Turner syndrome: New insights from prenatal genomics and transcriptomics

Area of Science:

• Genetics
• Prenatal Diagnostics
• Reproductive Medicine

Background:

• Cell-free DNA (cfDNA) analysis is used in routine prenatal care for conditions like trisomy 21.
• Limited guidelines exist for Turner syndrome screening using cfDNA, with low positive predictive values (PPVs) for monosomy X (~26%).
• Maternal plasma contains both maternal and placental cfDNA, complicating fetal genetic analysis.

Purpose of the Study:

• To evaluate the accuracy and implications of cfDNA screening for monosomy X (Turner syndrome).
• To discuss biological reasons for false positive cfDNA screening results in Turner syndrome.
• To highlight the need for diagnostic follow-up and explore early pathophysiology of Turner syndrome.

Main Methods:

• Analysis of existing literature and clinical data on cfDNA screening for monosomy X.
• Review of biological mechanisms contributing to false positive results.
• Examination of cell-free mRNA research in amniotic fluid for insights into early Turner syndrome pathophysiology.

Main Results:

• cfDNA screening for trisomy 21 has high PPVs, but for monosomy X, PPVs are significantly lower.
• False positives for monosomy X are attributed to confined placental mosaicism, co-twin demise, maternal mosaicism, and aging-related X chromosome loss.
• Cell-free mRNA studies indicate early fetal gene dysregulation in Turner syndrome, suggesting prenatal onset.

Conclusions:

• A positive cfDNA screen for 45,X does not confirm fetal Turner syndrome; diagnostic testing is essential.
• Understanding maternal mosaicism and placental factors is key to interpreting cfDNA results.
• Early fetal pathophysiology of Turner syndrome opens avenues for potential antenatal interventions.