Clinical Features of Aberrations Chromosome 22q: A Pilot Study

Abstract

Objective A significant number of genetic variations have been identified in chromosome 22, using molecular genetic techniques. Various genomic disorders on chromosome 22, including cat's eye syndrome caused by extra copies of the proximal region of the 22q chromosome, are now well-defined. Our aim in the study was to show phenotypic variability associated with rearrangements of the 22q chromosomal region.
Methods We focused our study on clinical aspects of these disorders, including genetic testing, genotype-phenotype correlation, and potential treatments. A total of 998 patients were referred for genetic analysis (Karyotyping, MLPA, array-CGH) during January 2015 to February 2020 because of intellectual deficiency, behavior issues, and/or multiple congenital abnormalities in several genetics departments. Informed consent was obtained from all the patients and/or their parents.
Results 22q11.21 or 22q13.33 microdeletions and 22q11.22-q11.23 microduplication were identified in 31 patients out of referrals. The 22q aberrations were detected in 31/998 patients, giving a prevalence of 3.1%. In this study, 18 patients with 22q11.2 (LCR22A-H) deletion, three patients with 22q13.31 deletion, 9 patients with 22q11.2 duplication and one patient with 22q13.31 duplication were identified. We report on the clinical and molecular characterization of 31 individuals with distal deletions and duplications of chromosome 22q.
Conclusions The current study demonstrated in the largest postnatal case series reporting the whole spectrum of atypical phenotypic and genotypic variations at 22q. We believe that when all the phenotypic differences are taken into account, various anomalies including developmental delay and intellectual disability might be considered as an indication to search for aberrations of 22q along with congenital heart diseases.

Keywords

22q deletions / 22q duplications / Array CGH

References

[1] Cole CG, McCann OT, Collins JE. et al. Finishing the finished human chromosome 22 sequence. Genome Biol 2008; 9(05): R78

[2] Dunham I, Shimizu N, Roe BA.et al.The DNA sequence of human chromosome 22. Nature 1999; 402(6761): 489-495

[3] Yu S, Graf WD, Shprintzen RJ.Genomic disorders on chromosome 22. Curr Opin Pediatr 2012; 24(06): 665-671

[4] Robin NH, Shprintzen RJ.Defining the clinical spectrum of deletion 22q11.2. J Pediatr 2005; 147(01): 90-96

[5] Yu S, Graf WD, Ramalingam A.et al.Identification of copy number variants on human chromosome 22 in patients with a variety of clinical findings. Cytogenet Genome Res 2011; 134(04): 260-268

[6] Shaikh TH, O'Connor RJ, Pierpont ME. et al. Low copy repeats mediate distal chromosome 22q11.2 deletions: sequence analysis predicts breakpoint mechanisms. Genome Res 2007; 17(04): 482-491

[7] Ben-Shachar S, Ou Z, Shaw CA.et al.22q11.2 distal deletion: a recurrent genomic disorder distinct from DiGeorge syndrome and velocardiofacial syndrome. Am J Hum Genet 2008; 82(01): 214-221

[8] Coppinger J, McDonald-McGinn D, Zackai E. et al. Identification of familial and de novo microduplications of 22q11.21-q11.23 distal to the 22q11.21 microdeletion syndrome region. Hum Mol Genet 2009; 18(08): 1377-1383

[9] Tropeano M, Ahn JW, Dobson RJ.et al.Male-biased autosomal effect of 16p13.11 copy number variation in neurodevelopmental disorders. PLoS One 2013; 8(04): e61365

[10] Wincent J, Bruno DL, van Bon BW. et al. Sixteen new cases contributing to the characterization of patients with distal 22q11.2 microduplications. Mol Syndromol 2010; 1(05): 246-254

[11] Ensenauer RE, Adeyinka A, Flynn HC.et al.Microduplication 22q11.2, an emerging syndrome: clinical, cytogenetic, and molecular analysis of thirteen patients. Am J Hum Genet 2003; 73(05): 1027-1040

[12] Courtens W, Schramme I, Laridon A.Microduplication 22q11.2: a benign polymorphism or a syndrome with a very large clinical variability and reduced penetrance?-Report of two families. Am J Med Genet A 2008; 146A(06): 758-763

[13] Ou Z, Berg JS, Yonath H.et al.Microduplications of 22q11.2 are frequently inherited and are associated with variable phenotypes. Genet Med 2008; 10(04): 267-277

[14] Wentzel C, Fernström M, Öhrner Y, Annerén G, Thuresson AC.Clinical variability of the 22q11.2 duplication syndrome. Eur J Med Genet 2008; 51(06): 501-510

[15] Saitta SC, Harris SE, Gaeth AP.et al.Aberrant interchromosomal exchanges are the predominant cause of the 22q11.2 deletion. Hum Mol Genet 2004; 13(04): 417-428

[16] Shaikh TH, Kurahashi H, Saitta SC.et al.Chromosome 22-specific low copy repeats and the 22q11.2 deletion syndrome: genomic organization and deletion endpoint analysis. Hum Mol Genet 2000; 9(04): 489-501

[17] Baumer A, Riegel M, Schinzel A.Non-random asynchronous replication at 22q11.2 favours unequal meiotic crossovers leading to the human 22q11.2 deletion. J Med Genet 2004; 41(06): 413-420

[18] Kurahashi H, Tsuda E, Kohama R.et al.Another critical region for deletion of 22q11: a study of 100 patients. Am J Med Genet 1997; 72(02): 180-185

[19] Botto LD, May K, Fernhoff PM.et al.A population-based study of the 22q11.2 deletion: phenotype, incidence, and contribution to major birth defects in the population. Pediatrics 2003; 112(Pt 1): 101-107

[20] Yamagishi H.The 22q11.2 deletion syndrome. Keio J Med 2002; 51(02): 77-88

[21] Shprintzen RJ, Goldberg RB, Young D, Wolford L.The velo-cardio-facial syndrome: a clinical and genetic analysis. Pediatrics 1981; 67(02): 167-172

[22] Scambler PJ, Kelly D, Lindsay E.et al.Velo-cardio-facial syndrome associated with chromosome 22 deletions encompassing the DiGeorge locus. Lancet 1992; 339(8802): 1138-1139

[23] Lindsay EA.Chromosomal microdeletions: dissecting del22q11 syndrome. Nat Rev Genet 2001; 2(11): 858-868

[24] Yamagishi H, Garg V, Matsuoka R, Thomas T, Srivastava D.A molecular pathway revealing a genetic basis for human cardiac and craniofacial defects. Science 1999; 283(5405): 1158-1161

[25] McQuade L, Christodoulou J, Budarf M.et al. Patient with a 22q11.2 deletion with no overlap of the minimal DiGeorge syndrome critical region (MDGCR). Am J Med Genet 1999; 86(01): 27-33

[26] Saitta SC, McGrath JM, Mensch H, Shaikh TH, Zackai EH, Emanuel BSA. A 22q11.2 deletion that excludes UFD1L and CDC45L in a patient with conotruncal and craniofacial defects. Am J Hum Genet 1999; 65(02): 562-566

[27] Sutherland HF, Wadey R, McKie JM. et al. Identification of a novel transcript disrupted by a balanced translocation associated with DiGeorge syndrome. Am J Hum Genet 1996; 59(01): 23-31

[28] Rauch A, Pfeiffer RA, Leipold G, Singer H, Tigges M, Hofbeck M.A novel 22q11.2 microdeletion in DiGeorge syndrome. Am J Hum Genet 1999; 64(02): 659-666

[29] Dallapiccola B, Pizzuti A, Novelli G.How many breaks do we need to CATCH on 22q11?. Am J Hum Genet 1996; 59(01): 7-11

[30] Hall JG.CATCH 22. J Med Genet 1993; 30(10): 801-802

[31] Kurnit DM, Layton WM, Matthysse S.Genetics, chance, and morphogenesis. Am J Hum Genet 1987; 41(06): 979-995

[32] Amati F, Conti E, Novelli A.et al.Atypical deletions suggest five 22q11.2 critical regions related to the DiGeorge/velo-cardio-facial syndrome. Eur J Hum Genet 1999; 7(08): 903-909

[33] Digilio MC, Marino B, Capolino R.et al.Familial recurrence of nonsyndromic congenital heart defects in first degree relatives of patients with deletion 22q11.2. Am J Med Genet A 2005; 134A(02): 158-164

[34] Heine-Suñer D, Armengol L, Torres-Juan L.et al. Clinical and molecular characterization of deletions, duplications and mutations in the 22q11.2 region. [abstract] Eur J Hum Genet2008; 16 (Suppl. 02) x

[35] Guris DL, Fantes J, Tara D, Druker BJ, Imamoto A.Mice lacking the homologue of the human 22q11.2 gene CRKL phenocopy neurocristopathies of DiGeorge syndrome. Nat Genet 2001; 27(03): 293-298

[36] Vorstman JAS, Chow EW, Ophoff RA.et al.Association of the PIK4CA schizophrenia-susceptibility gene in adults with the 22q11.2 deletion syndrome. Am J Med Genet B Neuropsychiatr Genet 2009; 150B(03): 430-433

[37] Guy C, Wang X, Lu X, Lu J, Li S.Two patients with small chromosome 22q11.21 alterations and central nervous system abnormalities. Mol Cytogenet 2015; 8: 102

[38] Firth HV.22q11.2 duplication - retired chapter, for historical reference only. In: Adam MP, Ardinger HH, Pagon RA. et al, eds. GeneReviews. Seattle: University of Washington; 2009

[39] Precht KS, Lese CM, Spiro RP.et al.Two 22q telomere deletions serendipitously detected by FISH. J Med Genet 1998; 35(11): 939-942

[40] Durand CM, Betancur C, Boeckers TM.et al.Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nat Genet 2007; 39(01): 25-27

[41] Prasad C, Prasad AN, Chodirker BN.et al.Genetic evaluation of pervasive developmental disorders: the terminal 22q13 deletion syndrome may represent a recognizable phenotype. Clin Genet 2000; 57(02): 103-109

[42] Han K, Holder Jr JL, Schaaf CP.et al.SHANK3 overexpression causes manic-like behaviour with unique pharmacogenetic properties. Nature 2013; 503(7474): 72-77

[43] Sarasua SM, Dwivedi A, Boccuto L.et al.22q13.2q13.32 genomic regions associated with severity of speech delay, developmental delay, and physical features in Phelan-McDermid syndrome. Genet Med 2014; 16(04): 318-328

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