Study On Genetic Detection Of Fetuses With Structural Abnormalities Revealed By Prenatal Ultrasound

Objective: The purpose of this study is to identify the genetic etiology of fetal structural abnormalities by chromosome karyotype analysis,low-depth whole genome copy number variation sequencing and whole exome sequencing in fetuses with structural abnormalities revealed by ultrasound.to study and explore the application process and strategy of sequential prenatal diagnosis in fetal structural abnormalities.Method: We selected 68 fetuses diagnosed as structural abnormalities by prenatal ultrasound.After informed consent,amniotic fluid or umbilical cord blood of pregnant women were taken as research samples.The collected samples were detected by chromosome karyotype analysis and CNV-seq detection,and the pathogenicity of the abnormalities was determined according to the relevant guidelines.For some cases of skeletal system abnormalities which were not detected by the above-mentioned detection methods or may result in disease,further WES detection should be done.The abnormal results were verified by other genetic techniques.Detailed genetic counseling was carried out before and after testing.Result: 1.Karyotype analysis and CNV-seq detection were performed in 68 fetuses with structural abnormalities,and 5 cases were detected by karyotype analysis.The abnormal detection rate of karyotype detection was 7.4%(5/ 68).There were 21 cases of copy number variation detected by CNV-seq,and the abnormal detection rate was 30.9%(21/68),3 cases were pathogenicity abnormalities caused by aneuploid changes,18 cases were microdeletions and microrepeats caused by copy number variation(including 6 cases of pathogenic changes,3 cases of possible pathogenicity,3 cases of unknown clinical significance of CNV,6 and 3 cases of benign CNV).2.No obvious pathogenicity was found in 3 pregnant women by chromosome karyotype analysis and CNV-seq detection,and WES was used to detect 2 cases of pathogenic mutation.Case 20 had a heterozygous mutation of FGFR3 gene c.1620C>G,which was related to the shortening of fetal long bone,resulting in the transformation of the stop codon 807 at the corresponding protein sequence level into leucine.In case 22,there was a heterozygous mutation of COL1A1 gene c.3505G>A,which led to the conversion of glycine to serine at 1169 position at the protein sequence level.There was a possible pathogenic gene mutation in 1 case.Case 21 had a heterozygous mutation of FGFR3 gene c.2420C>G,which led to the conversion of asparagine to lysine at position 540 th.The gene mutations in all the above cases were missense mutations,and the results of Sanger verification were consistent with those of WES,and all of them were new mutations by pedigree analysis.Conclusion: 1.The detection rate of pathogenicity and suspected pathogenicity by CNV-seq detection was higher than that by chromosome karyotype analysis.The existence of occult balanced translocation is confirmed and proposed for the first time.2.By using the prenatal diagnosis process of high-resolution karyotype combined detection of CNV-seq,we can find potential small structural abnormalities in parents,which can improve the detection rate of abnormalities in parents and fetuses,and provide a perfect basis for genetic counseling for the choice of pregnancy mode in the next step.3.According to the technical route and results of this study,fetuses with structural abnormalities indicated by prenatal ultrasound should carry out perfect genetic counseling and sequential genetic testing,and joint genetic testing strategies can also be carried out when a single gene is highly suspected.In order to seek comprehensive genetic testing,improve the detection rate of prenatal diagnosis and improve the performance-to-price ratio.4.When the existing prenatal diagnosis process can not identify the genetic etiology,WES can improve the genetic diagnostic potential of fetuses with structural abnormalities,especially skeletal abnormalities,and further improve the efficiency of pathogenic genetic etiology detection.5.Using WES in the genetic diagnosis and differential diagnosis of abnormal fetuses,the genetic pathogenesis of new mutations in abnormal fetuses was clarified,the new evidence for suspected pathogenic sites was added,and the exon database of fetal hypochondroplasia and brittle bone disease was improved.6.Professional genetic counseling is of great significance in sequential prenatal diagnosis and should be carried out throughout prenatal testing.