High‐resolution analysis of copy number variants in adults with simple‐to‐moderate congenital heart disease

Abstract

As patients with congenital heart disease (CHD) increasingly survive to childbearing age, it becomes important to understand the genetic origins of CHD. In children, CHD is frequently caused by chromosomal imbalances. We searched for submicroscopic imbalances in adults with CHD focusing on simple-to-moderate phenotypes, without associated dysmorphic features, a group not previously examined. A total of 100 Han Chinese adults with a diverse range of isolated CHD and 65 ethnically matched controls were screened using whole-genome array comparative genomic hybridization. Forty-five large (>100 kb) rare copy number variants (CNVs) were identified in 36/100 patients. These variants were not listed in the Database of Genomic Variants nor found in controls. In three of these genomic imbalances (22q11.2, 18q23, 3q21.3), genes that play an important role in cardiac development were implicated, including CRKL, NFATC1, PLXNA1, the latter has not been associated with human CHD before. This study detected a 0.7 Mb 22q11.2 deletion, which marginally overlapped the common 3 Mb 22q11.2 deletion, in one patient with a perimembranous ventricular septal defect without any extracardiac manifestation. Furthermore, we detected a novel inherited aberration dup (16q23.1). Although a causal relationship with CHD remains to be established, this CNVs profile provides a spectrum of genomic imbalances in this condition, and improves the CNV-phenotype correlations.

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.…”

“…Patient 3 of Jalali et al [2008] had a conotruncal heart defect, but it is not noted whether patient 4 (the parent of patient 3) has the same defect. Zhao et al [2013] reported on a cohort specifically with cardiac defects, and identified a single individual with a central deletion, but the types of cardiac defects are not specified. In Racedo et al [2015], 8/20 B-D deletion subjects and 1/5 C-D deletion subjects had cardiac 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].…”

Copy Number Variation in Congenital Heart Defects

“…A study of 105 patients with varying types of CHD performed by Erdogan et al [31] found de novo pathogenic CNVs in 3 % of their patients with isolated CHD. Zhao et al [49] examined CNVs in 100 Han Chinese adults with simple-to moderate-isolated CHD. They found large, rare CNVs in 39 % of their patients, compared with 21 % of the control group.…”

Nuclear factor of activated T-cells (NFATC) as a possible diagnostic and prognostic marker in congenital valvular diseases and myocardial hypertrophy

“…Так, встановили значущу кореляцію між трьома поліморфізмами гена NFATс1 (rs7240256, rs11665469, rs754505) і виникненням дефек-ту міжшлуночкової перетинки (ДМШП) серця в однієї китайської популяції [15]. [16,17].…”