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

Fernandes, A. M.; Rocha-Braz, M. G. M.; França, M. M.; Lerario, A. M.; Simões, V. R. F.; Zanardo, E. A.; Kulikowski, L. D.; Martin, R. M.; Mendonca, B. B.; Ferraz-de-Souza, B.

Affiliations

¹Laboratorio 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, Brazil

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

³Department of Medicine, Section of Endocrinology, The University of Chicago, Chicago, USA

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

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

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

Abstract and keywords

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.

Keywords: Gene panel; Molecular diagnosis; Osteogenesis imperfecta; Phenotypic variability; Type 1 collagen; Targeted massively parallel sequencing

Links

DOI: 10.1007/s00198-020-05366-4

PubMed: 32123938

WoS: 000517721100002

History

Received: 2019-11-28

Accepted: 2020-02-21

Online: 2020-03-02

Cited Works (3)

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Cited By (2)

Year	Entry
2022	Tüysüz B, Elkanova L, Uludağ Alkaya D, Güleç Ç, Toksoy G, Güneş N, Yazan H, Bayhan AI, Yıldırım T, Yeşil G, Uyguner ZO. Osteogenesis imperfecta in 140 Turkish families: molecular spectrum and, comparison of long-term clinical outcome of those with col1a1/a2 and biallelic variants. Bone. February 2022;155:116293.
2023	Holtz AP, Souza LT, Ribeiro EM, Acosta AX, Lago RMRS, Simoni G, Llerena JC, Félix TM. Genetic analysis of osteogenesis imperfecta in a large Brazilian cohort. Bone. April 2023;169:116683.