When Fetal Anomalies Lead to Prognostic Clarification: An Underrecognized Application of Exome Sequencing.

Prenatal exome diagnosis reassigning an ultrasound or biochemical anomaly to a mild, isolated or transient entity rather than a severe syndrome, as with the GLI1, STS, CFAP52 and MAGED2 variants reported here.

This single-centre retrospective study reviewed all fetal exome studies performed between 2017 and 2025 for structural or biochemical anomalies, in order to identify diagnoses that refined prognosis. Among 1692 fetuses, a molecular diagnosis was reached in 291 (17%). Of these, five cases (about 2%) were considered reassuring: isolated postaxial polydactyly due to a GLI1 variant, X-linked ichthyosis (STS) in a fetus with low estriol, isolated situs inversus, CFAP52-related situs inversus totalis, and MAGED2-associated transient antenatal Bartter syndrome. In each case exome sequencing refined the prognosis and reduced the likelihood of a severe syndromic condition, enabling clearer counselling. The authors conclude that fetal exome sequencing not only detects severe disorders but also distinguishes mild or manageable conditions from complex syndromes.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The message is useful because it is counterintuitive: in the prenatal setting exome sequencing is almost always framed as a tool that worsens prognosis, whereas it can also resolve uncertainty in a favourable direction and change a decision about continuing the pregnancy. The proportions must nonetheless be kept in mind before transposing this to clinic: five cases out of 1692 fetuses, roughly 2% of the diagnoses made, with retrospective selection of the cases the authors themselves judged reassuring. Prenatal exome should therefore never be offered as a reassurance test; pre-test counselling must still state that the most likely outcome is no diagnosis.

Analysis by Dr Thibaut Benquey