Genomic Landscape and Perinatal Outcomes of Fetal Polydactyly: A Retrospective Cohort Study Integrating CNV‐seq and Trio‐ES

OBJECTIVE: To evaluate the clinical characteristics, genomic landscape, and perinatal outcomes of fetal polydactyly using combined copy number variation sequencing (CNV-seq) and trio-exome sequencing (trio-ES). METHODS: This retrospective cohort study included 44 prenatally confirmed fetuses with polydactyly. Cases were stratified into isolated (n = 21) and non-isolated (n = 23) groups. Polydactyly was further subclassified according to anatomical distribution, laterality, and duplication axis. Genetic etiology was investigated using CNV-seq and trio-ES, and pregnancy outcomes were ascertained through clinical follow-up. RESULTS: The overall genetic diagnostic yield was 36.4% (16/44), comprising aneuploidies (n = 6), one pathogenic CNV and monogenic disorders (n = 9). Causative variants were identified in NEK1, EVC2, BBS4, GLI3, TBX3, MYCN, and KIAA0825, with one incidental finding in PIK3CD. The diagnostic yield was significantly higher in the non-isolated group than in the isolated group (60.9% vs. 9.5%, p < 0.001). Specific anatomical features were associated with markedly increased genetic burden, including concurrent involvement of both upper and lower limbs (100%), bilateral presentation (64.7% vs. 18.5% for unilateral; p < 0.01), and postaxial polydactyly (PAP) compared with preaxial polydactyly (PPD) (65.0% vs. 12.5%; p < 0.001). Pregnancy outcomes differed substantially between phenotypic subgroups, with a live birth rate of 100% in isolated cases versus 34.8% in non-isolated cases (p < 0.001). CONCLUSION: Fetal polydactyly exhibits profound genetic and phenotypic heterogeneity. Although non-isolated, multi-limb, bilateral, and postaxial presentations are strong predictors of underlying chromosomal or monogenic disorders, apparently isolated cases still carry a clinically relevant genetic risk. The integration of detailed prenatal sonographic phenotyping with CNV-seq and trio-ES improves diagnostic precision, facilitates prognostic assessment, and informs prenatal counseling and long-term postnatal surveillance.