Genomic Landscape and Perinatal Outcomes of Fetal Polydactyly: A Retrospective Cohort Study Integrating CNV‐seq and Trio‐ES
Hui Li, Xiaohong Yang, Lijun Liu, Yayun Qin, Yangyang Song, Yanyi YaoABSTRACT
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.