a. Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China;
b. State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China;
c. Beijing Key Laboratory of Big Data Innovation and Application for Skeletal Health Medical Care, Beijing 100730, China;
d. Key Laboratory of Big Data for Spinal Deformities, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China;
e. Department of Obstetrics, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China;
f. Stem Cell Facility, Institute of Clinical Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China;
g. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA;
h. Department of Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Science, Beijing 100730, China
Funds:
This study was funded in part by the National Key Research and Development Program of China (2022YFC2703100 to S.Z., 2024YFC2707100 for Q.Q., 2023YFC2507700 to J.Z. and N.W., 2022YFC2703102 to N.W., 2022YFC2703901 to Z.W.)
National High Level Hospital Clinical Research Funding (2022-PUMCH-D-004 to J.Z. and N.W., 2022-PUMCH-C-033 to N.W., 2022-PUMCH-D-002 to Z.W.)
Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (2019PT320025 to N.W.).
CAMS Innovation Fund for Medical Sciences (CIFMS, 2021-I2M-1-051 to J.Z. and N.W., 2021-I2M-1-052 and 2022-I2M-2-001 to Z.W., 2023-I2M-C&T-A-003 to J.Z.)
National Natural Science Foundation of China (82172525 to G.Q., 82172382 to J.Z., 82372366 to S.W., 82172517 to Y.W.)
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 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.
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