Clinical Study Of Copy Number Variation In The Etiological Diagnosis Of Fetal Congenital Heart Disease

Research background and purpose:Congenital heart disease(congenital heart disease)is the most common birth defect in newborns,with an incidence of about 0.8%to 1.2%.Studies have confirmed that the pathogenesis of congenital heart disease is a process involving and interacting with many factors,in which genetic factors play an important role,but the specific genetic pathogenesis is still unclear.Copy number variations(CNVs)are variations caused by genome rearrangement.Studies have shown that CNVs are associated with fetal congenital heart disease,but the specific pathogenesis has not been clarified.Therefore,by analyzing the results of chromosome microarray analysis(CMA)in pregnant women with fetal heart structure abnormalities,this study preliminarily explored the relationship between CNVs and fetal congenital heart disease,so as to supplement the potential etiology and possible pathogenesis of fetal congenital heart disease.Materials and Methods:This study adopts the method of retrospective analysis.(1)A total of 3386 patients who underwent amniotic fluid puncture examination during the second trimester in Women and Children’s Hospital Affiliated to Sichuan Maternal and Child Health Hospital and Chengdu Medical College from January 2020 to August 2022 were collected.A total of 697 pregnant women diagnosed with cardiac malformations by prenatal fetal echocardiography were selected as the experimental group.A total of 2689 fetuses who underwent amniotic fluid puncture examination in our hospital were divided into 3 subgroups according to the severity of intracardiac malformations and whether there were extracardiac abnormalities,namely simple CHDS,complex CHDS without extracardiac abnormalities(hereinafter referred to as complex CHDS),and CHDS with extracardiac abnormalities.(2)Clinical data of each group were collected,pregnancy outcomes were followed up,chromosome karyotype results and CNVs results of each group were analyzed,and classified statistics were conducted.(3)By referring to relevant databases and literature,the detected CNVs with unknown clinical significance were analyzed,and the correlation between their variation and fetal CHD was discussed.Results:1.CNVs were detected in 53 cases(7.6%)of 697 cases with abnormal fetal heart development,and 34 cases(64.15%)were pathogenic or likely to cause CNVs.There were 36 cases(1.38%)of CNVs detected in 2689 patients in the control group,and 30 cases(83.33%)of CNVs were pathogenic or possibly pathogenic.In the experimental group,there were 602 cases of pure CHD,27 cases of pathogenic and possible pathogenic CNVs(4.49%).There were 65 cases of complex CHDS,5 of which were pathogenic and potentially pathogenic CNVs(7.69%),and 26 cases of complex CHDS with cardiac anomalies of which were pathogenic and potentially pathogenic CNVs(7.69%).The detection rate was comparable to that of complex CHDS,and was significantly higher than that of simple CHDS,with statistical significance(P<0.05).The detection rate of CNVs in the three combinations with heart abnormalities was higher than that in the control group(1.38%),and the difference was statistically significant(P<0.05).2.The detection rates of karyotype abnormalities in simple CHDS,complex CHDS and CHDS with extracardial abnormalities were 6.99%,15.09%,25%,respectively,and 4.71%in the control group.Compared with the control group in pairs,the detection rate of chromosome karyotype abnormality in the experimental group was higher than that in the control group,and the difference was statistically significant(P<0.05).In addition,under the condition of normal chromosome karyotype,the detection rate of CNVs in the three groups of experimental group and control group was compared,the results showed that the detection rate of CNVs pathogenicity combined with cardiac abnormalities was significantly higher than that in the control group,and the difference was statistically significant(P<0.05).3.A total of 9 cases of CNVs(VOUS)of unknown clinical significance were detected.After searching and analyzing the existing database,8 cases were found to be potentially pathogenic,among which NF1,HNF1B and MAP3K20 may be related to the occurrence of fetal CHD.4.Pregnancy outcome:All 697 cases in the experimental group were followed up by telephone,with an average follow-up time of 3-6 months.There were 513 live births(73.6%),61 induced labor in eugenic birth,3 induced labor in stillbirth,21 refused to follow up or had wrong contact information,and 120 cases had not delivered by the time of writing this paper.Among 513 live births,9 cases were found to be accompanied by abnormal cardiac structure,and 1 case died after birth due to abnormal metabolism.The other newborns are generally doing well.Conclusion:The detection rates of abnormal CHD chromosome karyotype and CNVs in fetuses were significantly higher than those in the normal group,and the detection rates of CNVs pathogenicity in CHDS of different types of fetuses were different under the condition of normal karyotype,suggesting that CNVs is related to the occurrence of fetal CHD,which may be the potential cause of fetal CHD.Some of the CNVs(VOUS)phenotypes of unknown clinical significance still need to be further verified.