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Osteoporosis International

, Volume 30, Issue 11, pp 2333–2342 | Cite as

Comprehensive genetic analyses using targeted next-generation sequencing and genotype-phenotype correlations in 53 Japanese patients with osteogenesis imperfecta

  • Y. Ohata
  • S. Takeyari
  • Y. Nakano
  • T. Kitaoka
  • H. Nakayama
  • V. Bizaoui
  • K. Yamamoto
  • K. Miyata
  • K. Yamamoto
  • M. Fujiwara
  • T. Kubota
  • T. Michigami
  • K. Yamamoto
  • T. Yamamoto
  • N. Namba
  • K. Ebina
  • H. Yoshikawa
  • K. OzonoEmail author
Original Article

Abstract

Summary

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.

Keywords

Fracture Genotype-phenotype correlation Next-generation sequencing Osteogenesis imperfecta Short stature Type I collagen 

Notes

Acknowledgments

We wish to thank the patients and their families for participating in this study.

Funding information

This study was financially supported by grants from Japan Agency for Medical Research and Development, titled “Development and application of innovative drug-screening technology using patient derived iPS cells for intractable bone and cartilage disease,” “Creation of a network for skeletal dysplasia research and care to develop clinical guidelines,” and “Initiative on Rare and Undiagnosed Disease.”

Compliance with ethical standards

Ethical approval

All procedures were performed in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Conflicts of interest

None.

Supplementary material

198_2019_5076_Fig3_ESM.png (33 kb)
Supplemental Fig 1

Comparison of annual fracture rate. (a) Comparison of fracture rate among the 4 groups with COL1A1 and COL1A2 mutations. (b) Comparison of fracture rate among the 4 groups with COL1A1 mutations only. (c) Comparison of fracture rate among the 3 groups with COL1A2 mutations only. (d) Comparison of fracture rate between COL1A1 and COL1A2 mutations with all groups of mutations. (e) Comparison of fracture rate between COL1A1 and COL1A2 mutations with GS. (f) Comparison of fracture rate between COL1A1 and COL1A2 mutations with non-truncating mutations. The numbers in parentheses represent the sample numbers. GS: glycine substitution group; TG: truncating group; NTG: non-truncating group; OS: other missense group, ⁎: p < 0.05, ⁎⁎: p < 0.01, ⁎⁎⁎: p < 0.001 (PNG 33 kb)

198_2019_5076_MOESM1_ESM.eps (1016 kb)
High resolution image (EPS 1015 kb)
198_2019_5076_Fig4_ESM.png (32 kb)
Supplemental Fig 2

Comparison of height. (a) Comparison of SDS of height among the 4 groups with COL1A1 and COL1A2 mutations. (b) Comparison of SDS of height among the 4 groups with COL1A1 mutations only. (c) Comparison of SDS of height among the 3 groups with COL1A2 mutations only. (d) Comparison of SDS of height between COL1A1 and COL1A2 mutations with all groups of mutations. (e) Comparison of SDS of height between COL1A1 and COL1A2 mutations with glycine substitutions. (f) Comparison of SDS of height between COL1A1 and COL1A2 mutations with non-truncating mutations. The numbers in parentheses represent the sample numbers. GS: glycine substitution group; TG: truncating group; NTG: non-truncating group; OS: other missense group; SDS: standard deviation score, ⁎: p < 0.05, ⁎⁎: p < 0.01, ⁎⁎⁎: p < 0.001 (PNG 32 kb)

198_2019_5076_MOESM2_ESM.eps (1022 kb)
High resolution image (EPS 1021 kb)
198_2019_5076_Fig5_ESM.png (41 kb)
Supplemental Fig 3

Comparison of L1-L4 BMD and TBS. (a) Comparison of SDS of L1-L4 BMD among the 4 groups with COL1A1 and COL1A2 mutations. (b) Comparison of SDS of L1-L4 BMD among the 4 groups with COL1A1 mutations only. (c) Comparison of SDS of L1-L4 BMD among the 3 groups with COL1A2 mutation only. (d) Comparison of SDS of L1-L4 BMD between COL1A1 and COL1A2 mutations with all groups of mutations. (e) Comparison of SDS of L1-L4 BMD between COL1A1 and COL1A2 mutations with glycine substitutions. (f) Comparison of SDS of L1-L4 BMD between COL1A1 and COL1A2 mutations with non-truncating mutations. The numbers in parentheses represent the sample numbers, GS: glycine substitution group; TG: truncating group; NTG: non-truncating group; OS: other missense group; SDS: standard deviation score. ⁎: p < 0.05 (PNG 40 kb)

198_2019_5076_MOESM3_ESM.eps (1.1 mb)
High resolution image (EPS 1177 kb)
198_2019_5076_Fig6_ESM.png (32 kb)
Supplemental Fig 4

Positional effect of mutations on fracture rate. (a) Comparison of fracture rates among N-terminal pro-peptide, triple helix, and C-terminal pro-peptide mutations in COL1A1 and COL1A2. (b) Comparison of fracture rates among N-terminal pro-peptide, triple helix, and C-terminal pro-peptide mutations in COL1A1 only. (c) Comparison of fracture rates between COL1A1 and COL1A2 mutations located on the triple helix. (d) Relationship between fracture rate and exon number for mutations located in COL1A1 and COL1A2. (e) Relationship between fracture rate and exon number for mutations located in COL1A1 only. (f) Relationship between fracture rate and exon number for mutations located in COL1A2 only. The numbers in parentheses represent the sample numbers. N: N-terminal pro-peptide; Helix: triple helix; C: C-terminal pro-peptide. No significant differences nor correlations were observed in these analyses (PNG 31 kb)

198_2019_5076_MOESM4_ESM.eps (983 kb)
High resolution image (EPS 982 kb)
198_2019_5076_Fig7_ESM.png (30 kb)
Supplemental Fig 5

Positional effect of mutations on height. (a) Comparison of SDS of height among N-terminal pro-peptide, triple helix, and C-terminal pro-peptide mutations in COL1A1 and COL1A2. (b) Comparison of SDS of height among N-terminal pro-peptide, triple helix, and C-terminal pro-peptide mutation in COL1A1 only. (c) Comparison of SDS of height between COL1A1 and COL1A2 mutations located in the triple helix. (d) Relationship between SDS of height and exon number for mutations located in COL1A1 and COL1A2. (e) Relationship between SDS of height and exon number for mutations located in COL1A1 only. (f) Relationship between SDS of height and exon number for mutations located in COL1A2 only. The numbers in parentheses represent the sample numbers. N: N terminal pro-peptide; Helix: triple helix; C: C terminal pro-peptide. No significant differences nor correlations were observed in these analyses (PNG 30 kb)

198_2019_5076_MOESM5_ESM.eps (1000 kb)
High resolution image (EPS 999 kb)
198_2019_5076_Fig8_ESM.png (33 kb)
Supplemental Fig 6

Positional effect of mutations on L1-L4 BMD. (a) Comparison of SDS of L1-L4 BMD among N-terminal pro-peptide, triple helix, and C-terminal pro-peptide mutations in COL1A1 and COL1A2. (b) Comparison of SDS of L1-L4 BMD among N-terminal pro-peptide, triple helix, and C-terminal pro-peptide mutations in COL1A1 only. (c) Comparison of SDS of L1-L4 BMD between COL1A1 and COL1A2 mutations located in the triple helix. (d) Relationship between SDS of L1-L4 BMD and exon number for mutations located in COL1A1 and COL1A2. (e) Relationship between SDS of L1-L4 BMD and exon number for mutations located in COL1A1 only. (f) Relationship between SDS of L1-L4 BMD and exon number for mutations located in COL1A2 only. A significant correlation was observed between L1-L4 BMD and location of mutations in COL1A2 (r2= 0.74, p = 0.003). The numbers in parentheses represent the sample numbers. N: N-terminal pro-peptide; Helix: triple helix; C: C-terminal pro-peptide. No significant differences nor correlations were observed in (a-e) (PNG 33 kb)

198_2019_5076_MOESM6_ESM.eps (1 mb)
High resolution image (EPS 1025 kb)
198_2019_5076_MOESM7_ESM.docx (12 kb)
Supplementary Table 1 (DOCX 12 kb)

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Copyright information

© International Osteoporosis Foundation and National Osteoporosis Foundation 2019

Authors and Affiliations

  • Y. Ohata
    • 1
  • S. Takeyari
    • 1
  • Y. Nakano
    • 1
  • T. Kitaoka
    • 1
  • H. Nakayama
    • 1
    • 2
  • V. Bizaoui
    • 1
    • 3
  • K. Yamamoto
    • 1
    • 4
  • K. Miyata
    • 1
  • K. Yamamoto
    • 1
    • 5
  • M. Fujiwara
    • 1
    • 6
  • T. Kubota
    • 1
  • T. Michigami
    • 7
  • K. Yamamoto
    • 8
  • T. Yamamoto
    • 9
  • N. Namba
    • 1
    • 10
  • K. Ebina
    • 11
  • H. Yoshikawa
    • 12
  • K. Ozono
    • 1
    Email author
  1. 1.Department of PediatricsOsaka University Graduate School of MedicineSuitaJapan
  2. 2.The Japan Environment and Children’s StudyOsaka Unit CenterSuitaJapan
  3. 3.Department of Medical Genetics, Reference Center for Skeletal DysplasiaHôpital Necker – Enfants MaladesParisFrance
  4. 4.Department of Statistical GeneticsOsaka University Graduate School of MedicineSuitaJapan
  5. 5.Department of PediatricsNational Hospital Organization Osaka National HospitalOsakaJapan
  6. 6.The First Department of Oral and Maxillofacial SurgeryOsaka University Graduate School of DentistrySuitaJapan
  7. 7.Department of Bone and Mineral ResearchOsaka Women’s and Children’s HospitalIzumiJapan
  8. 8.Department of Pediatric Nephrology and MetabolismOsaka Women’s and Children’s HospitalIzumiJapan
  9. 9.Department of PediatricsMinoh City HospitalMinohJapan
  10. 10.Department of Pediatrics, Osaka HospitalJapan Community Healthcare Organization (JCHO)OsakaJapan
  11. 11.Department of Musculoskeletal Regenerative MedicineOsaka University Graduate School of MedicineSuitaJapan
  12. 12.Department of Orthopaedic SurgeryOsaka University Graduate School of MedicineSuitaJapan

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