Cell-free DNA testing of an extended range of chromosomal anomalies: clinical experience with 6,388 consecutive cases

Abstract

Purpose:Cell-free DNA (cfDNA) testing for fetal aneuploidies was broadly implemented for common trisomies and sex-chromosome anomalies (SCAs). However, such an approach identifies only 75 to 85% of clinically relevant aneuploidies.Methods:We present a consecutive series of 6,388 cases, thus uncovering a broader array of aneuploidies, including the rare autosomal trisomies (RATs) and the maternally inherited deletion and duplication copy-number variations (CNVs), with complete and stratified follow-up by amniocentesis. Combined measurements of z-scores and the fetal fraction, in conjunction with fetal cfDNA enrichment, were used to stratify the likelihood of true and false results.Results:We obtained an incremental diagnostic yield of 50%; RATs and CNVs were found to be significant causes of fetal pathology. Scrutinizing z-scores and the fetal fraction made it possible to distinguish the sources of false-negative results; predict the likelihood of false-positive results for major trisomies and SCAs; classify maternal mosaic SCAs and CNVs, preventing false-positive results; and robustly identify maternally inherited CNVs and detect recurrent genomic disorders as a standardized function of the fetal fraction.Conclusion:With the clinical pertinence of this broader detection scheme confirmed, we offer recommendations for its implementation.Genet Med 19 2, 169–175.

Unexpected finding of uniparental disomy mosaicism in term placentas: Is it a common feature in trisomic placentas?

“…It is now recognized that confined placental mosaicism (CPM) with the chromosome aberration restricted to the placenta and absent in the fetus is the major origin of discordant results of non‐invasive prenatal testing (NIPT) . Those who perform extended NIPT, investigating all chromosomes, already discovered that chromosome aberrations typically involved in CPM, like trisomy 16 and trisomy 7, are also commonly found with NIPT . The trisomies involved in CPM may have a mitotic as well as meiotic origin.…”

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“…They found rare autosomal trisomies and sub‐microscopic imbalances in 0.78% and 0.56% of all cases tested, respectively . For comparison, the common trisomies and sex chromosome abnormalities accounted for 1.86% and 0.83% of all cases, respectively . Surprisingly, these rare aneuploidies made up 22.5% of the abnormal cases (excluding microdeletions) and were associated with significant fetal sequelae .…”

“…In a recent study of 2779 fetuses that had CMA following invasive prenatal diagnosis, Sotiriadis and colleagues calculated that approximately 50% of the abnormal CMA results would not have been detected by the standard NIPT assays (ie, did not involve trisomies 13, 18, 21, monosomy X, or a sex chromosome trisomy) . On the flip side, Pescia et al demonstrated an incremental diagnostic yield of 50% in a study of 6388 consecutive cases screened for an extended range of chromosomal anomalies by genome‐wide NIPT . They found rare autosomal trisomies and sub‐microscopic imbalances in 0.78% and 0.56% of all cases tested, respectively .…”

“…On the flip side, Pescia et al demonstrated an incremental diagnostic yield of 50% in a study of 6388 consecutive cases screened for an extended range of chromosomal anomalies by genome‐wide NIPT . They found rare autosomal trisomies and sub‐microscopic imbalances in 0.78% and 0.56% of all cases tested, respectively . For comparison, the common trisomies and sex chromosome abnormalities accounted for 1.86% and 0.83% of all cases, respectively .…”

Should we ‘open the kimono’ to release the results of rare autosomal aneuploidies following noninvasive prenatal whole genome sequencing?

“…Within the past year, several independent groups have presented oral or written data demonstrating that rare autosomal trisomies are an important underlying reason for false positive noninvasive prenatal screening test results, or cases in which there was a failure to generate a result. [1][2][3][4][5][6] The reason why this occurs is that the bioinformatics algorithms applied to interpret the results of raw massively parallel sequencing data use non-target reference chromosomes as a denominator for the most common target chromosomes (chromosomes 13, 18, 21, X, and Y). If the fetus is euploid, the number of mapped fragments in the target and reference chromosomes is approximately equal.…”