Trio-whole-exome sequencing and preimplantation genetic diagnosis for unexplained recurrent fetal malformations

Whole-exome sequencing (WES) is widely used to detect genetic mutations that cause Mendelian diseases, and has been successfully applied in combination with preimplantation genetic diagnosis (PGD) to avoid the transmission of genetic defects. We investigated 40 nonconsanguineous families with unexplained, recurrent fetal malformations (two or more malformed fetuses) from May 2016 to December 2018. Using Trio-WES, we identified 32 disease-associated variants in 40 families (80% positive rate), which were subsequently verified. Known Mendelian diseases were identified in 12 families (30%), highly suspected Mendelian diseases in 12 families (30%), variants with uncertain significance in 8 families (20%), and no noticeable variants for 8 families (20%). Further analysis showed variants in 22 genes may cause fetal malformations. Four gene variants were detected in fetuses for the first time, which expanded the spectrum of the disease phenotype. Two novel candidate genes may be related to fetal malformations. Of 26 couples receiving PGD on disease-associated genes, 3 healthy newborns were delivered, and 4 couples are undergoing pregnancies. We reported the fetal data and developed an optimized genetic testing strategy. Our finding strongly suggests the presence of single gene Mendelian disorders in 60% of those families, and PGD services for couples to have healthy babies.