Dextrocardia, a condition where the heart is located on the right side of the thoracic cavity, occurs in approximately 0.83 of 10,000 pregnancies and is often associated with complex congenital heart diseases (CHDs).
, and whether the applicability of the"omnigenic" threshold to explain such complex traits remain unclear.
This study was led by Prof. Hongyan Wang , Prof. Qihua Fu , Prof. Haifa Hong , and Prof. Jianguo Zhang . First, Chen et al. identified that 44% of dextrocardia patients carried loss-of-function variants in well-established candidate ciliopathy-associated genes, indicating the pathogenic roles of ciliary genes in dextrocardia.
Subsequently, they demonstrated that dextrocardia shares an omnigenic genetic architecture. They revealed that a threshold number of singleton loss-of-function variants for dextrocardia risk. When the number of SLoFVs reached 8, the OR for dextrocardia was greater than 1 [OR=6.9 ]. As the number of SLoFVs increases, the risk for dextrocardia increases exponentially, with an OR of 22.8 for 12, OR=59.6 for 14, and OR=357.8 for 16 SLoFVs.
By further exploring the various weighted genes on cardiac malformation, they found that the heart-tissue/group-enriched expressed genes knockdown produced significantly higher rates of heart abnormalities and played more direct roles than broadly expressed enhanced genes knockdown in zebrafish, which confirm the biologically interpretable roles of genes specifically expressed inThis team demonstrates that the existence of a genome-wide genetic risk threshold for dextrocardia based on SLoFVs...