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Comparison of prenatal cell-free DNA screen positive for monosomy X with diagnostic maternal and fetal cytogenetic studies: a single-center study

Laboratory Genetics and Genomics
  • Primary Categories:
    • Prenatal Genetics
  • Secondary Categories:
    • Prenatal Genetics
Introduction:
Prenatal cell-free DNA screening has been clinically available since 2011 to screen for the common fetal aneuploidies, including trisomy 13, 18, 21, and sex chromosome abnormalities. It has become the preferred modality for aneuploidy screenning in pregnancy supported by recommendations from ACOG and ACMG. However, prenatal cell-free DNA testing is not equivalent to diagnostic testing. False positive and false negative results from prenatal cfDNA screening are caused by a variety of biologic mechanisms, including confined placental mosaicism, a vanishing twin, and maternal factors. The positive predictive values (PPV) of prenatal cfDNA screening are dependent upon the chromosome in question, analytical sensitivity and specificity, and a priori risk for aneuploidy. The PPV is highest for trisomy 21 at advanced maternal age (91-99%). The PPV of monosomy X (45,X) is lower at 25-40%, irrespective of age.

Methods:
We sought to assess the performance of prenatal cfDNA screening to detect monosomy X in an unselected obstetrical population of 15,674 individuals using a low-pass whole-genome sequencing platform and review of diagnostic cytogenetic testing. Diagnostic studies included G-banded chromosome analysis (karyotype), FISH using the AneuVysion Multicolor DNA Probe Kit (Vysis CEP 18/X/Y - alpha satellite / LSI 13/21), and/or chromosomal microarray (Illumina’s Infinium CytoSNP-850K BeadChip). Specimen sources for diagnostic studies included cells derived from amniotic fluid, products on conception, infant umbilical cord blood, and maternal peripheral blood.

Results:
Of 15,674 individuals screened, 54 had a cfDNA screen positive result for monosomy X. Eight were lost to follow-up and 3 have diagnostic studies pending. Of the remaining 43 individuals, 18 (42%) had conceptions with true fetal monosomy X. Among the 18 true fetal positives, there were 9 in utero deaths, 6 terminations of pregnancy, and 3 live-born infants. Two of the 3 live-born infants had cytogenetic variants of Turner syndrome. In one of these 18 true positives, an adult woman was diagnosed with mosaic monosomy X (45% of cells showed loss of X in peripheral blood) after her third pregnancy resulted in a fetus with monosomy X. Five (12%) women had loss of X identified by peripheral blood karyotype or interphase FISH studies and normal fetal cytogenetic studies. One of these five women most likely has age-related loss of the X chromosome (4% mosaicism), but three likely have constitutional mosaic monosomy X (45,X in 20-30% of blood cells). Another woman had loss of X within the expected range of age-related loss (6%) but an obstetric history that confounds the clinical interpretation of her karyotype results. Five of the six women with mosaic monosomy X were carefully examined in Genetics Clinic and none had obvious features of mosaic Turner syndrome. Twenty individuals (46%) had false positive cfDNA screen results based on normal fetal diagnostic studies (amniocentesis or postnatal cord blood testing).  Nine of these 20 also had normal maternal peripheral blood karyotype results. One individual is unresolved; two independent pregnancies (2 years apart) have screened positive for monosomy X despite having normal fetal and maternal cytogenetic analyses.

Conclusion:
The PPV of fetal monosomy X remains low, 42% in our experience, compared to fetal autosomal aneuploidies. Maternal mosaic X chromosome loss accounts for 12% of discordant prenatal cfDNA screen positives in our cohort. Our understanding of mosaic monosomy X and its implications for fertility and medical management is evolving. This study contributes to the increasing number of reports about adult women who are unexpectedly found to have mosaic monosomy X through referral for abnormal prenatal cfDNA screening of a spontaneous pregnancy, and highlights some of the challenges in reporting, interpretation, and clinical care.

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