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Gene mutation spectrum and genotype-phenotype correlation in a cohort of Chinese osteogenesis imperfecta patients revealed by targeted next generation sequencing.
Osteoporos Int. 2017 10; 28(10):2985-2995.OI

Abstract

The achievement of more accurate diagnosis would greatly benefit the management of patients with osteogenesis imperfecta (OI). In this study, we present the largest OI sample in China as screened by next generation sequencing. In particular, we successfully identified 81 variants, which included 45 novel variants. We further did a genotype-phenotype analysis, which helps make a better understanding of OI.

INTRODUCTION

This study aims to reveal the gene mutation spectrum and the genotype-phenotype relationship among Chinese OI patients by next generation sequencing (NGS).

METHODS

We developed a NGS-based panel for targeted sequencing of all exons of 14 genes related to OI, and performed diagnostic gene sequencing for a cohort of 103 Chinese OI patients from 101 unrelated families. Mutations identified by NGS were further confirmed by Sanger sequencing and co-segregation analysis.

RESULTS

Of the 103 patients from 101 unrelated OI families, we identified 79 mutations, including 43 novel mutations (11 frameshift, 17 missense, 5 nonsense, 9 splice site, and 1 chromosome translocation) in 90 patients (87.4%). Mutations in genes encoding type I collagen, COL1A1 (n = 37), and COL1A2 (n = 29) accounts for 73.3% of all molecularly diagnosed patients, followed by IFITM5 (n = 9, 10%), SERPINF1 (n = 4, 4.4%), WNT1 (n = 4, 4.4%), FKBP10 (n = 3, 3.3%), TMEM38B (n = 3, 3.3%), and PLOD2 (n = 1, 1.1%). This corresponds to 75 autosomal dominant inherited (AD) OI patients and 15 autosomal recessive (AR) inherited patients. Compared with AD inherited OI patients, AR inherited patients had lower bone mineral density (BMD) at spine (P = 0.05) and less frequent blue sclera (P = 0.001). Patients with type I collagen qualitative defects had lower femoral neck BMD Z-score (P = 0.034) and were shorter compared with patients with type I collagen quantitative defects (P = 0.022).

CONCLUSION

We revealed the gene mutation spectrum in Chinese OI patients, and novel mutations identified here expanded the mutation catalog and genotype and phenotype relationships among OI patients.

Authors+Show Affiliations

Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, 100730, China.Tianjin Medical Laboratory, BGI-Tianjin, BGI-Shenzhen, Tianjin, 300308, China. Binhai Genomics Institute, BGI-Tianjin, Tianjin, 300308, China.Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, 100730, China.Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, 100730, China.Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, 100730, China.Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, 100730, China.Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, 100730, China.Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, 100730, China.Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, 100730, China.Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, 100730, China.Department of Radiology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, 100730, China.Tianjin Medical Laboratory, BGI-Tianjin, BGI-Shenzhen, Tianjin, 300308, China. Binhai Genomics Institute, BGI-Tianjin, Tianjin, 300308, China.Tianjin Medical Laboratory, BGI-Tianjin, BGI-Shenzhen, Tianjin, 300308, China. Binhai Genomics Institute, BGI-Tianjin, Tianjin, 300308, China.Tianjin Medical Laboratory, BGI-Tianjin, BGI-Shenzhen, Tianjin, 300308, China. Binhai Genomics Institute, BGI-Tianjin, Tianjin, 300308, China.Tianjin Medical Laboratory, BGI-Tianjin, BGI-Shenzhen, Tianjin, 300308, China. Binhai Genomics Institute, BGI-Tianjin, Tianjin, 300308, China.BGI-Shenzhen, Shenzhen, 518083, China. James D. Watson Institute of Genome Sciences, Hangzhou, 310058, China.BGI-Shenzhen, Shenzhen, 518083, China. James D. Watson Institute of Genome Sciences, Hangzhou, 310058, China.Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, 100730, China. limeilzh@sina.com.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

28725987

Citation

Liu, Y, et al. "Gene Mutation Spectrum and Genotype-phenotype Correlation in a Cohort of Chinese Osteogenesis Imperfecta Patients Revealed By Targeted Next Generation Sequencing." Osteoporosis International : a Journal Established as Result of Cooperation Between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA, vol. 28, no. 10, 2017, pp. 2985-2995.
Liu Y, Asan , Ma D, et al. Gene mutation spectrum and genotype-phenotype correlation in a cohort of Chinese osteogenesis imperfecta patients revealed by targeted next generation sequencing. Osteoporos Int. 2017;28(10):2985-2995.
Liu, Y., Asan, ., Ma, D., Lv, F., Xu, X., Wang, J., Xia, W., Jiang, Y., Wang, O., Xing, X., Yu, W., Wang, J., Sun, J., Song, L., Zhu, Y., Yang, H., Wang, J., & Li, M. (2017). Gene mutation spectrum and genotype-phenotype correlation in a cohort of Chinese osteogenesis imperfecta patients revealed by targeted next generation sequencing. Osteoporosis International : a Journal Established as Result of Cooperation Between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA, 28(10), 2985-2995. https://doi.org/10.1007/s00198-017-4143-8
Liu Y, et al. Gene Mutation Spectrum and Genotype-phenotype Correlation in a Cohort of Chinese Osteogenesis Imperfecta Patients Revealed By Targeted Next Generation Sequencing. Osteoporos Int. 2017;28(10):2985-2995. PubMed PMID: 28725987.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Gene mutation spectrum and genotype-phenotype correlation in a cohort of Chinese osteogenesis imperfecta patients revealed by targeted next generation sequencing. AU - Liu,Y, AU - Asan,, AU - Ma,D, AU - Lv,F, AU - Xu,X, AU - Wang,J, AU - Xia,W, AU - Jiang,Y, AU - Wang,O, AU - Xing,X, AU - Yu,W, AU - Wang,J, AU - Sun,J, AU - Song,L, AU - Zhu,Y, AU - Yang,H, AU - Wang,J, AU - Li,M, Y1 - 2017/07/19/ PY - 2017/02/10/received PY - 2017/07/03/accepted PY - 2017/7/21/pubmed PY - 2018/7/26/medline PY - 2017/7/21/entrez KW - Genotype-phenotype correlation KW - Next generation sequencing KW - Osteogenesis imperfecta SP - 2985 EP - 2995 JF - Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA JO - Osteoporos Int VL - 28 IS - 10 N2 - : The achievement of more accurate diagnosis would greatly benefit the management of patients with osteogenesis imperfecta (OI). In this study, we present the largest OI sample in China as screened by next generation sequencing. In particular, we successfully identified 81 variants, which included 45 novel variants. We further did a genotype-phenotype analysis, which helps make a better understanding of OI. INTRODUCTION: This study aims to reveal the gene mutation spectrum and the genotype-phenotype relationship among Chinese OI patients by next generation sequencing (NGS). METHODS: We developed a NGS-based panel for targeted sequencing of all exons of 14 genes related to OI, and performed diagnostic gene sequencing for a cohort of 103 Chinese OI patients from 101 unrelated families. Mutations identified by NGS were further confirmed by Sanger sequencing and co-segregation analysis. RESULTS: Of the 103 patients from 101 unrelated OI families, we identified 79 mutations, including 43 novel mutations (11 frameshift, 17 missense, 5 nonsense, 9 splice site, and 1 chromosome translocation) in 90 patients (87.4%). Mutations in genes encoding type I collagen, COL1A1 (n = 37), and COL1A2 (n = 29) accounts for 73.3% of all molecularly diagnosed patients, followed by IFITM5 (n = 9, 10%), SERPINF1 (n = 4, 4.4%), WNT1 (n = 4, 4.4%), FKBP10 (n = 3, 3.3%), TMEM38B (n = 3, 3.3%), and PLOD2 (n = 1, 1.1%). This corresponds to 75 autosomal dominant inherited (AD) OI patients and 15 autosomal recessive (AR) inherited patients. Compared with AD inherited OI patients, AR inherited patients had lower bone mineral density (BMD) at spine (P = 0.05) and less frequent blue sclera (P = 0.001). Patients with type I collagen qualitative defects had lower femoral neck BMD Z-score (P = 0.034) and were shorter compared with patients with type I collagen quantitative defects (P = 0.022). CONCLUSION: We revealed the gene mutation spectrum in Chinese OI patients, and novel mutations identified here expanded the mutation catalog and genotype and phenotype relationships among OI patients. SN - 1433-2965 UR - https://www.unboundmedicine.com/medline/citation/28725987/Gene_mutation_spectrum_and_genotype_phenotype_correlation_in_a_cohort_of_Chinese_osteogenesis_imperfecta_patients_revealed_by_targeted_next_generation_sequencing_ L2 - https://doi.org/10.1007/s00198-017-4143-8 DB - PRIME DP - Unbound Medicine ER -