Rare copy number variants in isolated sporadic and syndromic atrioventricular septal defects

Priest, James R.; Girirajan, Santhosh; Vu, Tiffany; Olson, Aaron K.; Eichler, Evan E.; Portman, Michael A.

doi:10.1002/ajmg.a.35315

Cited by 38 publications

(27 citation statements)

References 29 publications

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“…Our study stands in agreement with the consensus of other studies reporting complex heterogeneity of genetic contributions to atrioventricular septum and valve development in both the disomic population and in individuals with trisomy 21 (Robinson et al 2003;Ackerman et al 2012;Al Turki et al 2014;Ramachandran et al 2015a,b;Priest et al 2012). Our data support the nuanced hypotheses that deletions on chromosome 21 on a trisomic background reduce the risk for AVSD and duplications on chromosome 21 further increase risk of AVSD in DS.…”

Section: Discussionsupporting

confidence: 82%

Analysis of copy number variants on chromosome 21 in Down syndrome-associated congenital heart defects

Rambo-Martin

Mullé

Cutler

et al. 2016

Preprint

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One in five people with Down syndrome (DS) are born with an atrioventricular septal defect (AVSD), an incidence 2000 times higher than in the euploid population. The genetic loci that contribute to this risk are poorly understood. In this study, we tested two hypotheses: (1) individuals with DS carrying chromosome 21 copy number variants (CNVs) that interrupt exons may be protected from AVSD, because these CNVs return AVSD susceptibility loci back to disomy, and (2) individuals with DS carrying chromosome 21 genes spanned by microduplications are at greater risk for AVSD because these microduplications boost the dosage of AVSD susceptibility loci beyond a tolerable threshold. We tested 198 case individuals with DS+AVSD, and 211 control individuals with DS and a normal heart, using a custom microarray with dense probes tiled on chromosome 21 for array CGH (aCGH). We found that neither an individual chromosome 21 CNV nor any individual gene intersected by a CNV was associated with AVSD in DS. Burden analyses revealed that African American controls had more bases covered by rare deletions than did African American cases. Inversely, we found that Caucasian cases had more genes intersected by rare duplications than did Caucasian controls. We also showed that previously DS+AVSD (DS and a complete AVSD)-associated common CNVs on chromosome 21 failed to replicate. This research adds to the swell of evidence indicating that DS-associated AVSD is similarly heterogeneous, as is AVSD in the euploid population.

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Section: Discussionsupporting

confidence: 82%

Analysis of copy number variants on chromosome 21 in Down syndrome-associated congenital heart defects

Rambo-Martin

Mullé

Cutler

et al. 2016

Preprint

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“…The role of CNVs in atrioventricular septal defects (AVSDs), both in patients with and without Down syndrome, was investigated (Priest et al 2012). None of the 29 individuals with AVSD without Down syndrome had a pathologic CNV on chromosome 21 and only two harbored rare CNVs elsewhere in the genome, deletions of 1-1.5 Mb that were deemed of uncertain significance.…”

Section: Copy Number Variationmentioning

confidence: 99%

Complex Genetics and the Etiology of Human Congenital Heart Disease

Gelb

Chung

2014

Cold Spring Harbor Perspectives in Medicine

128

116

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Congenital heart disease (CHD) is the most common birth defect. Despite considerable advances in care, CHD remains a major contributor to newborn mortality and is associated with substantial morbidities and premature death. Genetic abnormalities appear to be the primary cause of CHD but identifying precise defects has proven challenging, principally because CHD is a complex genetic trait. Due largely to recent advances in genomic technology such as next-generation DNA sequencing, scientists have begun to identify the genetic variants underlying CHD. In this chapter, the roles of modifier genes, de novo mutations, copy number variants, common variants and non-coding mutations in the pathogenesis of CHD are reviewed.

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“…Also, CNVs are important components of the overall genomic variability among individual genomes (Sharp et al 2005;Beckmann et al 2007). Rare and common CNVs have been associated with various phenotypes (Redon et al 2006;Beckmann et al 2007;Conrad et al 2010;Craddock et al 2010;Priest et al 2012), and possibly they could also be one cause of the CHD risk in DS.…”

mentioning

confidence: 99%

The complex SNP and CNV genetic architecture of the increased risk of congenital heart defects in Down syndrome

et al. 2013

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Congenital heart defect (CHD) occurs in 40% of Down syndrome (DS) cases. While carrying three copies of chromosome 21 increases the risk for CHD, trisomy 21 itself is not sufficient to cause CHD. Thus, additional genetic variation and/or environmental factors could contribute to the CHD risk. Here we report genomic variations that in concert with trisomy 21, determine the risk for CHD in DS. This case-control GWAS includes 187 DS with CHD (AVSD = 69, ASD = 53, VSD = 65) as cases, and 151 DS without CHD as controls. Chromosome 21-specific association studies revealed rs2832616 and rs1943950 as CHD risk alleles (adjusted genotypic P-values <0.05). These signals were confirmed in a replication cohort of 92 DS-CHD cases and 80 DS-without CHD (nominal P-value 0.0022). Furthermore, CNV analyses using a customized chromosome 21 aCGH of 135K probes in 55 DS-AVSD and 53 DS-without CHD revealed three CNV regions associated with AVSD risk (FDR £ 0.05). Two of these regions that are located within the previously identified CHD region on chromosome 21 were further confirmed in a replication study of 49 DS-AVSD and 45 DS-without CHD (FDR £ 0.05). One of these CNVs maps near the RIPK4 gene, and the second includes the ZBTB21 (previously ZNF295 ) gene, highlighting the potential role of these genes in the pathogenesis of CHD in DS. We propose that the genetic architecture of the CHD risk of DS is complex and includes trisomy 21, and SNP and CNV variations in chromosome 21. In addition, a yetunidentified genetic variation in the rest of the genome may contribute to this complex genetic architecture.

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Rare copy number variants in isolated sporadic and syndromic atrioventricular septal defects

Cited by 38 publications

References 29 publications

Analysis of copy number variants on chromosome 21 in Down syndrome-associated congenital heart defects

Analysis of copy number variants on chromosome 21 in Down syndrome-associated congenital heart defects

Complex Genetics and the Etiology of Human Congenital Heart Disease

The complex SNP and CNV genetic architecture of the increased risk of congenital heart defects in Down syndrome

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