Molecular Therapy: Nucleic Acids (Jun 2021)
Deciphering the mutational signature of congenital limb malformations
- Liying Sun,
- Yingzhao Huang,
- Sen Zhao,
- Junhui Zhao,
- Zihui Yan,
- Yang Guo,
- Mao Lin,
- Wenyao Zhong,
- Yuehan Yin,
- Zefu Chen,
- Nan Zhang,
- Yuanqiang Zhang,
- Zongxuan Zhao,
- Qingyang Li,
- Lianlei Wang,
- Xiying Dong,
- Yaqi Li,
- Xiaoxin Li,
- Guixing Qiu,
- Terry Jianguo Zhang,
- Zhihong Wu,
- Wen Tian,
- Nan Wu
Affiliations
- Liying Sun
- Department of Hand Surgery, Beijing Jishuitan Hospital, Beijing 100035, China
- Yingzhao Huang
- Department of Orthopedic Surgery, 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; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing 100730, China; Key Laboratory of Big Data for Spinal Deformities, Chinese Academy of Medical Sciences, Beijing 100730, China
- Sen Zhao
- Department of Orthopedic Surgery, 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; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing 100730, China; Key Laboratory of Big Data for Spinal Deformities, Chinese Academy of Medical Sciences, Beijing 100730, China
- Junhui Zhao
- Department of Hand Surgery, Beijing Jishuitan Hospital, Beijing 100035, China
- Zihui Yan
- Department of Orthopedic Surgery, 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; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing 100730, China; Key Laboratory of Big Data for Spinal Deformities, Chinese Academy of Medical Sciences, Beijing 100730, China
- Yang Guo
- Department of Hand Surgery, Beijing Jishuitan Hospital, Beijing 100035, China
- Mao Lin
- Department of Orthopedic Surgery, 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; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing 100730, China; Key Laboratory of Big Data for Spinal Deformities, Chinese Academy of Medical Sciences, Beijing 100730, China
- Wenyao Zhong
- Department of Hand Surgery, Beijing Jishuitan Hospital, Beijing 100035, China
- Yuehan Yin
- Department of Hand Surgery, Beijing Jishuitan Hospital, Beijing 100035, China
- Zefu Chen
- Department of Orthopedic Surgery, 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; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing 100730, China; Key Laboratory of Big Data for Spinal Deformities, Chinese Academy of Medical Sciences, Beijing 100730, China
- Nan Zhang
- Department of Hand Surgery, Beijing Jishuitan Hospital, Beijing 100035, China
- Yuanqiang Zhang
- Department of Orthopedic Surgery, 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; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing 100730, China; Key Laboratory of Big Data for Spinal Deformities, Chinese Academy of Medical Sciences, Beijing 100730, China
- Zongxuan Zhao
- Department of Hand Surgery, Beijing Jishuitan Hospital, Beijing 100035, China
- Qingyang Li
- Department of Hand Surgery, Beijing Jishuitan Hospital, Beijing 100035, China
- Lianlei Wang
- Department of Orthopedic Surgery, 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; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing 100730, China; Key Laboratory of Big Data for Spinal Deformities, Chinese Academy of Medical Sciences, Beijing 100730, China
- Xiying Dong
- Department of Orthopedic Surgery, 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; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing 100730, China; Key Laboratory of Big Data for Spinal Deformities, Chinese Academy of Medical Sciences, Beijing 100730, China
- Yaqi Li
- Department of Orthopedic Surgery, 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; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing 100730, China; Key Laboratory of Big Data for Spinal Deformities, Chinese Academy of Medical Sciences, Beijing 100730, China
- Xiaoxin Li
- Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing 100730, China; Medical Research Center, 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
- Guixing Qiu
- Department of Orthopedic Surgery, 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; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing 100730, China; Key Laboratory of Big Data for Spinal Deformities, Chinese Academy of Medical Sciences, Beijing 100730, China
- Terry Jianguo Zhang
- Department of Orthopedic Surgery, 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; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing 100730, China; Key Laboratory of Big Data for Spinal Deformities, Chinese Academy of Medical Sciences, Beijing 100730, China
- Zhihong Wu
- Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing 100730, China; Key Laboratory of Big Data for Spinal Deformities, Chinese Academy of Medical Sciences, Beijing 100730, China; Medical Research Center, 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; Corresponding author: Zhihong Wu, Medical Research Center, 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.
- Wen Tian
- Department of Hand Surgery, Beijing Jishuitan Hospital, Beijing 100035, China; Corresponding author: Wen Tian, Department of Hand Surgery, Beijing Jishuitan Hospital, Beijing 100035, China.
- Nan Wu
- Department of Orthopedic Surgery, 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; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing 100730, China; Key Laboratory of Big Data for Spinal Deformities, Chinese Academy of Medical Sciences, Beijing 100730, China; Corresponding author: Nan Wu, Department of Orthopedic Surgery, 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.
- Journal volume & issue
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Vol. 24
pp. 961 – 970
Abstract
Congenital limb malformations (CLMs) affect 1 in 500 live births. However, the value of exome sequencing (ES) for CLM is lacking. The purpose of this study was to decipher the mutational signature of CLM on an exome level. We enrolled a cohort of 66 unrelated probands (including 47 families) with CLM requiring surgical correction. ES was performed for all patients and available parental samples. A definite molecular diagnosis was achieved in 21 out of 66 (32%) patients. We identified 19 pathogenic or likely pathogenic single-nucleotide variants and three copy number variants, of which 11 variants were novel. We identified four variants of uncertain significance. Additionally, we identified RPL9 and UBA2 as novel candidate genes for CLM. By comparing the detailed phenotypic features, we expand the phenotypic spectrum of diastrophic dysplasia and chromosome 6q terminal deletion syndrome. We also found that the diagnostic rate was significantly higher in patients with a family history of CLM (p = 0.012) or more than one limb affected (p = 0.034). Our study expands our understanding of the mutational and phenotypic spectrum of CLM and provides novel insights into the genetic basis of these syndromes.
