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Diagnostic yield and clinical effects of exome sequencing analysis in patients with early-onset scoliosis
Poster Abstracts
Diagnostic yield and clinical effects of exome sequencing analysis in patients with early-onset scoliosis Sen Zhao, Yuanqiang Zhang, Weisheng Chen, Shengru Wang, Pengfei Liu, Shuyang Zhang, Carol A Wise, James R Lupski, for Deciphering disorders Involving Scoliosis and COmorbidities (DISCO) study, Zhihong Wu, Guixing Qiu, Jianguo Zhang, Nan Wu for Deciphering disorders Involving Scoliosis and COmorbidities (DISCO) study
Abstract
Background Scoliosis is clinically defined as a spine deformity with lateral curvature greater than 10° and the cause of the disease is elusive. Early onset scoliosis, defined by an onset age before 10 years, conveys a substantial health risk to affected children. Although exome sequencing has emerged as a first-line diagnostic method for rare diseases, genetic testing is not routinely done for children with early onset scoliosis. We aimed to explore the diagnostic yield of exome sequencing in patients with early onset scoliosis. Methods We recruited a Chinese cohort of patients who were clinically diagnosed with early onset scoliosis through the Deciphering disorders Involving Scoliosis and COmorbidities (DISCO). We did exome sequencing on these individuals and available family members. Exome sequencing data were interpreted according to the American College of Medical Genetics and Genomics guidelines. Patients were followed up for a minimum of 2 years. We also recruited an American cohort of 13 patients with clinically diagnosed idiopathic early onset scoliosis, who underwent exome sequencing. Findings We recruited 447 patients in the Chinese cohort and 323 (72%) of 447 patients with early onset scoliosis were followed up for a minimum of 2 years. In the Chinese cohort, we detected diagnostic variants in 92 (21%) of 447 patients with early onset scoliosis, encompassing 33 disease-causing genes and five genomic regions. The age at presentation, the number of organ systems involved, and the Cobb angle were the three features that were most predictive of a molecular diagnosis. Notably, 14 (41%) of 34 patients with non-TBX6-associated congenital scoliosis (TACS) molecular diagnoses had a higher post-surgery complication rate than did the 24 (9·2%) of 260 patients who were molecularly undiagnosed (p=0·000008). In the American cohort, one (8%) of 13 patients had a molecular diagnosis of Sotos syndrome, making the total number of patients in whom we found diagnostic variants 93 (20·2%) of 460. Interpretation Exome sequencing could identify the genetic cause in patients with early onset scoliosis. Specific clinical features and feature pairs provided indications for genetic testing in these patients. The prevention of postsurgery complications could potentially be implemented for patients with a non-TACS molecular diagnosis. Funding National Natural Science Foundation of China, Beijing Natural Science Foundation, 2016 Milstein Medical Asian American Partnership Foundation Fellowship Award in Translational Medicine, CAMS Initiative Fund for Medical Sciences, the Central Level Public Interest Program for Scientific Research Institute, the National Key Research and Development Program of China, the National Undergraduates Innovation and Training Program of Peking Union Medical College, US National Institutes of Health, National Institute of Neurological Disorders and Stroke, National Human Genome Research Institute and National Heart, Lung, and Blood Institute, the National Human Genome Research Institute, TX Scottish Rite Hospital Research Fund, Foundation Cotrel, and P01 HD084387. Contributors NW, JZ, GQ, and ZW contributed to the study concept and design. SZ and YZ contributed to the acquisition of data and technique support. WC, SW, and PL analysed and interpreted the data. NW and SZ drafted the manuscript. CAW, SZ, and JRL critically revised the manuscript. Declaration of interests JRL has stock ownership in 23andMe, is a paid consultant for Regeneron Pharmaceuticals, and is a co-inventor on multiple US and European patents related to molecular diagnostics for inherited neuropathies, eye diseases, and bacterial genomic fingerprinting. The Department of Molecular and Human Genetics at Baylor College of Medicine derives revenue from the chromosomal microarray analysis and clinical exome sequencing offered in the Baylor Genetics Laboratory. JRL also serves on the scientific advisory board of Baylor Genetics. All other authors declare no competing interests.
www.thelancet.com
Published Online October 18, 2019 Department of Orthopedic Surgery (S Zhao BS, Y Zhang MD, W Chen MD PhD, S Wang MD, J Zhang MD, N Wu MD), and Department of Cardiology (S Zhang MD), Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China (S Zhao BS, Y Zhang MD, W Chen MD PhD, S Wang MD, Z Wu MD, G Qiu MD, J Zhang MD, N Wu MD); Department of Molecular and Human Genetics (Pengfei Liu PhD, J R Lupski MD PhD, N Wu MD), and Departments of Pediatrics (J R Lupski MD PhD), Baylor College of Medicine; Houston, TX, USA; Sarah M and Charles E Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, Dallas, TX, USA (C A Wise PhD); Texas Children’s Hospital, Houston, TX, USA (J R Lupski MD PhD); and Medical Research Center of Orthopedics, Chinese Academy of Medical Sciences, Beijing, China (Z Wu MD, G Qiu MD, N Wu MD) Correspondence to: Dr Jianguo Zhang MD, Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China [email protected] or Dr Nan Wu MD, Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China [email protected]
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Diagnostic yield and clinical effects of exome sequencing analysis in patients with early-onset scoliosis Sen Zhao, Yuanqiang Zhang, Weisheng Chen, Shengru Wang, Pengfei Liu, Shuyang Zhang, Carol A Wise, James R Lupski, for Deciphering disorders Involving Scoliosis and COmorbidities (DISCO) study, Zhihong Wu, Guixing Qiu, Jianguo Zhang, Nan Wu for Deciphering disorders Involving Scoliosis and COmorbidities (DISCO) study
Abstract
Background Scoliosis is clinically defined as a spine deformity with lateral curvature greater than 10° and the cause of the disease is elusive. Early onset scoliosis, defined by an onset age before 10 years, conveys a substantial health risk to affected children. Although exome sequencing has emerged as a first-line diagnostic method for rare diseases, genetic testing is not routinely done for children with early onset scoliosis. We aimed to explore the diagnostic yield of exome sequencing in patients with early onset scoliosis. Methods We recruited a Chinese cohort of patients who were clinically diagnosed with early onset scoliosis through the Deciphering disorders Involving Scoliosis and COmorbidities (DISCO). We did exome sequencing on these individuals and available family members. Exome sequencing data were interpreted according to the American College of Medical Genetics and Genomics guidelines. Patients were followed up for a minimum of 2 years. We also recruited an American cohort of 13 patients with clinically diagnosed idiopathic early onset scoliosis, who underwent exome sequencing. Findings We recruited 447 patients in the Chinese cohort and 323 (72%) of 447 patients with early onset scoliosis were followed up for a minimum of 2 years. In the Chinese cohort, we detected diagnostic variants in 92 (21%) of 447 patients with early onset scoliosis, encompassing 33 disease-causing genes and five genomic regions. The age at presentation, the number of organ systems involved, and the Cobb angle were the three features that were most predictive of a molecular diagnosis. Notably, 14 (41%) of 34 patients with non-TBX6-associated congenital scoliosis (TACS) molecular diagnoses had a higher post-surgery complication rate than did the 24 (9·2%) of 260 patients who were molecularly undiagnosed (p=0·000008). In the American cohort, one (8%) of 13 patients had a molecular diagnosis of Sotos syndrome, making the total number of patients in whom we found diagnostic variants 93 (20·2%) of 460. Interpretation Exome sequencing could identify the genetic cause in patients with early onset scoliosis. Specific clinical features and feature pairs provided indications for genetic testing in these patients. The prevention of postsurgery complications could potentially be implemented for patients with a non-TACS molecular diagnosis. Funding National Natural Science Foundation of China, Beijing Natural Science Foundation, 2016 Milstein Medical Asian American Partnership Foundation Fellowship Award in Translational Medicine, CAMS Initiative Fund for Medical Sciences, the Central Level Public Interest Program for Scientific Research Institute, the National Key Research and Development Program of China, the National Undergraduates Innovation and Training Program of Peking Union Medical College, US National Institutes of Health, National Institute of Neurological Disorders and Stroke, National Human Genome Research Institute and National Heart, Lung, and Blood Institute, the National Human Genome Research Institute, TX Scottish Rite Hospital Research Fund, Foundation Cotrel, and P01 HD084387. Contributors NW, JZ, GQ, and ZW contributed to the study concept and design. SZ and YZ contributed to the acquisition of data and technique support. WC, SW, and PL analysed and interpreted the data. NW and SZ drafted the manuscript. CAW, SZ, and JRL critically revised the manuscript. Declaration of interests JRL has stock ownership in 23andMe, is a paid consultant for Regeneron Pharmaceuticals, and is a co-inventor on multiple US and European patents related to molecular diagnostics for inherited neuropathies, eye diseases, and bacterial genomic fingerprinting. The Department of Molecular and Human Genetics at Baylor College of Medicine derives revenue from the chromosomal microarray analysis and clinical exome sequencing offered in the Baylor Genetics Laboratory. JRL also serves on the scientific advisory board of Baylor Genetics. All other authors declare no competing interests.
www.thelancet.com
Published Online October 18, 2019 Department of Orthopedic Surgery (S Zhao BS, Y Zhang MD, W Chen MD PhD, S Wang MD, J Zhang MD, N Wu MD), and Department of Cardiology (S Zhang MD), Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China (S Zhao BS, Y Zhang MD, W Chen MD PhD, S Wang MD, Z Wu MD, G Qiu MD, J Zhang MD, N Wu MD); Department of Molecular and Human Genetics (Pengfei Liu PhD, J R Lupski MD PhD, N Wu MD), and Departments of Pediatrics (J R Lupski MD PhD), Baylor College of Medicine; Houston, TX, USA; Sarah M and Charles E Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, Dallas, TX, USA (C A Wise PhD); Texas Children’s Hospital, Houston, TX, USA (J R Lupski MD PhD); and Medical Research Center of Orthopedics, Chinese Academy of Medical Sciences, Beijing, China (Z Wu MD, G Qiu MD, N Wu MD) Correspondence to: Dr Jianguo Zhang MD, Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China [email protected] or Dr Nan Wu MD, Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China [email protected]
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