Biological reasons for the discordance of Monosomy X results from Non-Invasive Prenatal Testing (NIPT)

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Biological reasons for the discordance of Monosomy X results from Non-Invasive Prenatal Testing (NIPT)

While a considerable amount of data exists for clinical trials and laboratory performance for non-invasive prenatal testing (NIPT) of autosomal aneuploidies (chromosomal abnormalities), relatively little data is available on laboratory performance for sex chromosome aneuploidies.

Meta-analyses that have measured the performance of NIPT for SCAs, have made use of small sample sizes. Further to this, while professional obstetric and genetic societies have made recommendations regarding NIPT for autosomal aneuploidies, they have remained relatively silent on screening for SCAs.

 According to the WHO, sex chromosome abnormalities occur at a frequency of 1 in 400 pregnancies. The high frequency of individuals with sex chromosome abnormalities (SCAs) is due to the fact that their effects are generally not as severe as autosomal abnormalities and are rarely lethal.

Turner syndrome or Monosomy X (45,XO) is a common sex chromosome abnormality, occurring in approximately 1-1.5% of recognisable gestations. Despite the fact that Monosomy X has a relatively high prevalence in gestations, the live birth rate of the condition is approximately 1 in 3,000, as only 1 in 4 affected zygotes develops to term6.

NIPT results for sex chromosome aneuploidy can be confounded by maternal or foetal biological phenomena. These phenomena were explored in a recent study by Dr Diana Bianchi9. A clinical summary of laboratory experience for NIPT testing of SCAs was presented, along with biological reasons for discordant SCA results. In this study, Bianchi et al. reported on 80 discordant SCA results observed in 18,161 NIPTs, where discordance was defined as an NIPT result that was not concordant with either an ultrasonography or karyotype result. A total of 18 (0.2%) and 14 (0.15%) results were noted to be discordant for 46, XX and 46,XY (no aneuploidy detected) NIPT findings, respectively. Where SCAs were reported on NIPT findings, 48 (23%) were observed to be discordant, with 35 (17%) attributed to Monosomy X. Thus, the overall false positive rate in this cohort was 48 of 18,161 (0.26%). This study noted that all but one of the discordant SCA results involved the X chromosome, with the greatest discordance for Monosomy X.

Investigations into the biological reasons for false positive discordant results for Monosomy X revealed that discordance can be attributed to:

  • Maternal constitutional Monosomy X (full or mosaic):  In a study by Wang et al. it was observed that in NIPT results that suggested an SCA involving the X chromosome, 8.6% of the cases showed that this originated from the mother, following karyotype analysis of maternal peripheral blood.
  • Maternal somatic mosaic Monosomy X due to age related loss of the X chromosome: Studies have recently shown an association has been observed between maternal X chromosome loss and maternal ageing.
  • Confined Placental Mosaicism
  • Demise of co-twin with Monosomy X

As highlighted above, healthcare providers and patients will occasionally encounter instances in which NIPT results for foetal sex are discordant with ultrasound or karyotype results – which may be attributed to biological reasons. Bianchi et al.9 propose that in such cases, clinicians should consider undertaking non-invasive steps before performing an invasive procedure. These include:

  • Contacting the NIPT laboratory for review of the X and Y values obtained
  • Assessing the maternal history for a prior transplant
  • Querying the pregnancy history for the use of assisted reproductive technology and the possibility of a co-twin demise
  • Performing a detailed ultrasound examination of the foetal genitalia
  • A maternal karyotype might also be considered, in an attempt to establish possible maternal mosaicism.

If these are unrevealing, an invasive diagnostic procedure could be then considered to resolve the sex discordance. Bianchi et al. further note that as a result of several biological explanations for discordance between NIPT and prenatal testing results (karyotype and clinical findings), considerable pre-test and post-test counselling is critical.

Click here to access the full study by Bianchi et al. mentioned above.



  1. Bianchi et al. (2015) Obstetrics & Gynaecology 125(2):375-382
  2. Abramsky & Chapple (1997) Prenatal Diagnosis, 17:363–368
  3. Hook & Warburton (2014) Human Genetics 133:417-424
  4. Hook & Warburton (1983) Human Genetics 64:24-27
  5. Wang et al. (2014) Clinical Chemistry 60:251-259
  6. Russell et al. (2007) Cytogenetic and Genome Research 116:181-185
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