Clinical Retrospective Analysis Of Congenital Heart Disease With Heterotaxy And Study On The Role Of CFAP157 In It

Background:Congenital Heart Disease（CHD）is the most common birth defect and still a cause of neonatal and infant mortality.Heterotaxy（HTX）is a comprehensive malformation that widely affects the heart and many extracardiac organs,manifested by the abnormal distribution of thoracic and/or abdominal organs along the left and right axis of the body.CHD with HTX is very rare,with primary cilia dysfunction（PCD）study found that 54%of PCD patients had HTX.In addition,a study focusing on HTX reported that 42%of HTX patients with CHD had respiratory motile ciliary dysfunction.Therefore,we speculate that CHD with HTX is also a special kind of ciliopathies,and its underlying etiology and mechanism are still unclear.The purpose of this research is to use whole exome sequencing（WES）and CRISPR/Cas9 technology to explore its pathogenesis.Methods:The clinical data and peripheral blood of CHD patients hospitalized in our hospital from January 2013 to December 2014 were collected,and the incidence of CHD patients complicated with HTX was statistically analyzed.WES was performed on those patients by high-throughput sequencing to screen for related pathogenic gene variants.Meanwhile,A model organism,Cfap157 knockout mice,constructed by CRISPR/Cas9 gene editing technology,were used to verify.And the related phenotypes of Cfap157^-/-mice were observed.Results:（1）A total of 3979 CHD patients hospitalized from 2013 to 2014,among them,37 patients were combined with HTX,and the incidence rate was 0.93%.There were 3385 patients with simple CHD,8 patients（0.24%）with HTX;594 patients with complex CHD,and 29 patients（4.88%）with HTX.The chi-square test was used for statistical analysis,and the results showed that the P value was less than 0.0001.Therefore,it was considered that the risk of HTX in patients with complex CHD was higher than that in simple CHD.（2）WES was performed on 37 patients with CHD and HTX,and a patient with complex CHD and HTX was identified as carrying a compound heterozygous variant of CFAP157.Biological information analysis predicted that it was a deleterious variant,and it was considered that CFAP157 may be a causative gene of CHD with HTX.（3）Cfap157^-/-male mice were sterile,but Cfap157^-/-mice had no phenotypes of CHD and HTX.Conclusions:（1）The risk of HTX in patients with complex CHD is higher than that in simple CHD.（2）CFAP157 may be the causative gene of a special type of ciliopathies.