Evaluation of Diagnostic Strategies for Fetal Skeletal Dysplasia Using Ultrasound Scan and Gene Testing: A Preliminary Study in Wu Han, China

Abstract Objective: The aim of this study was to deliver prenatal diagnosis through sonographic examination and gene variation testing, and to evaluate the outcome of applied strategies in prenatal diagnosis Methods : From September 2015 to April 2021, the study investigated 24 cases with suspected short long bones, which were obtained from the prenatal diagnosis center of Tongji Hospital affiliated to Tongji Medical College of Huazhong University of Science and Technology. The likely pathogenic gene variants were analyzed by multiple approaches (including karyotype analysis, copy number variations and whole exome sequencing) and further determined with the accuracy of the prenatal diagnosis for fetal skeletal dysplasia through one year follow-up survey. Results : ① We found fetal skeletal dysplasia or malformation in 8 cases (account for 33.3%) before 24 weeks of gestation and in the rest cases after 30 weeks of gestation. ② Out of 24 cases, likely pathogenic gene variants in FGFR3, FBN2, COL1A2, CUL7 and DYNC2H1 were detected for 6 cases; genetic variants in FGFR3, IMPAD1 and GORAB as possibly lethal mutations were identified in other 6 cases; and gene variants in WNT1, FBN1, OBSL1, COL1A1, DYNC2H1 and NEK1 , known as Variant of Undetermined Significance (VUS), were found in 4 cases. The rest 8 cases showed undetectable mutation in the whole exome sequencing (WES) analysis.③ A genetic diagnosis determined 12 different skeletal dysplasia genotypes in 14/24 (58.3%) cases. The other 10 cases with wild type gene (41.7%) were normal and well developed in one-year follow-up survey after study. Conclusion : Features of fatal skeletal dysplasia can be identified in utero using fetal ultrasound and gene testing. Sonographic examination combining with genetic diagnosis showed advance in prenatal diagnosis in the preliminary study and the applied strategy could be used to help with improving the accuracy of prenatal diagnosis for fetal skeletal dysplasia.