Genetic testing and diagnostic strategies of fetal skeletal dysplasia: a preliminary study in Wu Han, China ​

Abstract

Abstract Background Fetal skeletal dysplasia (FSD) is a diverse group of degenerative diseases of bone and cartilage disorders that can lead to movement disorder and even death. This study aims to deliver prenatal diagnosis through sonographic examination and genetic testing. Methods From September 2015 to April 2021, the study investigated 24 cases with suspected short-limb fetuses, which were obtained from Tongji Hospital affiliated to Tongji Medical College of Huazhong University of Science and Technology. To identify the causative gene, multiple approaches (including karyotype analysis, copy number variations and whole exome sequencing) were performed on these fetuses. And further segregation analysis of the candidate variant was performed in parents by using Sanger sequencing. Results ① 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. ②A 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 Genetic testing combining with ultrasound scanning enhances the accurate diagnosis of fatal skeletal dysplasia in utero, and then provides appropriate genetic counseling.