Why atypical findings matter: Follow up testing finds diagnostic results related to cfDNA screen.

Abstract

Atypical results from prenatal cfDNA screens are on the rise; however, the impact on pregnancy outcomes has not been studied on a large scale. This study aims to determine the diagnostic yield of invasive testing after atypical cfDNA findings and to describe the types of findings that can trigger an atypical cfDNA screen. Ten years of FISH, karyotype, and chromosomal microarray analysis (CMA) testing performed on prenatal, newborn, and/or maternal samples were matched to previous cfDNA screenings with atypical results. This generated a total of 204 index cases. 102/204 index cases had a diagnostic finding. Most abnormal results (87/102) were related to the atypical cfDNA screen. 55 abnormal results were pathogenic, 18 were variants of uncertain significance (VUS), and 8 were likely benign (LB). Copy number variation (CNV) was the most common finding (38/102), followed by aneuploidy (37/102) and chromosome rearrangements (20/102). Uniparental disomy (UPD) and consanguinity were also detected. Diagnostic testing clarifies atypical cfDNA results and detects clinically relevant abnormalities in the fetus and the pregnant person. We encourage cfDNA laboratories to provide details on the suspected abnormality origin and type as these data inform downstream testing.