Abstract
Spondylocostal dysostosis (SCDO) encompasses a group of skeletal disorders characterized by multiple segmentation defects in the vertebrae and ribs. SCDO has a complex genetic etiology. This study aimed to analyze and identify pathogenic variants in a fetus with SCDO. Copy number variant sequencing and whole exome sequencing were performed on a Chinese fetus with SCDO, followed by bioinformatics analyses, in vitro functional assays and a systematic review on the reported SCDO cases with LFNG pathogenic variants. Ultrasound examinations in utero exhibited that the fetus had vertebral malformation, scoliosis and tethered cord, but rib malformation was not evident. We found a novel homozygous variant (c.1078 C > T, p.R360C) within the last exon of LFNG. The variant was predicted to cause loss of function of LFNG by in silico prediction tools, which was confirmed by an in vitro assay of LFNG enzyme activity. The systematic review listed a total of 20 variants of LFNG in SCDO. The mutational spectrum spans across all exons of LFNG except the last one. This study reported the first Chinese case of LFNG-related SCDO, revealing the prenatal phenotypes and expanding the mutational spectrum of the disorder.
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Acknowledgements
We thank the patients and their families for their help to the study.
Funding
This study was supported by Key Research & Develop program of Shaanxi Province (Grant nos. 2023-YBSF-305), Interior Program in Northwest Women’s and Children’s Hospital (2022YN24), Supporting Program of Innovation Capability Shaanxi Province (2024CX-GXPT-40, L.G.), Young Talent Support Plan from Xi’an Jiaotong University (YX6J033, L.G.), Provincial Talent Research Support Fund (71240000000131, L.G.), a Grant-in-Aid for Scientific Research (C) 23K06142 (to S.M.) from the Japan Society for the Promotion of Science, Pathogenesis of Intractable Diseases from the Research Institute of Meijo University (S.M. and S.Y.), Health Research Foundation of ShaanXi Province (Grant No. 2022D058), National Natural Science Foundation of China (Grant No. 82201865), and Basic scientific research funds of Xi’an Jiaotong University (Grant No. xzy012021074).
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Long Guo and Rong Qiang designed the study. Lin Wang, Shuji Mizumoto, Shuhei Yamada, Ruixue Zhang, Xin Li, Wenjing Cheng, Jiaqi Han, Lianying Jiao, Yating Wang, Qiujie Jin, Lihui Yang carried out the research. Long Guo, Lin wang, Shuji Mizumoto, Shuhei Yamada, Ruixue Zhang, Min Dan, Chunyan Zhang, Xinru Gao, Juan Wang, Chenxing Li, Jinhui Zhu, Shuxian Li, Hai Jiang, Gen Nishimura, Takahiro Yamada, Na Cai analyzed and interpreted data. Lin Wang drafted the manuscript. Long Guo, Rong Qiang revised it. All authors read and approved the final manuscript.
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The research project was approved by Ethics Committee of Northwest Women’s and Children’s Hospital (No. 21-036).
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Wang, L., Mizumoto, S., Zhang, R. et al. Identification of a novel LFNG variant in a Chinese fetus with spondylocostal dysostosis and a systematic review. J Hum Genet (2024). https://doi.org/10.1038/s10038-024-01248-3
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DOI: https://doi.org/10.1038/s10038-024-01248-3
