Central 22q11.2 deletions

Abstract

22q11.2 deletion syndrome is one of the most common microdeletion syndromes. Most patients have a deletion resulting from a recombination of low copy repeat blocks LCR22-A and LCR22-D. Loss of the TBX1 gene is considered the most important cause of the phenotype. A limited number of patients with smaller, overlapping deletions distal to the TBX1 locus have been described in the literature. In these patients, the CRKL gene is deleted. Haploinsufficiency of this gene has also been implicated in the pathogenesis of 22q11.2 deletion syndrome. To distinguish these deletions (comprising the LCR22-B to LCR22-D region) from the more distal 22q11.2 deletions (located beyond LCR22-D), we propose the term "central 22q11.2 deletions". In the present study we report on 27 new patients with such a deletion. Together with information on previously published cases, we review the clinical findings of 52 patients. The prevalence of congenital heart anomalies and the frequency of de novo deletions in patients with a central deletion are substantially lower than in patients with a common or distal 22q11.2 deletion. Renal and urinary tract malformations, developmental delays, cognitive impairments and behavioral problems seem to be equally frequent as in patients with a common deletion. None of the patients had a cleft palate. Patients with a deletion that also encompassed the MAPK1 gene, located just distal to LCR22-D, have a different and more severe phenotype, characterized by a higher prevalence of congenital heart anomalies, growth restriction and microcephaly. Our results further elucidate genotype-phenotype correlations in 22q11.2 deletion syndrome spectrum.

22q11.21 Deletion Syndromes: A Review of Proximal, Central, and Distal Deletions and Their Associated Features

“…Overall Kurahashi et al, 1996;Garcia-Miñaur et al, 2002;Rauch et al, 2005;D'Angelo et al, 2007;Jalali et al, 2008;Fernández et al, 2009;Yu et al, 2011;Verhagen et al, 2012;Zhao et al, 2013;Rump et al, 2014; and this study. * Includes cases of Racedo et al, 2015 who only examined cardiac features of 25 individuals.…”

“…Rump et al [2014] have proposed 'central' 22q deletions, a terminology which is adopted in this review. As such, these CNVs are discussed in the next section.…”

“…In the studies by Rump et al [2014], Breckpot et al [2012], Ogilvie et al [2009], and Garavelli et al [2011], the authors also included individuals with deletions spanning LCR22C-E (C-E) in the central group. Given the similarity between those individuals and individuals with distal type I deletions as described in Mikhail et al [2014], we propose that deletions spanning C-E be classified as distal type I deletions and have included them in the next section.…”

“…c Data from Rauch et al, 1999Rauch et al, , 2005Saitta et al, 1999;Mikhail et al, 2007Mikhail et al, , 2014Ben-Shachar et al, 2008;Jalali et al, 2008;Rødningen et al, 2008;Xu et al, 2008;Ogilvie et al, 2009;Bruce et al, 2010;Madan et al, 2010;Garavelli et al, 2011;Tan et al, 2011;Verhoeven et al, 2011;Yu et al, 2011;Breckpot et al, 2012;Fagerberg et al, 2013;Molck et al, 2013;Rump et al, 2014. d Data from Shaikh et al, 2000;Rauch et al, 2005;Nik-Zainal et al, 2011;Yu et al, 2011;Mikhail et al, 2014. e Data from Wieser et al, 2005;Jackson et al, 2007;Lafay-Cousin et al, 2009;Beddow et al, 2011;Bourdeaut et al, 2011;Tan et al, 2011;Toth et al, 2011. f Index cases and familial carriers.…”

“…Deletions of more distal regions have also been reported extensively, and many of those individuals were referred for suspicion of DGS, highlighting the similarity of phenotypic features for these CNVs [Kurahashi et al, 1996;Rauch et al, 1999Rauch et al, , 2005Saitta et al, 1999;Shaikh et al, 2000;Garcia-Miñaur et al, 2002;Wieser et al, 2005;Jackson et al, 2007;Mikhail et al, 2007Mikhail et al, , 2014Ben-Shachar et al, 2008;Jalali et al, 2008;Rødningen et al, 2008;Xu et al, 2008;Lafay-Cousin et al, 2009;Ogilvie et al, 2009;Bruce et al, 2010;Madan et al, 2010;Beddow et al, 2011;Bourdeaut et al, 2011;Eaton et al, 2011;Garavelli et al, 2011;Nik-Zainal et al, 2011;Tan et al, 2011;Toth et al, 2011;Verhoeven et al, 2011;Yu et al, 2011;Breckpot et al, 2012;Pebrel-Richard et al, 2012;Verhagen et al, 2012;Fagerberg et al, 2013;Zhao et al, 2013;Rump et al, 2014;Racedo et al, 2015]. The literature for these other CNVs is not uniform with respect to the designation of particular intervals, and previous reviews have grouped proximal and distal CNVs together [Tan et al, 2010;Yu et al, 2011].…”