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

Abstract

Objectives: To describe a cohort of fetuses with abnormal prenatal findings in whom exome sequencing (ES) identified genetic diagnoses that refined prognostic assessment and reduced prognostic uncertainty.

Methods: We retrospectively reviewed all fetal ES studies performed at our center between 2017 and 2025 for structural or biochemical abnormalities. Cases with a definitive molecular diagnosis were identified, and those with predicted mild, isolated, transient, or treatable phenotypes were classified as having comparatively favorable prognostic implications. Clinical findings and expected postnatal outcomes were analyzed.

Results: Among 1692 fetuses undergoing ES, a molecular diagnosis was identified in 291 (17%). Of these, five cases (∼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 all cases, ES refined prognosis and reduced the likelihood of severe syndromic conditions, enabling clearer counseling.

Conclusions: Beyond detecting severe disorders, ES may help distinguish mild or manageable conditions from complex syndromes. In selected cases, it provides meaningful reassurance, reduces uncertainty, and supports informed prenatal decision-making.