Congenital heart defects in a novel recurrent 22q11.2 deletion harboring the genes CRKL and MAPK1

Abstract

The proximal region of the long arm of chromosome 22 is rich in low copy repeats (LCR). Non-allelic homologous recombination (NAHR) between these substrates explains the high prevalence of recurrent rearrangements within this region. We have performed array comparative genomic hybridization in a normally developing girl with growth delay, microcephaly, and truncus arteriosus, and have identified a novel recurrent 22q11 deletion that spans LCR22-4 and partially affects the common 22q11.2 deletion syndrome and the distal 22q11 deletion syndrome. This deletion is atypical as it did not occur by NAHR between any of the major LCRs found on 22q11.2. However, the breakpoint containing regions coincide with highly homologous regions. An identical imbalance was reported previously in a patient with striking phenotypic similarity. Computational gene prioritization methods and biological evidence denote the genes CRKL and MAPK1 as the highest ranking candidates for causing congenital heart disease within the deleted region.

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

“…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.…”

“…Based on the classification system of Mikhail et al [2014] and the clinical issues unique to distal type I deletion carriers, we include deletions spanning LCR22C-E (C-E) with the type I group [Ogilvie et al, 2009;Garavelli et al, 2011;Breckpot et al, 2012;Mikhail et al, 2014;Rump et al, 2014]. The reported deletions have largely been de novo and fetuses/neonates having distal type I deletions tended to require pregnancy and delivery management that individuals with the other types of deletions typically do not ( table 3 ).…”

“…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.…”

“…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].…”

A Mouse Splice-Site Mutant and Individuals with Atypical Chromosome 22q11.2 Deletions Demonstrate the Crucial Role for Crkl in Craniofacial and Pharyngeal Development

“…The analysis of Tbx1 ; Crkl compound heterozygous mice revealed an interaction between these two 22q11.2 genes during pharyngeal development, suggesting that 22q11DS is a contiguous gene disorder and implicated altered retinoic acid signalling as an underlying cause of abnormal pharyngeal development . Atypical 22q11.2 microdeletions that encompass CRKL , but spare TBX1 , have been demonstrated in a number of individuals [Breckpot et al, 2012;Verhagen et al, 2012], suggesting that a loss of CRKL alone may be responsible for 22q11DS phenotypes in some cases.…”