Prior to the clinical and commercial introduction of noninvasive prenatal testing (NIPT) by sequencing of maternal plasma cell-free DNA in 2011, most fetuses with Turner syndrome were detected by sonographic findings related to lymphedema or incidentally. NIPT, however, has transformed prenatal genetic screening, and an estimated 46 million tests have been performed worldwide. In the maternal plasma sample there is both maternal and placental cell-free DNA. Following a screen positive NIPT result, it is universally recommended to confirm the screening test by a diagnostic procedure such as amniocentesis or CVS. While NIPT performance is excellent for trisomy 21 (positive predictive value [PPV] ~91%), it is less so for 45, X (PPV ~25%). The reasons for the relatively high number of false positive results include high rates of confined placental mosaicism, demise of a co-twin, and maternal incidental findings. The mother can have constitutional mosaicism for 45, X, or somatic mosaicism resulting from physiologic X-chromosome loss due to ageing. At present there is a significant knowledge gap as to how to clinically manage pregnant women ascertained through NIPT to have 45, X mosaicism. Transcriptomic analyses of cell-free RNA from living mid-trimester fetuses with 45, X demonstrate a consistent and unique pattern of gene expression. As expected, XIST is significantly down-regulated. Dysregulated genes of interest include NFATC3, LDLR, and IGFBP5. These genes are involved in perivascular tissue remodeling, hyperlipidemia, and growth and fertility, respectively. Using a dysregulated pathway approach, novel treatments could be developed that could be given antenatally to a pregnant woman carrying a fetus known to have 45, X. Prenatal screening for Turner syndrome creates ethical challenges for the fetus and mother, yet it also provides novel opportunities for treatments to prevent infertility and cardiovascular disease.
27 - 29 Sep 2018
European Society for Paediatric Endocrinology