Advanced Course in Genetic Prenatal Diagnosis 2025 [ENG]

Over the past decade, there has been a true “revolution” in genetic analysis techniques in Prenatal Diagnosis. On one hand, fetal DNA in maternal circulation, which had already gained traction in private healthcare, has now been incorporated into public health programs — in high-risk cases where the pregnant person wishes to avoid an invasive procedure and in intermediate-risk cases. In the field of prenatal diagnosis, chromosomal microarrays, initially introduced for specific indications, have now replaced karyotyping in most cases. Lastly, exon sequencing is being implemented in clinical practice to uncover the etiology of monogenic diseases and is now available as gene panels, clinical exome, or whole exome sequencing.

Cell-free DNA has emerged as the best screening method due to its high detection rate and low false-positive rate. However, the expansion of detectable anomalies through cell-free DNA to sex chromosomes, all chromosomes, microdeletions, or even selected monogenic anomalies remains controversial. Fetal ultrasound, which is gradually but steadily improving in precision and resolution, offers the possibility of a genetic sonogram, which still has some specific indications. Since prenatal screening and diagnostic methods have diversified, couples must understand the pros and cons of each method so they can choose the screening or diagnostic option that best suits their needs. Likewise, obstetricians and midwives must deepen their understanding of the advantages and limitations of each method in order to provide couples with appropriate, understandable, and non-directive information.

The number of invasive diagnostic procedures has decreased in recent years, though they remain essential for conducting genetic diagnoses. QF-PCR is becoming the go-to test for rapid diagnosis of common aneuploidies, and chromosomal microarray — which analyzes the entire genome at higher resolution than conventional karyotyping — is now used for diagnosing chromosomal and submicroscopic anomalies. Finally, gene panels and clinical exomes are being introduced for selected groups of fetal malformations following a normal microarray result.

Prenatal diagnosis of monogenic diseases has received less attention, despite being as common as chromosomal anomalies. In some countries, carrier screening for cystic fibrosis and other common recessive diseases among prospective parents is already being performed — whereas in our region, it is still reserved for gamete donors in assisted reproduction. While karyotyping already presented some results that were difficult to interpret, such as mosaicisms, placental-confined anomalies, and sex chromosome aneuploidies — and microarrays can reveal variants of uncertain significance, pathogenic variants with incomplete penetrance or susceptibility, and incidental findings — monogenic diseases are currently the area of prenatal genetics with the most uncertainty. Thus, if genetic counseling in the case of a sex chromosome aneuploidy with a normal ultrasound was already complex, the current abundance of monogenic syndromes with incomplete penetrance and variable expressivity makes genetic counseling even more challenging — both pre-test, to explain the limitations of the tests, and post-test, to interpret the results. These are areas of knowledge that many obstetric professionals currently lack.