Whole-exome sequencing and whole genome re-sequencing for prenatal diagnosis of achondroplasia.

objectiveTo investigate the feasibility of whole exome sequencing (WES) and whole genome re-sequencing (WGS) in the prenatal diagnosis of achondroplasia (ACH).

methodsEleven highly suspected with ACH or hypochondroplasia (HCH) fetuses and their parents were enrolled in this study. Routine prenatal examinations were carried out in all pregnant women. WGS was performed for the detection of copy number variation (CNV). WES was conducted to determine the mutation of fibroblast growth factor receptor 3 (FGFR3) gene in one special family with rickets and dwarfism. Moreover, all subjects were performed Sanger sequencing for the screening of high frequent mutation sites in FGFR3 gene.

resultsFor ultrasound (US) examination, short femur was noted in all fetuses with FL less than 4SD and 2SD in 8 cases and one case compared with those of normal gestational weeks, respectively. CNV abnormality was identified in 5 cases, including heterozygous deletion in 4 cases and heterozygous duplication in one case. Among these variation, one case was acknowledged to be pathogenic, one case was identified as genomic polymorphism, while the pathogenicity remained unknown in other 3 cases. For the exome and Sanger sequencing, heterozygous mutation p.Tyr278Cys (833A>G) was noted in the fetus and husband of the special family, while homozygous c.1959+19G>A mutation was identified in another case.

conclusionMultiple sequencing technologies may provide an additional diagnostic tool and facilitates genetic counseling in the patients with ACH. Further improvement of gene sequencing should be done in the prenatal diagnosis for the mutant screening in other genes.