Frontiers in Endocrinology (Sep 2021)
Whole Exome Sequencing Uncovered the Genetic Architecture of Growth Hormone Deficiency Patients
- Chenxi Yu,
- Chenxi Yu,
- Chenxi Yu,
- Bobo Xie,
- Bobo Xie,
- Bobo Xie,
- Zhengye Zhao,
- Zhengye Zhao,
- Sen Zhao,
- Sen Zhao,
- Lian Liu,
- Lian Liu,
- Xi Cheng,
- Xi Cheng,
- Xiaoxin Li,
- Xiaoxin Li,
- Bingyan Cao,
- Jiashen Shao,
- Jiashen Shao,
- Jiajia Chen,
- Hengqiang Zhao,
- Hengqiang Zhao,
- Zihui Yan,
- Zihui Yan,
- Chang Su,
- Yuchen Niu,
- Yuchen Niu,
- Yanning Song,
- Liya Wei,
- Yi Wang,
- Xiaoya Ren,
- Lijun Fan,
- Beibei Zhang,
- Chuan Li,
- Chuan Li,
- Chuan Li,
- Baoheng Gui,
- Baoheng Gui,
- Baoheng Gui,
- Yuanqiang Zhang,
- Lianlei Wang,
- Shaoke Chen,
- Shaoke Chen,
- Shaoke Chen,
- Jianguo Zhang,
- Jianguo Zhang,
- Jianguo Zhang,
- Zhihong Wu,
- Zhihong Wu,
- Zhihong Wu,
- Zhihong Wu,
- Chunxiu Gong,
- Xin Fan,
- Xin Fan,
- Xin Fan,
- Nan Wu,
- Nan Wu,
- Nan Wu,
- Nan Wu
Affiliations
- Chenxi Yu
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Chenxi Yu
- Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China
- Chenxi Yu
- Department of Joint Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
- Bobo Xie
- Department of Pediatrics, The Second Affiliated Hospital of Guangxi Medical University, Guangxi, China
- Bobo Xie
- Center for Medical Genetics and Genomics, The Second Affiliated Hospital of Guangxi Medical University, Guangxi, China
- Bobo Xie
- Department of Pediatric Endocrine and Metabolism, Maternal and Child Health Hospital of Guangxi, Nanning, China
- Zhengye Zhao
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Zhengye Zhao
- Beijing Key Laboratory for Genetic Research of Skeletal Deformity, 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
- Sen Zhao
- Beijing Key Laboratory for Genetic Research of Skeletal Deformity, 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
- Lian Liu
- Beijing Key Laboratory for Genetic Research of Skeletal Deformity, 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
- Xi Cheng
- Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China
- Xiaoxin Li
- Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China
- Xiaoxin Li
- Medical Research Center, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, 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
- Jiashen Shao
- Beijing Key Laboratory for Genetic Research of Skeletal Deformity, 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
- Hengqiang Zhao
- Beijing Key Laboratory for Genetic Research of Skeletal Deformity, 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
- Zihui Yan
- Beijing Key Laboratory for Genetic Research of Skeletal Deformity, 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
- Yuchen Niu
- Medical Research Center, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, 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
- Chuan Li
- Center for Medical Genetics and Genomics, The Second Affiliated Hospital of Guangxi Medical University, Guangxi, China
- Chuan Li
- Department of Pediatric Endocrine and Metabolism, Maternal and Child Health Hospital of Guangxi, Nanning, China
- Baoheng Gui
- Department of Pediatrics, The Second Affiliated Hospital of Guangxi Medical University, Guangxi, China
- Baoheng Gui
- Center for Medical Genetics and Genomics, The Second Affiliated Hospital of Guangxi Medical University, Guangxi, China
- Baoheng Gui
- Department of Pediatric Endocrine and Metabolism, Maternal and Child Health Hospital of Guangxi, Nanning, 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
- Shaoke Chen
- Center for Medical Genetics and Genomics, The Second Affiliated Hospital of Guangxi Medical University, Guangxi, China
- Shaoke Chen
- Department of Pediatric Endocrine and Metabolism, Maternal and Child Health Hospital of Guangxi, Nanning, China
- Jianguo Zhang
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Jianguo Zhang
- Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China
- Jianguo Zhang
- 0Key Laboratory of Big Data for Spinal Deformities, Chinese Academy of Medical Sciences, Beijing, China
- Zhihong Wu
- Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China
- Zhihong Wu
- Medical Research Center, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Zhihong Wu
- 0Key Laboratory of Big Data for Spinal Deformities, Chinese Academy of Medical Sciences, Beijing, China
- Zhihong Wu
- 1State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, 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
- Xin Fan
- Center for Medical Genetics and Genomics, The Second Affiliated Hospital of Guangxi Medical University, Guangxi, China
- Xin Fan
- Department of Pediatric Endocrine and Metabolism, Maternal and Child Health Hospital of Guangxi, Nanning, China
- Nan Wu
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Nan Wu
- Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China
- Nan Wu
- 0Key Laboratory of Big Data for Spinal Deformities, Chinese Academy of Medical Sciences, Beijing, China
- Nan Wu
- 1State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
- DOI
- https://doi.org/10.3389/fendo.2021.711991
- Journal volume & issue
-
Vol. 12
Abstract
PurposeCongenital 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 via a candidate gene-based mutational burden analysis.MethodsWe 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.ResultsIn 19 patients with molecular diagnosis, we found 5 possible GHD patients received known molecular diagnosis associated with GHD (NF1 [c.2329T>A, c.7131C>G], GHRHR [c.731G>A], STAT5B [c.1102delC], HRAS [c.187_207dup]). By mutational burden analysis of predicted deleterious variants in 90 patients without molecular diagnosis, we found that POLR3A (p = 0.005), SUFU (p = 0.006), LHX3 (p = 0.021) and CREB3L4 (p = 0.040) represented top genes enriched in GHD patients.ConclusionOur 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.
Keywords
- growth hormone deficiency
- whole exome sequencing
- genetic architecture
- molecular diagnosis
- mutational burden analysis
