Jun-Seok Bae1,2, Nayoung K D Kim1, Chung Lee1,2, Sang Cheol Kim1, Hey Ran Lee3, Hae-Ryong Song4, Kun Bo Park5, Hyun Woo Kim6, Soon Hyuck Lee7, Ha Yong Kim8, Soon Chul Lee9, Changhoon Jeong10, Moon Seok Park11, Won Joon Yoo3, Chin Youb Chung11, In Ho Choi3, Ok-Hwa Kim12, Woong-Yang Park1,2,13, Tae-Joon Cho3. 1. Samsung Genome Institute, Samsung Medical Center, Seoul, Korea. 2. Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Korea. 3. Division of Pediatric Orthopaedics, Seoul National University Children's Hospital, Seoul, Korea. 4. Department of Orthopaedic Surgery, Korea University Guro Hospital, Seoul, Korea. 5. Department of Orthopaedic Surgery, Inje University Haeundae Hospital, Busan, Korea. 6. Department of Orthopaedic Surgery, Severance Children's Hospital, Yonsei University College of Medicine, Seoul, Korea. 7. Department of Orthopaedic Surgery, Korea University Anam Hospital, Seoul, Korea. 8. Department of Orthopaedic Surgery, Eulji University Daejeon Hospital, Daejeon, Korea. 9. Department of Orthopaedic Surgery, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Korea. 10. Department of Orthopaedic Surgery, Bucheon St. Mary's Hospital, the Catholic University of Korea, Bucheon, Korea. 11. Department of Orthopaedic Surgery, Seoul National University Bundang Hospital, Seongnam, Korea. 12. Department of Radiology, Woorisoa Children's Hospital, Seoul, Korea. 13. Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Korea.
Abstract
PURPOSE: The purpose of this study was to evaluate the clinical utility of targeted exome sequencing (TES) as a molecular diagnostic tool for patients with skeletal dysplasia. METHODS: A total of 185 patients either diagnosed with or suspected to have skeletal dysplasia were recruited over a period of 3 years. TES was performed for 255 genes associated with the pathogenesis of skeletal dysplasia, and candidate variants were selected using a bioinformatics analysis. All candidate variants were confirmed by Sanger sequencing, correlation with the phenotype, and a cosegregation study in the family. RESULTS: TES detected "confirmed" or "highly likely" pathogenic sequence variants in 74% (71 of 96) of cases in the assured clinical diagnosis category and 20.3% (13 of 64 cases) of cases in the uncertain clinical diagnosis category. TES successfully detected pathogenic variants in all 25 cases of previously known genotypes. The data also suggested a copy-number variation that led to a molecular diagnosis. CONCLUSION: This study demonstrates the feasibility of TES for the molecular diagnosis of skeletal dysplasia. However, further confirmation is needed for a final molecular diagnosis, including Sanger sequencing of candidate variants with suspected, poorly captured exons.Genet Med 18 6, 563-569.
PURPOSE: The purpose of this study was to evaluate the clinical utility of targeted exome sequencing (TES) as a molecular diagnostic tool for patients with skeletal dysplasia. METHODS: A total of 185 patients either diagnosed with or suspected to have skeletal dysplasia were recruited over a period of 3 years. TES was performed for 255 genes associated with the pathogenesis of skeletal dysplasia, and candidate variants were selected using a bioinformatics analysis. All candidate variants were confirmed by Sanger sequencing, correlation with the phenotype, and a cosegregation study in the family. RESULTS: TES detected "confirmed" or "highly likely" pathogenic sequence variants in 74% (71 of 96) of cases in the assured clinical diagnosis category and 20.3% (13 of 64 cases) of cases in the uncertain clinical diagnosis category. TES successfully detected pathogenic variants in all 25 cases of previously known genotypes. The data also suggested a copy-number variation that led to a molecular diagnosis. CONCLUSION: This study demonstrates the feasibility of TES for the molecular diagnosis of skeletal dysplasia. However, further confirmation is needed for a final molecular diagnosis, including Sanger sequencing of candidate variants with suspected, poorly captured exons.Genet Med 18 6, 563-569.
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