Exome sequencing for prenatal diagnosis of fetuses with sonographic abnormalities

Abstract

Objective In the absence of aneuploidy or other pathogenic cytogenetic abnormality, fetuses with increased nuchal translucency (NT ≥ 3.5 mm) and/or other sonographic abnormalities have a greater incidence of genetic syndromes, but defining the underlying pathology can be challenging. Here, we investigate the value of whole exome sequencing in fetuses with sonographic abnormalities but normal microarray analysis.Method Whole exome sequencing was performed on DNA extracted from chorionic villi or amniocytes in 24 fetuses with unexplained ultrasound findings. In the first 14 cases sequencing was initially performed on fetal DNA only. For the remaining 10, the trio of fetus, mother and father was sequenced simultaneously.Results In 21% (5/24) cases, exome sequencing provided definitive diagnoses (Milroy disease, hypophosphatasia, achondrogenesis type 2, Freeman-Sheldon syndrome and Baraitser-Winter Syndrome). In a further case, a plausible diagnosis of orofaciodigital syndrome type 6 was made. In two others, a single mutation in an autosomal recessive gene was identified, but incomplete sequencing coverage precluded exclusion of the presence of a second mutation.Conclusion Whole exome sequencing improves prenatal diagnosis in euploid fetuses with abnormal ultrasound scans.In order to expedite interpretation of results, trio sequencing should be employed, but interpretation can still be compromised by incomplete coverage of relevant genes.

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

“…The average diagnostic rate in our study of families with two or more fetuses with malformations reached approximately 60% (24/40), for which the diagnosis is solved or probably solved. The diagnostic rate and detection efficiency of WES in our study are much higher compared with the 30% using the trio testing and 14% for fetus‐only WES tests among families with at least one malformation in Drury's study (Drury et al, ). The detection rate is also higher than the 24% with Trio‐WES and 14% singleton testing among families with one or more fetus malformation in Yates's study (Yates et al, ).…”

Two Consecutive Pregnancies with Simpson-Golabi-Behmel Syndrome Type 1: Case Report and Review of Published Prenatal Cases

“…For molecular confirmation of the diagnosis, WES is a promising method, enabling genetic diagnosis in up to 40% of the cases with severely dysmorphic fetuses [Carss et al, 2014;Alamillo et al, 2015;Drury et al, 2015]. WES enabled ultimate molecular diagnosis in our case, but due to the long turnaround time (15-18 weeks in Estonia), the results were available only during the second pregnancy.…”

Recent advances in prenatal genetic screening and testing

“…They found a genetic diagnosis in three (10%) and sequence variants of potential significance in five (17%) 8 . More recently, Alamillo et al reported relevant mutations in four of seven prenatal cases 135 , and Drury et al found a 25% total detection rate in 24 fetuses with abnormal ultrasound findings, including a definitive diagnosis in five and plausible diagnosis in one 11 . Our early results also indicate that the detection rate of a significant genetic abnormality with prenatal exome sequencing for fetuses with single or multiple congenital anomalies is at least 30% 18, 128 .…”