Exome sequencing improves genetic diagnosis of fetal increased nuchal translucency.

OBJECTIVE The aim of this retrospective study is to determine the monogenic syndromes in fetuses with isolated first-trimester increased nuchal translucency (NT) in order to provide more accurate parental counseling. METHOD Medical trio exome sequencing (ES) was performed on DNA extracted from chorionic villi in 73 fetuses with isolated first-trimester increased NT (≥3.5 mm) and normal chromosomal microarray analysis (CMA). This testing targets coding exons for 4200 clinically relevant disease-causing genes. The interpretation of variants was performed according to the American College of Medical Genetics guidelines. RESULTS Pathogenic variants were detected in four cases in which phenotypes and genotypes correlate well. Medical trio ES offered a 5.5% (4/73) increase in diagnostic rate over CMA in cases with isolated increased NT. Three of four cases with pathogenic variants developed structural anomalies on ultrasound at mid pregnancy, leading to the pregnancy termination. Only one case with a pathogenic variant demonstrated normal ultrasound throughout pregnancy. CONCLUSION Our results indicate that after a normal CMA, fetuses with isolated first-trimester increased NT have a 1.4% (1/73) risk of significant childhood genetic syndromes caused by known disease-causing variants, which will not be detectable on prenatal ultrasound. This information may be useful in parental counseling. This article is protected by copyright. All rights reserved.