SNP‐based non‐invasive prenatal testing detects sex chromosome aneuploidies with high accuracy

Abstract

Objective To develop a single nucleotide polymorphism- and informatics-based non-invasive prenatal test that detects sex chromosome aneuploidies early in pregnancy. Methods Fifteen aneuploid samples, including thirteen 45,X, two 47,XXY, and one 47,XYY, along with 185 euploid controls, were analyzed. Cell-free DNA was isolated from maternal plasma, amplified in a single multiplex PCR assay that targeted 19,488 polymorphic loci covering chromosomes 13, 18, 21, X, and Y, and sequenced. Sequencing results were analyzed using a Bayesian-based maximum likelihood statistical method to determine copy number of interrogated chromosomes, calculating sample-specific accuracies. Results Of the samples that passed a stringent quality control metric (93%), the algorithm correctly identified copy number at all five chromosomes in all 187 samples, for 934/935 correct calls as early as 9.4 weeks of gestation. We detected 45,X with 91.7% sensitivity (CI: 61.5-99.8%) and 100% specificity (CI: 97.9-100%), and 47,XXY and 47,XYY. The average calculated accuracy was 99.78%. Conclusion This method non-invasively detected 45,X, 47,XXY, and 47,XYY fetuses from cfDNA isolated from maternal plasma with high calculated accuracies, and thus offers a non-invasive method with the potential to function as a routine screen allowing for early prenatal detection of rarely diagnosed yet commonly occurring sex aneuploidies.

Noninvasive prenatal screening for fetal aneuploidy, 2016 update: a position statement of the American College of Medical Genetics and Genomics

“…53 The detection rate (clinical validity) of sex chromosome aneuploidies after NIPS is reported to be more than 90% and has a false-positive rate of approximately 1%. [54][55][56][57] The PPV (clinical utility) for the aggregate of sex chromosome aneuploidies among prospectively collected samples was 48.4% (range for specific aneuploidies, 30-67%). 57 A PPV in these ranges is considerably higher than those accepted for conventional screening of Patau, Edwards, and Down syndromes.…”

Response to “Noninvasive prenatal screening at low fetal fraction: comparing whole‐genome sequencing and single‐nucleotide polymorphism methods”

“…Ryan and Martin further argue that our simulations are incomplete because we treated SNPs independently and did not model linkage across neighboring SNPs: their argument is based on the fact that the SNP‐method algorithm incorporates “crossover frequency data from the HapMap database” to generate hypotheses that link SNPs probabilistically into the haplotype blocks that are highly likely to be co‐inherited 4. However, rather than handicap the SNP method by omitting this HapMap information from our model, we actually modeled the SNP method in its best‐case scenario, where no crossing over occurs at all.…”

Cell-Free Fetal DNA in Prenatal Screening

“…Cinsiyet kromozomu testleri için bu oranlar daha yüksek olarak (%4-7) rapor edilmiştir. [21][22][23] Durumların üçte ikisinde testin yeni bir örnekle tekrarlanması sonuç-suzluk durumunu ortadan kaldırmaktadır.…”