Rare DNA copy number variants in cardiovascular malformations with extracardiac abnormalities.
ABSTRACT Clinically significant cardiovascular malformations (CVMs) occur in 5-8 per 1000 live births. Recurrent copy number variations (CNVs) are among the known causes of syndromic CVMs, accounting for an important fraction of cases. We hypothesized that many additional rare CNVs also cause CVMs and can be detected in patients with CVMs plus extracardiac anomalies (ECAs). Through a genome-wide survey of 203 subjects with CVMs and ECAs, we identified 55 CNVs >50 kb in length that were not present in children without known cardiovascular defects (n=872). Sixteen unique CNVs overlapping these variants were found in an independent CVM plus ECA cohort (n=511), which were not observed in 2011 controls. The study identified 12/16 (75%) novel loci including non-recurrent de novo 16q24.3 loss (4/714) and de novo 2q31.3q32.1 loss encompassing PPP1R1C and PDE1A (2/714). The study also narrowed critical intervals in three well-recognized genomic disorders of CVM, such as the cat-eye syndrome region on 22q11.1, 8p23.1 loss encompassing GATA4 and SOX7 and 17p13.3-p13.2 loss. An analysis of protein-interaction databases shows that the rare inherited and de novo CNVs detected in the combined cohort are enriched for genes encoding proteins that are direct or indirect partners of proteins known to be required for normal cardiac development. Our findings implicate rare variants such as 16q24.3 loss and 2q31.3-q32.1 loss, and delineate regions within previously reported structural variants known to cause CVMs.European Journal of Human Genetics advance online publication, 29 August 2012; doi:10.1038/ejhg.2012.155.
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ABSTRACT: Cardiac left ventricular outflow tract (LVOT) defects represent a common but heterogeneous subset of congenital heart disease for which gene identification has been difficult. We describe a 46,XY,t(1;5)(p36.11;q31.2)dn translocation carrier with pervasive developmental delay who also exhibited LVOT defects, including bicuspid aortic valve (BAV), coarctation of the aorta (CoA) and patent ductus arteriosus (PDA). The 1p breakpoint disrupts the 5Õ-UTR of AHDC1, which encodes AT hook DNA binding motif containing 1 protein, and AHDC1 truncating mutations have recently been described in a syndrome that includes developmental delay, but not congenital heart disease (Am. J. Hum. Genet. 94, 784-9, 2014). On the other hand, the 5q translocation breakpoint disrupts the 3Õ-UTR of MATR3 which encodes the nuclear matrix protein Matrin 3, and mouse Matr3 is strongly expressed in neural crest, developing heart, and great vessels, whereas Ahdc1 is not. To further establish MATR3 3Õ-UTR disruption as the cause of the probandÕs LVOT defects, we prepared a mouse Matr3(Gt-ex13) gene trap allele that disrupted the 3Õ portion of the gene. Matr3(Gt-ex13) homozygotes are early embryo lethal, but Matr3(Gt-ex13) heterozygotes exhibit incompletely penetrant BAV, CoA and PDA phenotypes similar to those in the human proband, as well as ventricular septal defect (VSD) and double outlet right ventricle (DORV). Both the human MATR3 translocation breakpoint and the mouse Matr3(Gt-ex13) gene trap insertion disturb the polyadenylation of MATR3 transcripts and alter Matrin 3 protein expression, quantitatively or qualitatively. Thus, subtle perturbations in Matrin 3 expression appear to cause similar LVOT defects in human and mouse. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: firstname.lastname@example.org.Human Molecular Genetics 01/2015; 24(8). DOI:10.1093/hmg/ddv004 · 6.68 Impact Factor
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ABSTRACT: The aim of this study was to investigate if pathogenic copy number variations (CNVs) are present in mosaic form in patients with congenital heart malformations. We have collected cardiac tissue and blood samples from 23 patients with congenital heart malformations that underwent cardiac surgery and screened for mosaic gene dose alterations restricted to cardiac tissue using array comparative genomic hybridization (array CGH). We did not find evidence of CNVs in mosaic form after array CGH analysis. Pathogenic CNVs that were present in both cardiac tissue and blood were detected in 2/23 patients (9%), and in addition we found several constitutional CNVs of unclear clinical significance. This is the first study investigating mosaicism for CNVs in heart tissue compared to peripheral blood and the results do not indicate that pathogenic mosaic copy number changes are common in patients with heart malformations. Importantly, in line with previous studies, our results show that constitutional pathogenic CNVs are important factors contributing to congenital heart malformations. Copyright © 2015 Elsevier Masson SAS. All rights reserved.European Journal of Medical Genetics 01/2015; DOI:10.1016/j.ejmg.2015.01.003 · 1.49 Impact Factor
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ABSTRACT: Cases with congenital heart defects (CHD) often have other associated anomalies. The purpose of this investigation was to assess the prevalence and the types of associated anomalies in CHD in a defined population. The anomalies associated with CHD were collected in all live births, stillbirths and terminations of pregnancy during 26 years in 346,831 consecutive pregnancies of known outcome in the area covered by our population based registry of congenital anomalies. Of the 4005 cases with CHD born during this period (total prevalence of 115.5 per 10,000), 1055(26.3 %) had associated major anomalies. There were 354 (8.8%) cases with chromosomal abnormalities including 218 trisomies 21, and 99 (2.5%) nonchromosomal recognized dysmorphic conditions. There were no predominant recognised dysmorphic conditions, but VACTERL association. However, other recognized dysmorphic conditions were registered including Noonan syndrome, fetal alcohol syndrome, and skeletal dysplasias. Six hundred and two (15.0 %) of the cases had non syndromic, non chromosomal multiple congenital anomalies (MCA). Anomalies in the urinary tract, the musculoskeletal, the digestive, and the central nervous systems were the most common other anomalies. Prenatal diagnosis was obtained in 18.7 % of the pregnancies. In conclusion the overall prevalence of associated anomalies, which was one in four infants, emphasizes the need for a thorough investigation of cases with CHD. A routine screening for other anomalies may be considered in infants and in fetuses with CHD. One should be aware that the anomalies associated with CHD can be classified into a recognizable anomaly, syndrome or pattern in one out of nine cases with CHD. Copyright © 2014. Published by Elsevier Masson SAS.European Journal of Medical Genetics 12/2014; 58(2). DOI:10.1016/j.ejmg.2014.12.002 · 1.49 Impact Factor