Implications of fetoplacental mosaicism on cell‐free DNA testing for sex chromosome aneuploidies

Grati, Francesca Romana; Bajaj, Komal; Zanatta, Valentina; Malvestiti, Francesca; Malvestiti, Barbara; Marcato, Livia; Grimi, Beatrice; Maggi, Federico; Simoni, Giuseppe; Gross, Susan J.; Ferreira, José Carlos

doi:10.1002/pd.5138

Cited by 39 publications

(67 citation statements)

References 21 publications

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“…The use of genome‐wide cfDNA panels impacts the usually extremely low false positive rate of the test, due to cases of confined placental mosaicism (CPM) . CPM is especially common in sex chromosomes, particularly monosomy X, and rare autosomal trisomies such as trisomy 7, 16, 8 and 20. This also negatively affects the positive predictive value of the screening test, which inevitably decreases .…”

Section: Discussionmentioning

confidence: 99%

“…CPM is especially common in sex chromosomes, particularly monosomy X, and rare autosomal trisomies such as trisomy 7, 16, 8 and 20. This also negatively affects the positive predictive value of the screening test, which inevitably decreases . The net result is that genome‐wide cfDNA undermines the main advantage of this screening test above the CT, which is to reduce the need for invasive testing.…”

Section: Discussionmentioning

confidence: 99%

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Is there still a role for nuchal translucency measurement in the changing paradigm of first trimester screening?

et al. 2019

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Objectives:To give an overview of the genetic and structural abnormalities occurring in fetuses with nuchal translucency (NT) measurement exceeding the 95th percentile at first-trimester screening and to investigate which of these abnormalities would be missed if cell-free fetal DNA (cfDNA) were used as a first-tier screening test for chromosomal abnormalities.Methods: This is a national study including 1901 pregnancies with NT≥95th percentile referred to seven university hospitals in the Netherlands between 1 January 2010 and 1 January 2016. All cases with unknown pregnancy outcome were excluded. Results of detailed ultrasound examinations, karyotyping, genotyping, pregnancy and neonatal outcomes, investigation by a clinical geneticist and post-mortem investigations were collected. Results:In total, 821 (43%) pregnancies had at least one abnormality. The rate of abnormalities was 21% for fetuses with NT between 95 th and 99 th percentile and 62% for fetuses with NT≥99 th percentile. Prevalence of single-gene disorders, submicroscopic, chromosomal and structural abnormalities was 2%, 2%, 30% and 9%, respectively. Conclusion:Although cfDNA is superior to the combined test, especially for the detection of trisomy 21, 34% of the congenital abnormalities occurring in fetuses with increased NT may remain undetected in the first trimester of pregnancy, unless cfDNA is used in combination with fetal sonographic assessment, including NT measurement.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Is there still a role for nuchal translucency measurement in the changing paradigm of first trimester screening?

et al. 2019

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“…This relates primarily to fetuses with monosomy 45, X with normal ultrasound findings. The positive predictive value of an abnormal cfDNA analysis is therefore only approximately 53 % in this group, while the PPV would be 98.8 % in the case of an abnormal ultrasound finding such as fetal nuchal edema or hygroma [134]. Both in the case of a normal finding regarding fetal sex after cfDNA and in a pathological finding, sonographic verification of the fetal sex organs should be performed to rule out developmental disorders [135].…”

Section: Sex Chromosome Aneuploidies Early Detection Of Fetal Sexmentioning

confidence: 88%

DEGUM, ÖGUM, SGUM and FMF Germany Recommendations for the Implementation of First-Trimester Screening, Detailed Ultrasound, Cell-Free DNA Screening and Diagnostic Procedures

Kozlowski¹,

Burkhardt

Gembruch³

et al. 2018

Ultraschall in Med

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First-trimester screening between 11 + 0 and 13 + 6 weeks with qualified prenatal counseling, detailed ultrasound, biochemical markers and maternal factors has become the basis for decisions about further examinations. It detects numerous structural and genetic anomalies. The inclusion of uterine artery Doppler and PlGF screens for preeclampsia and fetal growth restriction. Low-dose aspirin significantly reduces the prevalence of severe preterm eclampsia. Cut-off values define groups of high, intermediate and low probability. Prenatal counseling uses detection and false-positive rates to work out the individual need profile and the corresponding decision: no further diagnosis/screening - cell-free DNA screening - diagnostic procedure and genetic analysis. In pre-test counseling it must be recognized that the prevalence of trisomy 21, 18 or 13 is low in younger women, as in submicroscopic anomalies in every maternal age. Even with high specificities, the positive predictive values of screening tests for rare anomalies are low. In the general population trisomies and sex chromosome aneuploidies account for approximately 70 % of anomalies recognizable by conventional genetic analysis. Screen positive results of cfDNA tests have to be proven by diagnostic procedure and genetic diagnosis. In cases of inconclusive results a higher rate of genetic anomalies is detected. Procedure-related fetal loss rates after chorionic biopsy and amniocentesis performed by experts are lower than 1 to 2 in 1000. Counseling should include the possible detection of submicroscopic anomalies by comparative genomic hybridization (array-CGH). At present, existing studies about screening for microdeletions and duplications do not provide reliable data to calculate sensitivities, false-positive rates and positive predictive values.

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“…However, if NIPT reveals abnormality, invasive prenatal test like amniocentesis is required for definitive diagnosis. And it is important to note that confined placental mosaic or vanishing twin can yield misleading results [18,19]. Sekizawa et al reported high accuracy of fetal gender determination using cfDNA since seven weeks of gestation [20].…”

Section: Discussionmentioning

confidence: 99%

Mismatch between fetal sexing and birth phenotype: a case of complete androgen insensitivity syndrome

et al. 2018

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Abstract. With advancing maternal age, the number of prenatal genetic tests is increasing in many countries. Prenatal genetic tests, such as amniocentesis, chorionic villus sampling and non-invasive prenatal testing, can disclose fetal chromosomal sex, although these tests were originally designed to prenatally diagnose chromosomal aneuploidies, such as trisomy 21, 18 and 13. Complete androgen insensitivity syndrome (CAIS) is an X-linked recessive disorder caused by an androgen receptor dysfunction leading to hormone resistance. The affected individuals are genetic males as shown by 46,XY but present complete female external genitalia and normal breast development at puberty albeit without menstruation. CAIS is commonly diagnosed in adolescence based on primary amenorrhea or in childhood based on inguinal hernia or testis-like masses in the inguinal region. In the present report, we describe a baby in whom CAIS was diagnosed immediately after birth based on a mismatch between the fetal karyotype detected by amniocentesis and the external genitalia phenotype at birth. We speculate that the increase in the number of prenatal genetic tests is contributing to the early detection of 46,XY disorders of sex development, especially those previously called complete sex reversal, which is supposedly diagnosed during childhood or adolescence. Hence, it is necessary to understand the disease-specific hormone profile at each developmental stage for accurate diagnosis.

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Implications of fetoplacental mosaicism on cell‐free DNA testing for sex chromosome aneuploidies

Cited by 39 publications

References 21 publications

Is there still a role for nuchal translucency measurement in the changing paradigm of first trimester screening?

Is there still a role for nuchal translucency measurement in the changing paradigm of first trimester screening?

DEGUM, ÖGUM, SGUM and FMF Germany Recommendations for the Implementation of First-Trimester Screening, Detailed Ultrasound, Cell-Free DNA Screening and Diagnostic Procedures

Mismatch between fetal sexing and birth phenotype: a case of complete androgen insensitivity syndrome

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