Application of whole exome sequencing in fetal cases with skeletal abnormalities.

OBJECTIVES

To investigate the role of whole exome sequencing (WES) technology in fetuses with skeletal abnormalities (SKA) for establishing an appropriate clinical diagnosis and treatment path.

METHODS

From April 2019 to August 2020, eight special families were enrolled into the study. Their fetuses showed abnormal SKA by ultrasonic testing during pregnancy, but it is inconsistent with the normal results identified by chromosomal microarray analysis (CMA) of amniotic fluid or abortion. For further diagnosis, WES was performed to detect the causative genes mutations followed by Sanger sequencing.

RESULTS

Among of these eight fetuses with SKA, we found more than half of pathogenic mutations were in gene, except for a known hotspot mutation in gene (c.1138G>A). Three heterozygous mutations of gene, c.2885G>A p (Gly962Asp), c.994G>A p (Gly332Arg) and c.1002 + 5G>T, were mutations. The c.1002 + 5G>T mutation in was firstly reported. In addition, one fetus carried a novel heterozygous mutation of c.644G>A p (Gly215Asp), which was inherited from the mother. Another novel heterozygous mutation c.2482G>T p (Val828Phe) in the gene was identified in another fetus and was inherited from the father. Among of these mutations, these results might involve in two novel splicing mutations.

CONCLUSION

Our study reported several novel heterozygous mutations which expands the mutation spectrum for prenatal diagnosis of SKA. Most importantly, WES technology is necessary as a routine step of the SKA diagnosis before or during pregnancy, combining with the detection of chromosome level.