Genetic analysis of fetal skeletal dysplasia via whole exome sequencing and non-invasive prenatal diagnosis

Fetal skeletal dysplasia (SD) is a complex group of bone and cartilage with high genetic heterogeneity and phenotypic diversity. Our study aimed to identify the genetic causes of fetal SD, provide an accurate prenatal diagnosis for those families investigate non-invasive prenatal detection strategy, and facilitate clinical diagnosis of fetal SD. A Total 34 fetuses with SD were recruited and analyzed using chromosomal microarray analysis (CMA) and whole exome sequencing (WES). Moreover, a non-invasive prenatal diagnosis (NIPD) based on next-generation sequencing (NGS) using circulating fetal DNA in maternal plasma was performed on 5 SD fetuses. A Total 55.88% (19/34) fetueses with SD were identified with the genetic etiologies. A Total 27 cases underwent karyotype and CMA analysis, and the diagnostic rate was 3.70% (1/27), while 34 cases accepted WES, and the diagnostic rate was 55.88% (19/34). Of the 19 positive cases, 2 cases were identified with pathogenic CNVs (10.53%, 2/19), and the other 17 cases were identified with pathogenic or likely pathogenic variations (89.47%, 17/19). The FGFR3 was the most prevalent SD-causing gene (47.06%, 8/17). In addition, 5 cases accepted the NIPD based on NGS for the detection of fetal SD, and the results were all consistent with those of amniocentesis. Our study highlights the advantages of WES compared with CMA in genetic diagnosis in fetal SD. Furthermore, our study revealed the excellent detection efficiency of NIPD based on NGS, which may be a potential noninvasive detection method in fetal SD. We identified the genetic causes of fetal SD and provided a accurate prenatal diagnosis for those families.Our results highlighted the advantages of WES compared with CMA in genetic diagnosis in fetal SD.Our study revealed the excellent detection efficiency of NIPD based on NGS, which may be a potential noninvasive detection methods in fetal SD. We identified the genetic causes of fetal SD and provided a accurate prenatal diagnosis for those families. Our results highlighted the advantages of WES compared with CMA in genetic diagnosis in fetal SD. Our study revealed the excellent detection efficiency of NIPD based on NGS, which may be a potential noninvasive detection methods in fetal SD.