Rare autosomal aneuploidies (RAAs) can cause miscarriage or other pregnancy complications and lead to inconsistent results of noninvasive prenatal testing (NIPT), but many NIPT providers have not yet started to provide related services. Our aim was to develop a semiconductor sequencing platform (SSP)-based method for detecting RAAs when pregnant women performed NIPT. Fifty-three aneuploidy samples with verified karyotyping or array comparative genomic hybridization (aCGH) results were collected and subjected to RAAs detection using an SSP to develop a method by genomic sequencing. Various trisomies on all chromosomes other than chromosomes 17 and 19, four multiple aneusomies, one monosomy and five sex chromosome abnormalities were got by our method which can directly identify RAAs via a z-score. Then, artificial mixtures of 10% and 5% DNA were created by adding fragmented fifty-three tissue samples and used in an NIPT simulation to develop a bioinformatics analysis method which can use in NIPT. And the results were in accordance with those of karyotyping and aCGH. Therefore, our method has potential for use in NIPT. Finally, 23,823 clinical plasma samples were tested to verify the performance of our approach. Karyotyping or aCGH was performed on the positive clinical samples. In total, 188 of 23,823 clinical samples were positive (T2, n = 1; T7, n = 1; T13, n = 15; T18, n = 45; T21, n = 125; and multiple aneusomies, n = 1) and verified by karyotyping or aCGH; no sample was a false negative. Several false positives were detected, one of which showed maternal copy number variation (CNV). One case of multiple aneusomies was caused by a maternal tumor. The method developed enables detection of RAAs without increasing costs.
Keywords: NIPT; artificial mixtures; discordant results; maternal tumor; rare autosomal aneuploidies.