配对末端测序片段大小信息降低X染色体非整倍体cfDNA筛查阳性率

原文

OBJECTIVE: Prenatal cfDNA screening has transformed care, yet it remains difficult to determine whether X aneuploidy signals originate from the patient or fetus, inflating screen positive and false positive rates. One potential solution is to incorporate fragment size data from paired-end sequencing (PES). METHOD: We use a large clinical cohort to examine the effect of incorporating fragment size information via PES on the performance of cfDNA screening for X chromosome aneuploidies. Within the same patients (n = 118,859), we compare screen positive rates for monosomy X (MX) and trisomy X (XXX) before and after incorporation of fragment size data. Additionally, we examine the rate of reported false positives from patients tested via PES versus single-end sequencing (SES, n = 141,364), which lacks fragment size. RESULTS: Incorporation of fragment size data from PES significantly reduced the screen positive rates for MX (-49.1%, 227/446) and XXX (-42.9%, 60/105). The rate of voluntarily reported MX false positives was lower among patients with PES fragment size information (0.0033%) compared with SES (0.0085%). No XXX false positives were reported. CONCLUSION: The results illustrate that the screen positive rate can be reduced by leveraging fragment size data from paired-end sequencing. This has the potential to reduce false positive rates in clinical cfDNA prenatal screening.