Deep insights and clinical benefits from the comprehensive cohort of fetal skeletal dysplasia in China

Fetal skeletal dysplasia (FSD) encompasses diverse clinical features and complicates prenatal diagnosis and perinatal care. In this retrospective study, we integrate prenatal deep phenotyping with exome or genome sequencing (ES/GS) to elucidate comprehensive genotype and phenotype landscapes, diagnostic outcomes, genotype-phenotype correlations, and postnatal follow-up findings and to refine genetic counseling and clinical decision-making. The study includes a cohort of 152 fetuses with FSD in China. All fetuses undergo prenatal deep phenotyping followed by ES/GS analysis. Prenatal deep phenotyping enables classification into isolated and non-isolated FSD groups and identifies previously unrecognized prenatal features associated with KBG syndrome and Segawa syndrome. Among skeletal anomalies, limb bone anomalies are the most common (72.4%). Genetic testing yields positive diagnoses in 88 fetuses (57.9%). Notably, fetuses with cranial and limb bone abnormalities demonstrate a higher diagnostic yield. Comparative analysis of prenatal and postnatal genotypes and phenotypes in individuals harboring pathogenic variants in four hotspot genes provides a deeper understanding of skeletal dysplasia phenotypes. Genetic findings from this cohort directly inform reproductive decisions in 16 subsequent pregnancies. Our findings significantly enhance genotype-phenotype correlations and contribute to improved prenatal counseling, informed clinical decision-making, and optimized perinatal care, and advance precision medicine strategies for FSD-affected families.