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Longitudinal clinical impact of dynamic variant re-classification on reproductive decision-making: a 3-year case study
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DOI：10.1007/s10815-026-03997-w.png)
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Abstract
En 中文
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.
Keywords:
SEC24D
Variant re-classification
Diagnostic uncertainty
PGT-M
Prenatal diagnosis
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