Identification of Novel Congenital Heart Disease Candidate Genes Using Chromosome Microarray

While the majority of patients have isolated heart disease, congenital heart disease (CHD) may be associated with other congenital anomalies or syndromes. Our institution utilizes chromosomal microarray (CMA) to identify chromosomal abnormalities, specifically copy number variations (CNVs). While CNVs have been associated with CHD, their direct impact on cardiac development remains unclear. This study sought to identify potential novel CHD candidate genes by comparing CNVs present in our institution's CHD population with those already recognized in the literature. A list of candidate genes was compiled from recent medical literature that utilized CMA. Records from neonatal cases at our institution over 10 years were reviewed. Genes identified from CMAs were compared with those reported in the literature and cross-referenced with the Online Mendelian Inheritance in Man catalog. We identified 375 CNVs reported in patients with CHD. At our institution between 2005 and 2015, 307 neonates with CHD had CMA. Of these, 77 patients (25%) had CNVs containing 832 unique candidate genes. 49 patients (16%) had isolated CHD with 353 candidate genes expressed within the CNVs, many of which were previously reported. However, there were 16 unique candidate genes identified that have been expressed with heart structure of the mouse knock-out models. Our findings demonstrate a high incidence of abnormal genes identified by CMA in CHD patients, including many CNVs of "unknown clinical significance". We conclude that a portion of these CNVs (including 16 genes expressed in the heart of the mouse knock-out models) could be candidate genes involved in CHD pathogenesis.