Down syndrome (DS) patients are often born with congenital heart defects (CHD), including atrioventricular septal defect (AVSD). The incidence of AVSD is 43% in DS-CHD patients (17% in the DS population) and very rare in the general population. Here we use chromosome 21-targeted deep sequencing (>120x) to perform a case-control association study in an AVSD population (102 cases, 145 controls) to identify SNPs, indels and CNVs associated with the AVSD in DS. SNPs and short indels are called through our in-house pipelines implementing BWA, GATK and Annovar. The association study is performed by Firth logistic regression following different genetic models and correcting for population stratification. Epistasis analysis is as well done using logistic interaction with interacting term. We also perform CNVs detection with the Nexus copy number software and statistical analysis with an in-house workflow. This study shows that common variants on chromosome 21 may contribute to the developmental phenotype of AVSD and provide insights into the understanding of the genetic mechanisms underlying the development of this heart defect.