Sequential prenatal diagnosis of fetal skeletal dysplasia: A cohort study

Genetic factors are considered to be the main factors leading to fetal skeletal dysplasia (SD), and chromosomal microarray analysis (CMA) has been used clinically for the detection of SD fetuses. At present, whole exome sequencing (WES) has been applied in SD fetuses, but there is still a lack of data accumulation. The aim of this study is to perform sequential prenatal diagnosis for fetuses with SD indicated by ultrasound and to explore the clinical value of CMA followed by WES.

From January 2019 to May 2024, 147 fetuses with SD were detected by prenatal ultrasound screening. After the collection of amniotic fluid or abortive tissue, CMA was performed first, then WES was performed in the cases with a negative CMA result.

147 cases accepted the prenatal CMA test, and 23 cases were reported to have chromosomal abnormalities, including 9 cases of chromosomal aneuploidies, 11 cases of pathogenic copy number variants, and 3 cases of likely pathogenic copy number variants. The detection rate of chromosomal abnormalities by the prenatal CMA test was 15.6% (23/147). 58 cases with negative results of CMA underwent WES, and 21 genes with pathogenic/likely pathogenic variants were detected in 21 cases, including FGFR3, COL2A1, COL1A1, COL1A2, RUNX2, LMX1B, GLI3, SHOX, ALPL, and DYNC2H1. The rate of abnormal prenatal WES was 36.2% (21/58). In the subgroup analysis of the SD phenotype, the detection rate of chromosomal abnormalities in isolated SD fetuses was 7.7% (7/91), which was significantly lower than that in SD fetuses combined with other system abnormalities (28.6%, 16/56) (p = 0.001). The detection rate of monogenic abnormalities in short long bones with other skeletal abnormalities was 62.5% (10/16), which was higher than that in short long bones with non-skeletal abnormalities 10.5% (2/19), and the difference was statistically significant (p = 0.003).

SD is mostly caused by monogenic abnormalities, and prenatal WES has significantly improved the detection rate of SD fetuses. The prenatal WES can be used as an important molecular genetic testing method combined with CMA in the sequential prenatal diagnosis of SD fetuses.