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

Abstract

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 diseaseassociated 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.

Clinical and molecular delineation of PUS3‐associated neurodevelopmental disorders

“…described by Guo et al 16 were anencephalic, but it is yet unknown whether this developmental feature can be attributed merely to PUS3 variants, and contribution of other genetic or environmental factors is a possibility. Facial dysmorphisms was reported in 17 out of 18 individuals, but a recognizable facial dysmorphism was not observed (Figure 1).…”

“…individual (family J, individual 11). 16 Variants of two individuals were identified in large genetic studies and phenotype information could not be obtained (Individuals 12 and 18). The percentiles of the physical measurements (height, weight, and head circumference) are calculated using the growth charts published by Grip et al 17 PUS3 variants were identified in the probands using massively…”

Prenatal Exome Sequencing in Recurrent Fetal Structural Anomalies: Systematic Review and Meta-Analysis

“…For the scoping review selection progress, 106 studies were initially selected from PubMed focusing on ES/GS and fetuses with a recurrent malformation. After full review, one study was deemed eligible and was included in this review [16]. Studies dealing with specific syndromes or malformations were excluded [17,18].…”

“…A single study was focused on recurrent anomalies [16], while the remaining eight also included anomalous fetuses with non-recurrent anomalies (the latter were not included in the study). All studies were of high quality according to modified Standards for Reporting of Di-agnostic Accuracy (STARD) criteria (Figure 2).…”

Whole‑exome sequencing identification of a recurrent CRYBB2 variant in a four‑generation Chinese family with congenital nuclear cataracts

“…Implementation of genetic testing using whole-exome sequencing (WES) has permitted the streamlining of the process of identifying pathogenic genetic variants, especially when it is widely used in the diagnosis of a variety of single-gene diseases ( 10 ). In the present study, WES was used to examine the genetic cause in a four-generation Chinese family with congenital nuclear cataracts.…”