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

M. Reza Sailani, Periklis Makrythanasis, Armand Valsesia, Federico A. Santoni, Samuel Deutsch, Konstantin Popadin, Christelle Borel, Eugenia Migliavacca, Andrew J. Sharp, Genevieve Duriaux Sail, Emilie Falconnet, Kelly Rabionet, Clara Serra-Juhé, Stefano Vicari, Daniela Laux, Yann Grattau, Guy Dembour, Andre Megarbane, Renaud Touraine, Samantha StoraSofia Kitsiou, Helena Fryssira, Chariklia Chatzisevastou-Loukidou, Emmanouel Kanavakis, Giuseppe Merla, Damien Bonnet, Luis A. Pérez-Jurado, Xavier Estivill, Jean M. Delabar, Stylianos E. Antonarakis

Research output: Contribution to journalArticlepeer-review


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 oncert 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.

Original languageEnglish
Pages (from-to)1410-1421
Number of pages12
JournalGenome Research
Issue number9
Publication statusPublished - Sept 2013

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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