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The molecular landscape of osteogenesis imperfecta in a Brazilian tertiary service cohort

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Abstract

Summary

We have sought the molecular diagnosis of OI in 38 Brazilian cases through targeted sequencing of 15 candidate genes. While 71% had type 1 collagen-related OI, defects in FKBP10, PLOD2 and SERPINF1, and a potential digenic P3H1/WNT1 interaction were prominent causes of OI in this underrepresented population.

Introduction

Defects in type 1 collagen reportedly account for 85–90% of osteogenesis imperfecta (OI) cases, but most available molecular data has derived from Sanger sequencing-based approaches in developed countries. Massively parallel sequencing (MPS) allows for systematic and comprehensive analysis of OI genes simultaneously. Our objective was to obtain the molecular diagnosis of OI in a single Brazilian tertiary center cohort.

Methods

Forty-nine individuals (84% adults) with a clinical diagnosis of OI, corresponding to 30 sporadic and 8 familial cases, were studied. Sixty-three percent had moderate to severe OI, and consanguinity was common (26%). Coding regions and 25-bp boundaries of 15 OI genes (COL1A1, COL1A2, IFITM5 [plus 5′UTR], SERPINF1, CRTAP, P3H1, PPIB, SERPINH1, FKBP10, PLOD2, BMP1, SP7, TMEM38B, WNT1, CREB3L1) were analyzed by targeted MPS and variants of interest were confirmed by Sanger sequencing or SNP array.

Results

A molecular diagnosis was obtained in 97% of cases. COL1A1/COL1A2 variants were identified in 71%, whereas 26% had variants in other genes, predominantly FKBP10, PLOD2, and SERPINF1. A potential digenic interaction involving P3H1 and WNT1 was identified in one case. Phenotypic variability with collagen defects could not be explained by evident modifying variants. Four consanguineous cases were associated to heterozygous COL1A1/COL1A2 variants, and two nonconsanguineous cases had compound PLOD2 heterozygosity.

Conclusions

Novel disease-causing variants were identified in 29%, and a higher proportion of non-collagen defects was seen. Obtaining a precise diagnosis of OI in underrepresented populations allows expanding our understanding of its molecular landscape, potentially leading to improved personalized care in the future.

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Acknowledgments

We are grateful to Amanda Narcizo for technical assistance with massively parallel sequencing.

Funding

This work was supported by the São Paulo Research Foundation (FAPESP, Multiusuário grant 2013/02162-8). BFdS also acknowledges support from FAPESP through a Young Investigator grant (2011/12696-4).

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Authors and Affiliations

  1. Laboratorio de Endocrinologia Celular e Molecular LIM-25 e Unidade de Doencas Osteometabolicas, Divisao de Endocrinologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil

    A.M. Fernandes, M.G.M. Rocha-Braz, V.R.F. Simões & B. Ferraz-de-Souza

  2. Laboratorio de Hormonios e Genetica Molecular LIM-42, Divisao de Endocrinologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil

    M.M. França, A.M. Lerario & R.M. Martin

  3. Department of Medicine, Section of Endocrinology, The University of Chicago, Chicago, IL, 60637, USA

    M.M. França

  4. Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, MI, USA

    A.M. Lerario

  5. Laboratorio de Citogenomica, Departamento de Patologia, Faculdade de Medicina FMUSP, Universidade de Sao Paulo, Sao Paulo, SP, Brazil

    E.A. Zanardo & L.D. Kulikowski

  6. Laboratorio de Sequenciamento em Larga Escala (SELA), Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, Brazil

    A.M. Lerario & B.B. Mendonca

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  1. A.M. Fernandes
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  5. V.R.F. Simões
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  7. L.D. Kulikowski
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  8. R.M. Martin
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  9. B.B. Mendonca
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  10. B. Ferraz-de-Souza
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Correspondence to B. Ferraz-de-Souza.

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Conflict of interest

Adriana Fernandes, Manuela Rocha-Braz, Monica França, Antonio Lerario, Vivian Simões, Evelin Zanardo, Leslie Kulikowski, Regina Martin, Berenice Mendonca and Bruno Ferraz-de-Souza declare that they have no conflict of interest that could be perceived as prejudicing the impartiality of this study. Manuela Rocha-Braz has received lecture fees from EMS and Amgen Brazil. Bruno Ferraz-de-Souza has received consulting fees from Sandoz Brazil, UCB Brazil and Hypera Brazil, and lecture fees from Amgen Brazil, Sandoz Brazil, Sanofi Brazil and Hypera Brazil.

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Fernandes, A., Rocha-Braz, M., França, M. et al. The molecular landscape of osteogenesis imperfecta in a Brazilian tertiary service cohort. Osteoporos Int 31, 1341–1352 (2020). https://doi.org/10.1007/s00198-020-05366-4

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