Detection Of Candidate Genes Associated With Congenital Heart Disease Using High-throughput Molecular Techniques

Objective: The present study aims to detect the pathogenic variants or genetic loci in fetuses with congenital heart disease(CHD),using chromosome microarray analysis(CMA)and targeted next-generation sequencing.Methods : Conventional karyotyping and CMA were both used to detect pathogenicities in fetuses with congenital heart disease and those with normal fetal structure.Fetuses with congenital heart disease were categorized into isolated group and non-isolated group(combined with extracardiac abnormalities).Additional diagnostic yield of CMA was calculated by comparing with karyotyping.Detection rate of CMA in fetuses with congenital heart disease was also compared with that in normal fetuses.Targeted next-generation sequencing was then used to detect the pathogenic variants in CHD fetuses with normal microarray results.Results : A total of 2261 prenatal fetuses were collected in the present study,including 173 CHD cases.In CHD fetuses,the detection rate and additional diagnostic yield of CMA was 19.1% and 8.1%,compared with conventional karyotyping.The detection rate of pathogenic copy number variations(CNVs)in CHD fetuses was significantly higher than fetuses with normal structure(p=0.000).15q11.2 microdeletion was found significantly enriched in CHD cases,compared with normal fetuses(p=0.000).Four pathogenic variants were detected by targeted next generation seuqencing in 37 CHD fetuses with normal microarray results,indicating the detection rate of 10.8%.Conclusions: CMA could improve the detection rate of pathogenicity for CHD fetuses.We suggest CMA should be the first-line testing for both isolated CHD and non-isolated CHD fetuses.Targeted next-generation sequencing could further improve the detection rate of pathogenic variants.Our results indicate 15q11.2microdeletion might be a potential genetic locus associated with cardiac development.