Increased RISK for 47,XXY on cell‐free DNA screen: Not always Klinefelter syndrome

Ronzoni, Luisa; Bedeschi, Maria Francesca; Silibello, Gaia; Accurti, Veronica; Segni, Matteo Di; Nicotra, Valeria; Vizziello, Paola; Lalatta, Faustina

doi:10.1002/pd.5890

Cited by 7 publications

(9 citation statements)

References 9 publications

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“…In the study by Ronzoni et al, four cases presented with mosaic forms of SCAs in the pre-or postnatal follow-up after cellfree NIPT showed an increased risk of Klinefelter syndrome in the fetus (Ronzoni et al, 2021). Various grades of mosaicism (47,XXY/46,XY) is known to be present in 10-20% of Klinefelter males and these individuals tend to present with a milder form of the syndrome (Kanakis and Nieschlag, 20182018).…”

Section: Discussionmentioning

confidence: 97%

“…The PPV for Klinefelter syndrome in twin pregnancies is unknown. In a recent study, Ronzoni et al performed prenatal or postnatal karyotyping after cell-free NIPT suggested an increased risk of 47,XXY in 34 pregnancies ( Ronzoni et al, 2021 ). In nine cases the cell-free NIPT result was not confirmed and in one third of these cases the fetus had a normal 46,XY karyotype corresponding to a false-positive rate of 8.8%.…”

Section: Discussionmentioning

confidence: 99%

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Cell-Based NIPT Detects 47,XXY Genotype in a Twin Pregnancy

Jeppesen

Hjortshøj

Hindkjær³

et al. 2022

Front. Genet.

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Background: The existing risk of procedure-related miscarriage following invasive sampling for prenatal diagnosis is higher for twin pregnancies and some women are reluctant to test these typically difficultly obtained pregnancies invasively. Therefore, there is a need for noninvasive testing options that can test twin pregnancies at an early gestational age and ideally test the twins individually.Case presentation: A pregnant woman opted for cell-based NIPT at GA 10 + 5. As cell-based NIPT is not established for use in twins, the test was provided in a research setting only, when an ultrasound scan showed that she carried dichorionic twins.Materials and Methods: Fifty mL of peripheral blood was sampled, and circulating fetal cells were enriched and isolated. Individual cells were subject to whole-genome amplification and STR analysis. Three fetal cells were analyzed by chromosomal microarray (aCGH).Results: We identified 20 fetal cells all sharing the same genetic profile, which increased the likelihood of monozygotic twins. aCGH of three fetal cells showed the presence of two X chromosomes and a gain of chromosome Y. CVS from both placentae confirmed the sex chromosomal anomaly, 47,XXY and that both fetuses were affected.Conclusion: NIPT options can provide valuable genetic information to twin pregnancies that help the couples in their decision-making on prenatal testing. Little has been published about the use of cell-based NIPT in twin pregnancies, but the method may offer the possibility to obtain individual cell-based NIPT results in dizygotic twins.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Cell-Based NIPT Detects 47,XXY Genotype in a Twin Pregnancy

Jeppesen

Hjortshøj

Hindkjær³

et al. 2022

Front. Genet.

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“…These 5 discordant results represent the imperative need for prenatal genetic counseling on NIPT results positive for SCAs to also include the possibility for an SCA diagnosis that is abnormal but discordant with the NIPT lab result. In a recent study this concern is articulated specific to NIPT results positive for 47,XXY, with the authors underlining the importance of a definitive diagnosis not only for excluding a false positive but also excluding other chromosomal variations which may have a different and more severe phenotype (Ronzoni et al, 2020). Our study findings reinforce the importance of counseling regarding possible other SCAs as there are significant phenotypic differences associated with higher risks of medical complexity and neurodevelopmental involvement when comparing sex chromosome trisomies vs. pentasomies, such as 48,XXYY (Raznahan et al, 2018; Skuse, Printzlau, & Wolstencroft, 2018; N.…”

Section: Discussionmentioning

confidence: 99%

Non-Invasive Prenatal Testing (NIPT) Results for Participants of the eXtraordinarY Babies Study: Screening, Counseling, Diagnosis, and Discordance

Howell

Davis

Thompson

et al. 2021

Preprint

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Sex chromosome aneuploidies (SCAs), including 47,XXY, 47,XXX, 47,XYY, and supernumerary variants, occur collectively in approximately 1/500 livebirths. Clinical phenotypes are highly variable resulting in previous ascertainment rates have been estimated to be only 10-25% during a lifetime. Historically, prenatal SCA diagnoses were incidental findings, accounting for ≤10% of cases, with the majority of diagnoses occurring postnatally during evaluations for neurodevelopmental, medical, or infertility concerns. The initiation of noninvasive prenatal testing (NIPT) in 2012 and adoption into standardized obstetric care provides a unique opportunity to significantly increase prenatal ascertainment of SCAs. However, the impact NIPT has had on ascertainment of SCAs is understudied, particularly for those who may defer diagnostic testing until after birth. This study evaluates the timing of diagnostic testing following positive NIPT in 152 infants with SCAs and potential factors influencing this decision. Eighty-seven (57%) elected to defer diagnostic testing after a positive NIPT until birth, and 8% (7/87) of those confirmed after birth were found to have discordant results on postnatal diagnostic testing, most of which would have influenced genetic counseling.

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“…For these and other reasons, NIPS remains classified as a screening, nondiagnostic test with standard recommendations that any positive NIPS result be followed by confirmatory diagnostic testing (Devers et al, 2013;Hartwig et al, 2017). However, five of our nine discord- severe phenotype (Ronzoni et al, 2021). Our study findings reinforce the importance of counseling regarding possible other SCAs as there are significant phenotypic differences associated with higher risks of medical complexity and neurodevelopmental involvement when comparing sex chromosome trisomies vs. tetrasomies, such as 48,XXYY (Raznahan et al, 2018;Skuse et al, 2018;Tartaglia et al, 2011Tartaglia et al, , 2012.…”

Section: Practice Implicationsmentioning

confidence: 99%

Noninvasive prenatal screening (NIPS) results for participants of the eXtraordinarY babies study: Screening, counseling, diagnosis, and discordance

Howell

Davis

Thompson

et al. 2022

Journal of Genetic Counseling

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Sex chromosome aneuploidies (SCAs), including Klinefelter syndrome/47,XXY, Trisomy X/47,XXX, 47,XYY syndrome, and 48,XXYY syndrome, are the most prevalent supernumerary chromosomal conditions, occurring collectively in approximately one of 500 live births. Clinical phenotypes are highly variable in these conditions, often with mild dysmorphic features or neurodevelopmental involvement, resulting in only 10%-25% lifetime ascertainment (Abramsky & Chapple, 1997). Historically, prenatal SCA diagnoses accounted for 10% or less of SCA cases and were often incidental findings following CVS or amniocentesis for advanced maternal age, and the majority of SCA diagnoses occurred in the postnatal period during clinical evaluations for neurodevelopmental, medical, or infertility concerns (Bojesen et al., 2003). The initiation of cell-free fetal DNA screening, commonly referred to as noninvasive prenatal screening (NIPS), in 2012 and subsequent adoption into standardized obstetric care, has drastically changed the landscape

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Increased RISK for 47,XXY on cell‐free DNA screen: Not always Klinefelter syndrome

Cited by 7 publications

References 9 publications

Cell-Based NIPT Detects 47,XXY Genotype in a Twin Pregnancy

Cell-Based NIPT Detects 47,XXY Genotype in a Twin Pregnancy

Non-Invasive Prenatal Testing (NIPT) Results for Participants of the eXtraordinarY Babies Study: Screening, Counseling, Diagnosis, and Discordance

Noninvasive prenatal screening (NIPS) results for participants of the eXtraordinarY babies study: Screening, counseling, diagnosis, and discordance

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