Downregulation of genes outside the deleted region in individuals with 22q11.2 deletion syndrome
- 265 Downloads
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.
- Bassett AS, Chow EW (2008) Schizophrenia and 22q11.2 deletion syndrome. Curr Psychiatry Rep 10:148–157Google Scholar
- 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. https://doi.org/10.3389/fgene.2017.00047 Google Scholar
- Burn J, Goodship J (1996) Developmental genetics of the heart. Curr Opin Genet Dev 6:322–325Google Scholar
- 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
- 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
- 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
- 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
- Merscher S et al (2001) TBX1 is responsible for cardiovascular defects in velo-cardio-facial/DiGeorge syndrome. Cell 104:619–629Google Scholar
- 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
- 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
- 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. https://doi.org/10.1176/ajp.153.12.1541 Google Scholar
- 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
- 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
- Yamagishi H et al (1998) Phenotypic discordance in monozygotic twins with 22q11.2 deletion. Am J Med Genet 78:319–321Google Scholar