877: Rare adds up: Characterization of mosaicism in rare autosomal aneuploidies via noninvasive prenatal screening

Reports of rare autosomal aneuploidy (RAA) from noninvasive prenatal screening (NIPS) via whole-genome sequencing (WGS) have important clinical implications due to placental mosaicism, uniparental disomy (UPD), and true fetal aneuploidy. We explored the prevalence of RAA and relative degree of mosaicism (DOM) detected via NIPS for RAA versus for common aneuploidies (13, 18, 21) and the effect on results interpretation. To characterize prevalence and the degree of mosaicism in all aneuploidies, a retrospective analysis of 48,965 sequential prenatal NIPS samples processed via WGS was performed. Aneuploidy was identified using a z-score that reflected the significance of enrichment or depletion in WGS read density. For the purposes of this study, we examined high confidence positives defined as having |z| > 6. DOM is defined as the ratio of the fetal fraction estimated from WGS read-density enrichment on the positive chromosome (FF_pos) to the orthogonal, regression- based fetal fraction measurement inferred from the collection of read density values across all autosomes (FF_inferred). DOM less than 0.5 was chosen for the threshold at which a positive RAA call was qualified as being mosaic. 266 out of 48,965 samples (0.5%) had an RAA. The most common RAAs occurred in chromosomes 7, 8, 15, 16, and 20. Near zero prevalences of RAAs on chromosomes 1, 11, 17, and 19 are consistent with previous reports. We showed that the frequency of mosaicism differed between common aneuploidies and RAAs; 4.44% of samples positive for chromosome 21 were estimated to have DOM less than 0.5. In contrast, for chromosome 7, 87.69% of positive samples were estimated to have DOM less than 0.5. Our findings suggest that mosaicism may be common—not an edge case—in RAA and, therefore, must be taken into account when reporting positives. Accurate screen-positive calls for RAA and common aneuploidy therefore uniquely depend on established laboratory criteria for DOM. Interpreting these results in the same manner as those for common aneuploidies may otherwise compromise the clinical value of screening for RAA due to potential false negatives.View Large Image Figure ViewerDownload Hi-res image Download (PPT)