AUTHOR=Jin Lihui , Han Zhenyuan , Jiang Zhongli , Lu Jieru , Wu Yizhuo , Yan Bingqian , Zhang Weibin , Lin Xuedong , Jiang Lvyan , Zhao Pengjun , Sun Kun 

TITLE=Integrated genomic analysis identifies novel low-frequency cis-regulatory variant rs2279658 associated with VSD risk in Chinese children

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=10

YEAR=2022

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2022.1062403

DOI=10.3389/fcell.2022.1062403

ISSN=2296-634X

ABSTRACT=<p>VSD combined with other cardiac or extracardiac malformations (defined as “complex VSD” by us) is one of the major causes of perinatal morbidity and mortality. Functional non-coding SNPs (<italic>cis</italic>-regulatory SNPs) have not been systematically studied in CHDs, including complex VSD. Here we report an exome-wide association analysis using WES data of 60 PA/VSD cases, 20 TOF cases and 100 controls in Chinese children. We identify 93 low-frequency non-coding SNPs associated with complex VSD risk. A functional genomics pipeline integrating ATAC-seq, ChIP-seq and promoter CHi-C recognizes the rs2279658 variant as a candidate <italic>cis</italic>-regulatory SNP. Specifically, rs2279658 resides in a cardiac-specific enhancer bound by <italic>FOXH1</italic> and <italic>PITX2</italic>, and would abrogate binding of these two transcription factors to the identified enhancer during cardiac morphogenesis. <italic>COQ2</italic> and <italic>FAM175A</italic> are predicted to be target genes for “rs2279658-<italic>FOXH1</italic> or <italic>PITX2</italic>” pairs in the heart. These findings highlight the importance of <italic>cis</italic>-regulatory SNPs in the pathogenesis of complex VSD and broaden our understanding of this disease.</p>