Combined Cell‐Free DNA Screening for Aneuploidies and Selected Single‐Gene Disorders for Pregnancies With Sonographically Detected Fetal Anomalies: Detection Rate and Residual Risk

Abstract

ObjectivesTo determine the additional detection rate (DR) and the residual risk (RR) of combined cell‐free DNA (cfDNA) screening for aneuploidies (not including copy number variants) and 25 dominant single‐gene disorders (SGD) in pregnancies with sonographic abnormalities.MethodOne hundred sixteen singleton pregnant women with abnormal fetal ultrasounds from week 12 were included in the study. They underwent combined cfDNA analysis, while exome sequencing and karyotyping were performed as reference standards. The results of the cfDNA analysis were compared with diagnostic genetic tests.ResultsThe positive rate of cfDNA analysis was 15/116 (12.9%), with a positive predictive value of 13/15 (86.7%). The incremental DR of combined cfDNA screening for aneuploidies and 25 SGD compared with cfDNA testing for aneuploidies in fetuses with sonographic anomalies was 22.9%. The RR of cfDNA analysis for aneuploidies and pathogenic/likely pathogenic gene variants, after excluding cfDNA testing‐detectable findings, was 2/101 (2.0%). The DR of cfDNA analysis for genetic aberrations in pregnancies with abnormal ultrasound was 13/35 (37.1%) compared with diagnostic testing.ConclusionIn fetuses with sonographic anomalies, the additional DR of combined cfDNA analysis for aneuploidies and 25 SGD was remarkable at 22.9% compared with cfDNA testing for aneuploidies; the overall RR of combined cfDNA analysis was approximately 2.0%. It is essential to provide detailed genetic counseling before using cfDNA analysis in these pregnancies.