Longitudinal clinical impact of dynamic variant re-classification on reproductive decision-making: a 3-year case...

The clinical application of sequencing guidelines often yields variants of uncertain significance (VUS), creating profound challenges in prenatal genetic counseling. This study demonstrates the clinical utility and real-world impact of dynamic, longitudinal variant re-classification on reproductive decision-making in a family affected by an atypical SEC24D-associated skeletal phenotype.

Over a 3-year period (2023-2026), a multidisciplinary diagnostic workflow was employed, integrating trio whole-exome sequencing, protein structural modeling, prenatal ultrasound, fetal magnetic resonance imaging, post-mortem histopathology, and preimplantation genetic testing for monogenic disorders (PGT-M). Variant pathogenicity was sequentially curated according to the American College of Medical Genetics and Genomics (ACMG) framework.

A homozygous SEC24D variant (c.1942G > C, p.Gly648Arg) was identified in a proband presenting with isolated craniofacial ossification defects without classic long-bone fractures. Over 3 years, the variant was dynamically re-classified from VUS to likely pathogenic (LP), back to VUS, and to LP again, driven by institutional peer-review debates regarding the conservative application of computational structural criteria versus clinical intuition. This diagnostic instability directly dictated a cascade of critical reproductive events: the termination of a second pregnancy demonstrating recurrent fetal cranial defects confirmed by amniocentesis and post-mortem examination, followed by the deployment of PGT-M within a diagnostic "gray zone." Ultimately, the successful delivery of a healthy, non-carrier infant in June 2026 provided crucial family co-segregation data, successfully resolving the classification loop and securing a definitive likely pathogenic status.

Diagnostic uncertainty in prenatal genomics is a persistent clinical reality rather than a transient evidence gap. Longitudinal variant reinterpretation combined with transparent shared decision-making is vital to safely navigate borderline classifications and optimize reproductive trajectories.