Res 44:W90–W97. Google Scholar
  27. Lieberman-Aiden E et al (2009) Comprehensive mapping of long range interactions reveals folding principles of the human genome. Science 326:289–293. Google Scholar
  28. Lindsay EA, Baldini A (1997) A mouse gene (Dgcr6) related to the Drosophila gonadal gene is expressed in early embryogenesis and is the homolog of a human gene deleted in DiGeorge syndrome. Cytogenet Cell Genet 79:243–247. Google Scholar
  29. Lin M et al (2016) Integrative transcriptome network analysis of iPSC-derived neurons from schizophrenia and schizoaffective disorder patients with 22q11.2 deletion. BMC Syst Biol 10:105. Google Scholar
  30. Lu JH, Chung MY, Hwang B, Chien HP (2001) Monozygotic twins with chromosome 22q11 microdeletion and discordant phenotypes in cardiovascular patterning. Pediatr Cardiol 22:260–263. Google Scholar
  31. Mantripragada KK, Tapia-Paez I, Blennow E, Nilsson P, Wedell A, Dumanski JP (2004) DNA copy-number analysis of the 22q11 deletion-syndrome region using array-CGH with genomic and PCR-based targets. Int J Mol Med 13:273–279Google Scholar
  32. Matsuoka M, Itoh H, Kozasa T, Kaziro Y (1988) Sequence analysis of cDNA and genomic DNA for a putative pertussis toxin-insensitive guanine nucleotide-binding regulatory protein alpha subunit. Proc Natl Acad Sci USA 85:5384–5388Google Scholar
  33. McDonald-McGinn DM et al (2015) 22q11.2 deletion syndrome. Nat Rev Dis Primers 1:15071. Google Scholar
  34. Merla G et al (2006) Submicroscopic deletion in patients with Williams-Beuren syndrome influences expression levels of the nonhemizygous flanking genes. Am J Hum Genet 79:332–341. Google Scholar
  35. Merscher S et al (2001) TBX1 is responsible for cardiovascular defects in velo-cardio-facial/DiGeorge syndrome. Cell 104:619–629Google Scholar
  36. Michel M, Schmidt MJ, Mirnics K (2012) Immune system gene dysregulation in autism and schizophrenia. Dev Neurobiol 72:1277–1287. Google Scholar
  37. Migliavacca E et al (2015) A potential contributory role for ciliary dysfunction in the 16p11.2 600 kb BP4-BP5 pathology. Am J Hum Genet 96:784–796. Google Scholar
  38. Mlynarski EE et al (2015) 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. Google Scholar
  39. Mlynarski EE et al (2016) Rare copy number variants and congenital heart defects in the 22q11.2 deletion syndrome. Hum Genet 135:273–285. Google Scholar
  40. Morsheimer M, Brown Whitehorn TF, Heimall J, Sullivan KE (2017) The immune deficiency of chromosome 22q11.2 deletion syndrome. Am J Med Genet A 173:2366–2372. Google Scholar
  41. Muller N, Hofschuster E, Ackenheil M, Eckstein R (1993) T-cells and psychopathology in schizophrenia: relationship to the outcome of neuroleptic therapy. Acta Psychiatr Scand 87:66–71Google Scholar
  42. Murphy KC, Jones LA, Owen MJ (1999) High rates of schizophrenia in adults with velo-cardio-facial syndrome. Arch Gen Psychiatry 56:940–945Google Scholar
  43. Papolos DF, Faedda GL, Veit S, Goldberg R, Morrow B, Kucherlapati R, Shprintzen RJ (1996) Bipolar spectrum disorders in patients diagnosed with velo-cardio-facial syndrome: does a hemizygous deletion of chromosome 22q11 result in bipolar affective disorder? Am J Psychiatry 153:1541–1547. Google Scholar
  44. Pavlicek A, House R, Gentles AJ, Jurka J, Morrow BE (2005) Traffic of genetic information between segmental duplications flanking the typical 22q11.2 deletion in velo-cardio-facial syndrome/DiGeorge syndrome. Genome Res 15:1487–1495. Google Scholar
  45. Pfuhl T et al (2005) Biochemical characterisation of the proteins encoded by the DiGeorge critical region 6 (DGCR6) genes. Hum Genet 117:70–80. Google Scholar
  46. Phillips HM et al (2002) Narrowing the critical region within 11q24-qter for hypoplastic left heart and identification of a candidate gene, JAM3 expressed during cardiogenesis. Genomics 79:475–478. Google Scholar
  47. Prescott K, Ivins S, Hubank M, Lindsay E, Baldini A, Scambler P (2005) Microarray analysis of the Df1 mouse model of the 22q11 deletion syndrome. Hum Genet 116:486–496. Google Scholar
  48. Reiter LT, Murakami T, Koeuth T, Pentao L, Muzny DM, Gibbs RA, Lupski JR (1996) A recombination hotspot responsible for two inherited peripheral neuropathies is located near a mariner transposon-like element. Nat Genet 12:288–297. Google Scholar
  49. Ripke S et al (2014) Biological insights from 108 schizophrenia-associated genetic loci. Nature 511:421–427. Google Scholar
  50. Riquelme Medina I, Lubovac-Pilav Z (2016) Gene co-expression network analysis for identifying modules and functionally enriched pathways in type 1 Diabetes. PLoS One 11:e0156006. Google Scholar
  51. Robin NH, Shprintzen RJ (2005) Defining the clinical spectrum of deletion 22q11.2. J Pediatr 147:90–96. Google Scholar
  52. Romaniello R, Arrigoni F, Bassi MT, Borgatti R (2015) Mutations in alpha- and beta-tubulin encoding genes: implications in brain malformations. Brain Dev 37:273–280. Google Scholar
  53. Shaikh TH et al (2000) Chromosome 22-specific low copy repeats and the 22q11.2 deletion syndrome: genomic organization and deletion endpoint analysis. Hum Mol Genet 9:489–501Google Scholar
  54. Taddei I, Morishima M, Huynh T, Lindsay EA (2001) Genetic factors are major determinants of phenotypic variability in a mouse model of the DiGeorge/del22q11 syndromes. Proc Natl Acad Sci USA 98:11428–11431. Google Scholar
  55. Urban AE et al (2006) High-resolution mapping of DNA copy alterations in human chromosome 22 using high-density tiling oligonucleotide arrays. Proc Natl Acad Sci USA 103:4534–4539. Google Scholar
  56. van Beveren NJ et al (2012) Functional gene-expression analysis shows involvement of schizophrenia-relevant pathways in patients with 22q11 deletion syndrome. PLoS One 7:e33473. Google Scholar
  57. Vitelli F, Morishima M, Taddei I, Lindsay EA, Baldini A (2002) Tbx1 mutation causes multiple cardiovascular defects and disrupts neural crest and cranial nerve migratory pathways. Hum Mol Genet 11:915–922Google Scholar
  58. Williams NM (2011) Molecular mechanisms in 22q11 deletion syndrome. Schizophr Bull 37:882–889. Google Scholar
  59. Yamagishi H et al (1998) Phenotypic discordance in monozygotic twins with 22q11.2 deletion. Am J Med Genet 78:319–321Google Scholar
  60. Ying X et al (2016) Novel protective role for ubiquitin-specific protease 18 in pathological cardiac remodeling. Hypertension 68:1160–1170. Google Scholar
  61. Yovel G, Sirota P, Mazeh D, Shakhar G, Rosenne E, Ben-Eliyahu S (2000) Higher natural killer cell activity in schizophrenic patients: the impact of serum factors, medication, and smoking. Brain Behav Immun 14:153–169. Google Scholar
  62. Zackai EH, Emanuel BS (1980) Site specific reciprocal translocation, t(11;22)(q23;q11) in several unrelated families with 3:1 meiotic disjunction. Am J Med Genet 7:507–521. Google Scholar
  63. Zhang X et al (2018) Local and global chromatin interactions are altered by large genomic deletions associated with human brain development. Nat Commun 9(1):5356. Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Genetics DivisionUniversidade Federal de São PauloSão PauloBrazil
  2. 2.Interdisciplinary Laboratory of Clinical Neurosciences (LiNC), Psychiatry DepartmentUniversidade Federal de São PauloSão PauloBrazil
  3. 3.Psychobiology DepartmentUniversidade Federal de São PauloSão PauloBrazil
  4. 4.Genetics Department, Instituto da CriançaUniversidade de São PauloSão PauloBrazil

Personalised recommendations