Cell-free fetal DNA analysis is used as a screening test to identify pregnancies that are at risk for common autosomal and sex chromosome aneuploidies.

The purpose of this study was to investigate the chromosomal abnormalities that would not be detected by cell-free fetal DNA in a single medical center.

This was a retrospective cohort analysis of 3182 consecutive invasive diagnostic procedures that were performed at Montefiore Medical Center’s Division of Reproductive and Medical Genetics from January 1, 2009 to August 31, 2014. All patients underwent cytogenetic analysis; one-third of the patients (1037/3182) went through chromosomal microarray analysis.

Clinically significant chromosomal abnormalities were detected in 220 of 3140 cases (7%) after we excluded multiple gestation pregnancies (n = 42). Of these 125 cases (57%) were diagnosed with the common autosomal trisomies that involved chromosomes 21, 18, and 13 and with sex chromosome aneuploidies. There were 23 mosaic karyotypes; 8 of them involved trisomy in chromosomes 21 and 13; 5 of them were sex chromosome mosaics, and 10 of them were other mosaic cases. Five cases of triploidy were detected. Additionally, 19 unbalanced chromosomal rearrangements, a rare autosomal trisomy, and 47 clinically significant findings on chromosomal microarray analysis were diagnosed. Based on the published detection rates of cell-free fetal DNA testing and considering the “no-results” rate, we calculated that 99 of 220 chromosomal changes (45%) could not have been detected by cell-free fetal DNA testing: 16 of the 125 common aneuploidies and sex chromosome aneuploidies, 1 of the 5 triploidy cases, 15 of the 23 mosaic cases, all cases of unbalanced chromosomal rearrangements (n = 19), rare autosomal trisomy (n = 1), and 47 clinically significant chromosomal microarray abnormalities.

Current cell-free DNA testing could not detect up to one-half of the clinically significant chromosomal abnormalities that were found, which included clinically significant chromosomal microarray abnormalities. Among the 99 abnormal karyotypes that were not identified by cell-free DNA screening, 79% were from women with abnormal screening or abnormal ultrasound finding; 21% were from women who underwent invasive testing simply for advanced maternal age/concern, with no other risk factors or ultrasound findings. This information highlights the limitations of cell-free DNA screening and the importance of counseling patients about all prenatal screening and diagnostic procedures and about the added gain of invasive testing with karyotype and microarray.