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

Sailani, M. Reza; Makrythanasis, Periklis; Valsesia, Armand; Santoni, Federico; Deutsch, Samuel; Popadin, Konstantin; Borel, Christelle; Migliavacca, Eugenia; Sharp, Andrew J.; Saïl, Geneviève Duriaux; Falconnet, Emilie; Rabionet, Raquel; Serra‐Juhé, Clara; Vicari, Stefano; Laux, Daniéla; Grattau, Yann; Dembour, Guy; Mégarbané, André; Touraine, Renaud; Stora, Samantha; Kitsiou, Sofia; Fryssira, Helena; Chatzisevastou-Loukidou, Chariklia; Kanavakis, Emmanouel; Merla, Giuseppe; Bonnet, Damien; Pérez-Jurado, Luís A.; Estivill, Xavier; Delabar, Jean Maurice; Antonarakis, Stylianos E.

doi:10.1101/gr.147991.112

Cited by 64 publications

(75 citation statements)

References 56 publications

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“…Some authors suggest that the presence of certain variants in specific genes could be the underlying cause for CHD in this population [5,36]. Others suggest a correlation with the presence of single nucleotides polymorphism (SNPs) and Copy Number Variations (CNVs) [18]. And there are also ethnical genetic differences, which could play a role in the different incidence of CHD among these patients [20,24].…”

Section: Discussionmentioning

confidence: 99%

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Gender differences in the prevalence of congenital heart disease in Down’s syndrome: a brief meta-analysis

et al. 2017

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Background: Down's syndrome (DS) affects one per 700 live births and congenital heart disease (CHD) occurs in 40-60% of these patients. Contributing factors to the association between DS and CHD are being unraveled. Gender could be one of them. Methods: We performed a meta-analysis of CHD prevalence in DS, separated by gender. Three search engines were used and 578 articles were reviewed. Twelve articles were included. Results: Quantitative analysis showed a higher prevalence of CHD, particularly atrioventricular septal defects (AVSD), in female patients. No differences were found in others forms of CHD. Conclusion: CHD, particularly AVSD, are more common in the female gender of Down's syndrome patients.

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Section: Discussionmentioning

confidence: 99%

“…The reported prevalence of these defects varies among studies [8][9][10][11][12][13][14]. This could reflect inherent characteristics of the studied populations, such a higher frequency of genetic variances that predispose to the presence of AVSD [5,[15][16][17][18][19].…”

Section: Introductionmentioning

confidence: 99%

Gender differences in the prevalence of congenital heart disease in Down’s syndrome: a brief meta-analysis

et al. 2017

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“…Replication study of Sailani et al (2013) Two common CNVs were found to be associated with DS+AVSD in the study by Sailani et al (2013). To replicate these findings, we used the identical NanoString probes in 96 cases and controls from our DS cohort.…”

Section: Cnv Callingmentioning

confidence: 99%

“…Controls (DS+NH) are individuals with Down syndrome without a congenital heart defect. (Sailani et al 2013). CNV1 at chr21: 43,193,374-43,198,244 (hg19) was observed as a deletion in 18% of the 55 cases with DS+AVSD and 0% of the 53 DS+NH controls, and as a duplication in 7% of cases and 0% in controls.…”

Section: Replication Of Previous Findings Of Common Cnvs Associated Wmentioning

confidence: 99%

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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“…Congenital heart defect (CHD) occurs in approximately 40% of the DS patients (Sailani et al, 2013). The relatively higher infant mortality rate in DS patients has been largely attributed to their having a higher incidence of CHD (Weijerman et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Identification of altered pathways in Down syndrome-associated congenital heart defects using an individualized pathway aberrance score

Yq¹,

T²,

Wy³

et al. 2016

Genet. Mol. Res.

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ABSTRACT. The aim of this study was to identify disrupted pathways related to Down syndrome (DS), and DS-associated congenital heart defects (DS-CHD). The gene expression profile and pathway data of 10 human DS patients and 5 control samples in E-GEOD-1789 were recruited and analyzed by the individualized pathway aberrance score (iPAS) method, consisting of the data processing, gene-level statistics, pathway-level statistics, and significant measurement steps. The pre-processing step identified 12,493 genes and 1022 pathways (4269 genes). The pathway significant analysis identified eight pathways (adjusted P value <0.1) that differed between the disease and control samples. The cross-presentation of particulate exogenous antigen (phagosomes) and methionine salvage pathways showed the most significant differences among these. The gene expression levels of key pathway genes, such as CYBB and ADI1, were higher in disease samples than in normal controls. Based on our results, we predicted that the cross-presentation of particulate exogenous antigens (phagosomes) and the methionine salvage pathway could be good indicators of DS-CHD.

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

Cited by 64 publications

References 56 publications

Gender differences in the prevalence of congenital heart disease in Down’s syndrome: a brief meta-analysis

Gender differences in the prevalence of congenital heart disease in Down’s syndrome: a brief meta-analysis

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

Identification of altered pathways in Down syndrome-associated congenital heart defects using an individualized pathway aberrance score

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