22q11.2 Distal Deletion Syndrome: Description of a New Case with Truncus Arteriosus Type 2 and Review

Abstract

22q11.2 deletion syndrome is mainly characterized by conotruncal congenital heart defects, velopharyngeal insufficiency, hypocalcemia and a characteristic craniofacial appearance. The etiology in the majority of patients is a 3-Mb recurrent deletion in region 22q11.2. Nevertheless, recently some cases of infrequent deletions with various sizes have been reported with a different phenotype. We report on a patient with congenital heart disease (truncus arteriosus type 2) in whom a de novo 1.3-Mb 22q11.2 deletion was detected by array comparative genomic hybridization. The deletion described corresponds to an atypical and distal deletion which spans low copy repeat (LCR) 4 and is associated with breakpoint sites that do not correspond to known LCRs of 22q11.2. We examine the clinical phenotype of our case and compare our findings with those published in the literature. The most prevalent clinical features in this type of deletion are a history of prematurity, pre-natal and post-natal growth retardation, slight facial dysmorphic features, microcephaly and developmental delay, with a speech defect in particular. These are clearly different from those found in the classic 22q11.2 deletion syndrome, and we believe that the main differential diagnosis should be with Silver-Russel syndrome. In our case we observe the cardiac phenotype with truncus arteriosus communis usually seen in the classic 22q11.2 deletion syndrome, and so far associated with the TBX1 gene. Significantly, however, TBX1 is not included in our patient’s deletion. The possible roles of a position effect or other genes are discussed.

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

“…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.…”

“…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 ).…”

“…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 ). A total of 45 individuals have been reported with distal type I deletions, including an atypical B-F deletion observed by Molck et al [2013] [ 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]. The individuals reported in Ravnan et al [2006] Cardiac defects were observed in 24/45 (53%) and were primarily septal defects.…”

“…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].…”