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Atypical Sex Chromosome Findings on Prenatal Cell-free DNA Screenings

Prenatal Genetics
  • Primary Categories:
    • Prenatal Genetics
  • Secondary Categories:
    • Prenatal Genetics
Introduction:
Since its introduction, prenatal screening by cell-free DNA (cfDNA) has expanded rapidly, and most laboratories now offer sex determination in addition to autosomal aneuploidy testing. About 0.66% of these screenings return a result of a sex chromosome aneuploidy (SCA). Genetic counseling regarding these results is complex – SCAs show wide variability in clinical presentation and positive predictive values are relatively low (29-74%, depending on the specific SCA). In addition to a High Risk SCA result, some screenings return no result for sex chromosomes with additional qualifying statements explaining an atypical finding involving the sex chromosomes attributable to fetal SCA, maternal SCA, or placental/fetal mosaicism. The positive predictive value of "atypical" screening results is not known. This study attempts to identify whether "atypical" sex chromosome findings on prenatal screening by cfDNA perform differently in identifying fetuses affected by SCAs compared to the typical "high risk" results.

Methods:
Data was obtained from review of cytogenetic test results for samples referred to the University of Iowa Cytogenetics Laboratory for diagnostic testing following an abnormal prenatal cfDNA screening result involving sex chromosomes. Cytogenetic test modalities included karyotype, CMA, or FISH and came from maternal blood, amniotic fluid, and infant blood samples. Screening results were assigned "Positive" if they reported a "High Risk for" a particular SCA, or "Atypical" for any other finding involving the sex chromosomes. 

Cases were grouped based on follow-up testing:  

  • A = maternal AND fetal/infant cytogenetic studies performed 

  • B = maternal OR fetal cytogenetic studies performed and showing an SCA 

  • C = maternal OR fetal cytogenetic studies performed, negative for an SCA   


Chi-squared tests for independence between screening results and cytogenetic outcome were performed on the combined A, B, and C cases, as well as on just the A and B cases together. Fischer exact tests were performed on A cases alone due to small sample size.

Results:
Of 58 cases, there were 22 Group A cases, 25 Group B cases, and 11 Group C cases. Thirty-three cases had "Positive" screening results and 25 cases had "Atypical" results. After cytogenetic testing, SCAs were identified in 35 cases (40%), including 15 maternal SCAs, 19 fetal/infant SCAs, and 1 case identified an SCA on both maternal and fetal cytogenetics. 

The overall rate of abnormal cytogenetic findings in at least one member of a fetus/infant-mother pair was not significantly different between "Positive" and "Atypical" screening results. However, chi-squared tests reached statistical significance when cytogenetic outcome was separated by whether SCA was identified in the maternal versus fetal/infant sample. These results indicated that "Atypical" screening results were more likely to be associated with maternal SCAs and "Positive" results were more likely to be associated with fetal/infant SCAs (A+B+C χ2=0.008, df=2; A+B χ2=0.007, df=2). 

Conclusion:
"Positive" and "Atypical" prenatal cfDNA screening results are equally likely to represent an SCA in either the mother or fetus. "Positive" screening may be more likely to represent fetal SCAs, while "Atypical" screenings may be more likely to represent maternal SCAs. Approximately half the Group A cases were negative for both maternal and fetal/infant SCAs. The validity of these conclusions is limited by this study’s small sample size and by the retrospective approach. Because we did not have both maternal and fetal/infant cytogenetic results in every case, cases in which diagnostic workup was not continued after diagnosis of maternal SCA may be subject to premature closure and fail to identify a co-occurring fetal SCA, and vice-versa. Further study is needed to establish positive predictive value of "Atypical" prenatal cfDNA screenings for fetal/infant SCAs and their impact on incidental diagnosis of maternal SCAs.

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