Objectives Whole exome sequencing technology can identify the undiscovered genetic etiology of product of concepts(POC) and improve the diagnosis rate of abortion.This study examines the value of a combined trio-WES strategy in identifying the etiology of abortion in the case of negative karyotype and chromosomal microarray sequencing. Design: A retrospective study Setting: Center of Prenatal Diagnosis Sample: Fourteen abortion samples with normal karyotype analysis and CMA Methods: In this study, Trio-WES was used to sequence 14 POC with normal CMA and karyotype analysis, and to evaluate the detection rate of abnormal abnormalities and the diagnostic value of variation. Main outcome measures: The detection rate of gene mutation sequence in flow products, the definite diagnosis rate of single gene disease and its relationship with clinical phenotype Results A total of 10 variants of 7 genes were detected, including 2 pathogenicity variant, 4 likely pathogenicity variant and 4 uncertain significance variant. Four families were accepted as positive results, with a definite diagnosis rate of 28.6% (4/14). Case 1 was type 4 of autosomal dominant polycystic kidney disease caused by complex heterozygous variation of PKHD1 gene, Case 2 was Alagille syndrome caused by heterozygous variation of JAG1 gene, Case 5 and Case7 were type 3 of short rib dysplasia caused by complex heterozygous variation of DYNC2HI gene. Conclusions These data support the application value of whole exome sequencing technology in the detection of abortion etiology and enhance the understanding of pathogenicity variation. Funding: National Key Research and Development Program (2018YFC1002203-2);

Objective: To explore whether CNV-seq can be used as a first-tier diagnostic method or even replace karyotyping for prenatal diagnosis alone. Method: A retrospective study was conducted to 4230 amniocentesis samples with CNV-seq detection and G-banding karyotyping simultaneously. The indications for prenatal diagnosis included abnormal result on Down’s Syndrome Screening, abnormal fetal ultrasound, abnormal result on noninvasive prenatal screening, and so on. The results that lead to birth defects definitely were defined as abnormalities, which included aneuploidy, mosaic aneuploidy, large deletion/duplication and pathogenic copy number variations (pCNVs). Results: 278 cases of abnormalities was identified by karyotyping with an abnormal detection rate of 6.69%(283/4230). In addition, for all the abnormalities identified by karyotyping, CNV-seq also identified another 58 cases of abnormalities. A total of 341 cases of abnormalities were identified by CNV-seq with an abnormal detection rate of 8.06%(341/4230), higher than that of karyotyping. Abnormal detection rate of CNV-seq for the groups with abnormal result on noninvasive prenatal screening, abnormal fetal ultrasound, abnormal parental chromosome, adverse pregnancy history, abnormal result on Down’s Syndrome Screening, volunory testing and advanced maternal age were increased by 2.53%, 1.91%, 1.44%, 1.24%, 1.01%, 0.99% and 0.62% over the karyotyping respectively. Conclusion: CNV-seq and karyotyping had the same effectiveness in identifying aneuploidies, but CNV-seq had absolute superiority in the detection of low proportion of mosaics, imbalanced structural abnormalities. This prevents the birth of fetuses with these chromosome abnormalities that cannot be identified by karyotyping. CNV-seq can replace karyotyping in prenatal diagnosis for chromosome test alone.