Whole Exome Sequencing Uncovered the Genetic Architecture of Growth Hormone Deficiency Patients.
Chenxi Yu, Bobo Xie, Zhengye Zhao, Sen Zhao, Lian Liu, Xi Cheng, Xiaoxin Li, Bingyan Cao, Jiashen Shao, Jiajia Chen, Hengqiang Zhao, Zihui Yan, Chang Su, Yuchen Niu, Yanning Song, Liya Wei, Yi Wang, Xiaoya Ren, Lijun Fan, Beibei Zhang, Chuan Li, Baoheng Gui, Yuanqiang Zhang, Lianlei Wang, Shaoke Chen, Jianguo Zhang, Zhihong Wu, Chunxiu Gong, Xin Fan, Nan Wu
Author Information
Chenxi Yu: Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
Bobo Xie: Department of Pediatrics, The Second Affiliated Hospital of Guangxi Medical University, Guangxi, China.
Zhengye Zhao: Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
Sen Zhao: Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
Lian Liu: Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
Xi Cheng: Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
Xiaoxin Li: Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China.
Bingyan Cao: Department of Endocrinology, Genetics and Metabolism, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University, Beijing, China.
Jiashen Shao: Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
Jiajia Chen: Department of Endocrinology, Genetics and Metabolism, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University, Beijing, China.
Hengqiang Zhao: Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
Zihui Yan: Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
Chang Su: Department of Endocrinology, Genetics and Metabolism, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University, Beijing, China.
Yuchen Niu: Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China.
Yanning Song: Department of Endocrinology, Genetics and Metabolism, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University, Beijing, China.
Liya Wei: Department of Endocrinology, Genetics and Metabolism, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University, Beijing, China.
Yi Wang: Department of Endocrinology, Genetics and Metabolism, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University, Beijing, China.
Xiaoya Ren: Department of Endocrinology, Genetics and Metabolism, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University, Beijing, China.
Lijun Fan: Department of Endocrinology, Genetics and Metabolism, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University, Beijing, China.
Beibei Zhang: Department of Endocrinology, Genetics and Metabolism, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University, Beijing, China.
Chuan Li: Department of Pediatrics, The Second Affiliated Hospital of Guangxi Medical University, Guangxi, China.
Baoheng Gui: Department of Pediatrics, The Second Affiliated Hospital of Guangxi Medical University, Guangxi, China.
Yuanqiang Zhang: Department of Orthopaedic Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
Lianlei Wang: Department of Orthopaedic Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
Shaoke Chen: Department of Pediatrics, The Second Affiliated Hospital of Guangxi Medical University, Guangxi, China.
Jianguo Zhang: Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
Zhihong Wu: Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China.
Chunxiu Gong: Department of Endocrinology, Genetics and Metabolism, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University, Beijing, China.
Xin Fan: Department of Pediatrics, The Second Affiliated Hospital of Guangxi Medical University, Guangxi, China.
Nan Wu: Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
Purpose: Congenital growth hormone deficiency (GHD) is a rare and etiologically heterogeneous disease. We aim to screen disease-causing mutations of GHD in a relatively sizable cohort and discover underlying mechanisms a candidate gene-based mutational burden analysis. Methods: We retrospectively analyzed 109 short stature patients associated with hormone deficiency. All patients were classified into two groups: Group I (n=45) with definitive GHD and Group II (n=64) with possible GHD. We analyzed correlation consistency between clinical criteria and molecular findings by whole exome sequencing (WES) in two groups. The patients without a molecular diagnosis (n=90) were compared with 942 in-house controls for the mutational burden of rare mutations in 259 genes biologically related with the GH axis. Results: In 19 patients with molecular diagnosis, we found 5 possible GHD patients received known molecular diagnosis associated with GHD ( [c.2329T>A, c.7131C>G], [c.731G>A], [c.1102delC], [c.187_207dup]). By mutational burden analysis of predicted deleterious variants in 90 patients without molecular diagnosis, we found that ( = 0.005), ( = 0.006), ( = 0.021) and ( = 0.040) represented top genes enriched in GHD patients. Conclusion: Our study revealed the discrepancies between the laboratory testing and molecular diagnosis of GHD. These differences should be considered when for an accurate diagnosis of GHD. We also identified four candidate genes that might be associated with GHD.
