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Comprehensive genetic analyses using targeted next-generation sequencing and genotype-phenotype correlations in 53 Japanese patients with osteogenesis imperfecta.
Osteoporos Int. 2019 Nov; 30(11):2333-2342.OI

Abstract

To elucidate mutation spectrum and genotype-phenotype correlations in Japanese patients with OI, we conducted comprehensive genetic analyses using NGS, as this had not been analyzed comprehensively in this patient population. Most mutations were located on COL1A1 and COL1A2. Glycine substitutions in COL1A1 resulted in the severe phenotype.

INTRODUCTION

Most cases of osteogenesis imperfecta (OI) are caused by mutations in COL1A1 or COL1A2, which encode α chains of type I collagen. However, mutations in at least 16 other genes also cause OI. The mutation spectrum in Japanese patients with OI has not been comprehensively analyzed, as it is difficult to identify using classical Sanger sequencing. In this study, we aimed to reveal the mutation spectrum and genotype-phenotype correlations in Japanese patients with OI using next-generation sequencing (NGS).

METHODS

We designed a capture panel for sequencing 15 candidate OI genes and 19 candidate genes that are associated with bone fragility or Wnt signaling. Using NGS, we examined 53 Japanese patients with OI from unrelated families.

RESULTS

Pathogenic mutations were detected in 43 out of 53 individuals. All mutations were heterozygous. Among the 43 individuals, 40 variants were identified including 15 novel mutations. We found these mutations in COL1A1 (n = 30, 69.8%), COL1A2 (n = 12, 27.9%), and IFITM5 (n = 1, 2.3%). Patients with glycine substitution on COL1A1 had a higher frequency of fractures and were more severely short-statured. Although no significant genotype-phenotype correlation was observed for bone mineral density, the trabecular bone score was significantly lower in patients with glycine substitutions.

CONCLUSION

We identified pathogenic mutations in 81% of our Japanese patients with OI. Most mutations were located on COL1A1 and COL1A2. This study revealed that glycine substitutions on COL1A1 resulted in the severe phenotype among Japanese patients with OI.

Authors+Show Affiliations

Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan.Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan.Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan.Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan.Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan. The Japan Environment and Children's Study, Osaka Unit Center, Suita, Japan.Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan. Department of Medical Genetics, Reference Center for Skeletal Dysplasia, Hôpital Necker - Enfants Malades, Paris, France.Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan. Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan.Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan.Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan. Department of Pediatrics, National Hospital Organization Osaka National Hospital, Osaka, Japan.Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan. The First Department of Oral and Maxillofacial Surgery, Osaka University Graduate School of Dentistry, Suita, Japan.Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan.Department of Bone and Mineral Research, Osaka Women's and Children's Hospital, Izumi, Japan.Department of Pediatric Nephrology and Metabolism, Osaka Women's and Children's Hospital, Izumi, Japan.Department of Pediatrics, Minoh City Hospital, Minoh, Japan.Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan. Department of Pediatrics, Osaka Hospital, Japan Community Healthcare Organization (JCHO), Osaka, Japan.Department of Musculoskeletal Regenerative Medicine, Osaka University Graduate School of Medicine, Suita, Japan.Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, Suita, Japan.Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan. keioz@ped.med.osaka-u.ac.jp.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31363794

Citation

Ohata, Y, et al. "Comprehensive Genetic Analyses Using Targeted Next-generation Sequencing and Genotype-phenotype Correlations in 53 Japanese Patients With Osteogenesis Imperfecta." Osteoporosis International : a Journal Established as Result of Cooperation Between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA, vol. 30, no. 11, 2019, pp. 2333-2342.
Ohata Y, Takeyari S, Nakano Y, et al. Comprehensive genetic analyses using targeted next-generation sequencing and genotype-phenotype correlations in 53 Japanese patients with osteogenesis imperfecta. Osteoporos Int. 2019;30(11):2333-2342.
Ohata, Y., Takeyari, S., Nakano, Y., Kitaoka, T., Nakayama, H., Bizaoui, V., Yamamoto, K., Miyata, K., Yamamoto, K., Fujiwara, M., Kubota, T., Michigami, T., Yamamoto, K., Yamamoto, T., Namba, N., Ebina, K., Yoshikawa, H., & Ozono, K. (2019). Comprehensive genetic analyses using targeted next-generation sequencing and genotype-phenotype correlations in 53 Japanese patients with osteogenesis imperfecta. Osteoporosis International : a Journal Established as Result of Cooperation Between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA, 30(11), 2333-2342. https://doi.org/10.1007/s00198-019-05076-6
Ohata Y, et al. Comprehensive Genetic Analyses Using Targeted Next-generation Sequencing and Genotype-phenotype Correlations in 53 Japanese Patients With Osteogenesis Imperfecta. Osteoporos Int. 2019;30(11):2333-2342. PubMed PMID: 31363794.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Comprehensive genetic analyses using targeted next-generation sequencing and genotype-phenotype correlations in 53 Japanese patients with osteogenesis imperfecta. AU - Ohata,Y, AU - Takeyari,S, AU - Nakano,Y, AU - Kitaoka,T, AU - Nakayama,H, AU - Bizaoui,V, AU - Yamamoto,K, AU - Miyata,K, AU - Yamamoto,K, AU - Fujiwara,M, AU - Kubota,T, AU - Michigami,T, AU - Yamamoto,K, AU - Yamamoto,T, AU - Namba,N, AU - Ebina,K, AU - Yoshikawa,H, AU - Ozono,K, Y1 - 2019/07/29/ PY - 2019/03/12/received PY - 2019/06/26/accepted PY - 2019/8/1/pubmed PY - 2020/6/17/medline PY - 2019/8/1/entrez KW - Fracture KW - Genotype-phenotype correlation KW - Next-generation sequencing KW - Osteogenesis imperfecta KW - Short stature KW - Type I collagen SP - 2333 EP - 2342 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 - 30 IS - 11 N2 - : To elucidate mutation spectrum and genotype-phenotype correlations in Japanese patients with OI, we conducted comprehensive genetic analyses using NGS, as this had not been analyzed comprehensively in this patient population. Most mutations were located on COL1A1 and COL1A2. Glycine substitutions in COL1A1 resulted in the severe phenotype. INTRODUCTION: Most cases of osteogenesis imperfecta (OI) are caused by mutations in COL1A1 or COL1A2, which encode α chains of type I collagen. However, mutations in at least 16 other genes also cause OI. The mutation spectrum in Japanese patients with OI has not been comprehensively analyzed, as it is difficult to identify using classical Sanger sequencing. In this study, we aimed to reveal the mutation spectrum and genotype-phenotype correlations in Japanese patients with OI using next-generation sequencing (NGS). METHODS: We designed a capture panel for sequencing 15 candidate OI genes and 19 candidate genes that are associated with bone fragility or Wnt signaling. Using NGS, we examined 53 Japanese patients with OI from unrelated families. RESULTS: Pathogenic mutations were detected in 43 out of 53 individuals. All mutations were heterozygous. Among the 43 individuals, 40 variants were identified including 15 novel mutations. We found these mutations in COL1A1 (n = 30, 69.8%), COL1A2 (n = 12, 27.9%), and IFITM5 (n = 1, 2.3%). Patients with glycine substitution on COL1A1 had a higher frequency of fractures and were more severely short-statured. Although no significant genotype-phenotype correlation was observed for bone mineral density, the trabecular bone score was significantly lower in patients with glycine substitutions. CONCLUSION: We identified pathogenic mutations in 81% of our Japanese patients with OI. Most mutations were located on COL1A1 and COL1A2. This study revealed that glycine substitutions on COL1A1 resulted in the severe phenotype among Japanese patients with OI. SN - 1433-2965 UR - https://www.unboundmedicine.com/medline/citation/31363794/Comprehensive_genetic_analyses_using_targeted_next_generation_sequencing_and_genotype_phenotype_correlations_in_53_Japanese_patients_with_osteogenesis_imperfecta_ L2 - https://doi.org/10.1007/s00198-019-05076-6 DB - PRIME DP - Unbound Medicine ER -