Prenatal diagnosis of fetal structure anomalies using whole exome sequencing

Fetal structure anomalies have a wide range of genetic causes including chromosomal aneuploidy, copy number variations and single nucleotide variations. When the results of karyotype and copy number variation tests come back negative, prenatal whole - exome sequencing (WES) is not only of great necessity but also seeing a growing trend in its application. Forty families were enrolled in the study. In these families, fetuses had exhibited structural anomalies detected by prenatal ultrasonography, while their karyotype and copy number variation test results were normal. Genomic DNA was isolated from the fetus and both of its parents. Subsequently, trio-WES was carried out on the collected specimens with Sanger sequencing as a validation method. The conservatism of amino acid residues affected by the detected missense and nonsense variants was analyzed by Uniprot online program. A molecular diagnosis was achieved in 5 of 40 fetuses (12.5%), with variants in PEX1 , BRAF , PCDH12 , PTPN11 , and SETD5 , associated respectively with Zellweger spectrum disorder, Noonan syndrome 7, Diencephalic - mesencephalic junction dysplasia syndrome 1, Noonan syndrome 1, and autosomal - dominant intellectual developmental disorder 23. The four respective residues affected by the detected missense and nonsense variants remained conserved across multiple species. A definitive genetic diagnosis was established for five families. This finding validates prenatal trio-WES as an effective approach for investigating fetal structural anomalies. However, more refinements are needed to better define fetal genotype-phenotype correlations.