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Diagnostic cytogenetic testing following positive noninvasive prenatal screening results of sex chromosome abnormalities: Report of five cases and systematic review of evidence.

ABSTRACT: BACKGROUND:Follow-up cytogenetic analysis has been recommended for cases with positive noninvasive prenatal screening (NIPS) results. This study of five cases with numerical and structural sex chromosomal abnormalities (SCA) and a review of large case series of NIPS provided guidance to improve prenatal diagnosis for SCA. METHODS:Following positive NIPS results for SCA, karyotype analysis, chromosomal microarray analysis (CMA), fluorescence in situ hybridization (FISH), and locus-specific quantitative PCR were performed on cultured amniocytes, chorionic villi cells, and stimulated lymphocytes. Review of large case series was performed to evaluate the NIPS positive rate, follow-up rate of cytogenetic analysis, positive predictive value (PPV) for major types of SCA, and relative frequencies of subtypes of major SCA. RESULTS:Of the five cases with positive NIPS for SCA, case 1 showed a mosaic pattern of monosomy X and isodicentric Y; case 2 showed a mosaic pattern of monosomy X confined to the placenta; cases 3 and 4 had an isochromosome of Xq, and case 5 showed a derivative chromosome 14 from a Yq/14p translocation of maternal origin. Review of literature showed that mean positive rate of NIPS for SCA was 0.61%, follow-up rate of cytogenetics analysis was 76%, and mean PPV for SCA was 48%. Mosaic patterns and structural rearrangements involving sex chromosomes were estimated in 3%-20% and 3% of SCA cases, respectively. CONCLUSION:These five cases further demonstrated the necessity to pursue follow-up cytogenetic analysis to characterize mosaic patterns and structural abnormalities involving sex chromosomes and their value for prenatal genetic counseling. A workflow showing the performance of current NIPS and cytogenetic analysis for SCA was summarized. These results could facilitate an evidence-based approach to guide prenatal diagnosis of SCA.

SUBMITTER: Xie X

PROVIDER: S-EPMC7336728 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Diagnostic cytogenetic testing following positive noninvasive prenatal screening results of sex chromosome abnormalities: Report of five cases and systematic review of evidence.

Xie Xiaolei X Tan Weihe W Li Fuguang F Carrano Eric E Ramirez Paola P DiAdamo Autumn A Grommisch Brittany B Amato Katherine K Chai Hongyan H Wen Jiadi J Li Peining P

Molecular genetics & genomic medicine 20200508 7

<h4>Background</h4>Follow-up cytogenetic analysis has been recommended for cases with positive noninvasive prenatal screening (NIPS) results. This study of five cases with numerical and structural sex chromosomal abnormalities (SCA) and a review of large case series of NIPS provided guidance to improve prenatal diagnosis for SCA.<h4>Methods</h4>Following positive NIPS results for SCA, karyotype analysis, chromosomal microarray analysis (CMA), fluorescence in situ hybridization (FISH), and locus- ...[more]

PMID: 32383339

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Project description:BackgroundPregnant people have a risk of carrying a fetus affected by a chromosomal anomaly. Prenatal screening is offered to pregnant people to assess their risk. Noninvasive prenatal testing (NIPT) has been introduced clinically, which uses the presence of circulating cell-free fetal DNA in the maternal blood to quantify the risk of a chromosomal anomaly. At the time of writing, NIPT is publicly funded in Ontario for pregnancies at high risk of a chromosomal anomaly.MethodsWe completed a health technology assessment, which included an evaluation of clinical benefits and harms, value for money, budget impact, and patient preferences related to NIPT. We performed a systematic literature search for studies on NIPT for trisomies 21, 18, and 13, sex chromosome aneuploidies, and microdeletions in the average-risk or general population. We evaluated the cost-effectiveness of traditional prenatal screening, NIPT as a second-tier test (performed after traditional prenatal screening), and NIPT as a first-tier test (performed instead of traditional prenatal screening). We also conducted a budget impact analysis to estimate the additional costs of funding first-tier NIPT. We interviewed people who had lived experience with NIPT and people living with the conditions NIPT screens for, or their families.ResultsThe pooled clinical sensitivity of NIPT in the average-risk or general population was 99.5% (95% confidence interval [CI] 81.8%-99.9%) for trisomy 21, 93.1% (95% CI 75.9%-98.3%) for trisomy 18, and 92.7% (95% CI 81.6%-99.9%) for trisomy 13. The clinical specificity for any trisomy was 99.9% (95% CI 99.8%-99.9%). Compared with traditional prenatal screening, NIPT was more accurate in detecting trisomies 21, 18, and 13, and decreased the need for diagnostic testing. We found limited evidence on NIPT for sex chromosome aneuploidies or microdeletions in the average-risk or general population. Positive NIPT results should be confirmed by diagnostic testing.Compared with traditional prenatal screening, second-tier NIPT detected more affected fetuses, substantially reduced the number of diagnostic tests performed, and slightly reduced the total cost of prenatal screening. Compared with second-tier NIPT, first-tier NIPT detected more affected cases, but also led to more diagnostic tests and additional budget of $35 million per year for average-risk pregnant people in Ontario.People who had undergone NIPT were largely supportive of the test and the benefits of earlier, more accurate results. However, many discussed the need for improved pre- and post-test counselling and raised concerns about the quality of the information they received from health care providers about the conditions NIPT can screen for.ConclusionsNIPT is an effective and safe prenatal screening method for trisomies 21, 18, and 13 in the average-risk or general population. Compared with traditional prenatal screening, second-tier NIPT improved the overall performance of prenatal screening and slightly decreased costs. Compared with second-tier NIPT, first-tier NIPT detected more chromosomal anomalies, but resulted in a considerable increase in the total budget. Interviewees were generally positive about NIPT, but they raised concerns about the lack of good informed-choice conversations with primary care providers and the quality of the information they received from health care providers about chromosomal anomalies.

Dataset Information

Diagnostic cytogenetic testing following positive noninvasive prenatal screening results of sex chromosome abnormalities: Report of five cases and systematic review of evidence.

Publications

Diagnostic cytogenetic testing following positive noninvasive prenatal screening results of sex chromosome abnormalities: Report of five cases and systematic review of evidence.

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