Genetic analysis of osteogenesis imperfecta in a large Brazilian cohort

• Published in: Bone (New York, N.Y.) Vol. 169; p. 116683
• Main Authors: Holtz, A.P., Souza, L.T., Ribeiro, E.M., Acosta, A.X., Lago, R.M.R.S., Simoni, G., Llerena, J.C., Félix, T.M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2023
• Subjects: Brazil; Collagen type 1; Collagen Type I - genetics; Gene panel; Genetic Association Studies; Humans; Molecular diagnosis; Mutation; Next generation sequencing; Osteogenesis imperfecta; Osteogenesis Imperfecta - genetics; Brazil; Osteogenesis imperfecta; Molecular diagnosis; Collagen type 1; Next generation sequencing; Gene panel
• ISSN: 8756-3282; 1873-2763; 1873-2763
• DOI: 10.1016/j.bone.2023.116683

Osteogenesis imperfecta (OI) is a genetically and clinically heterogeneous disorder caused by disruption of type I collagen synthesis. Previous Brazilian molecular OI studies have been restricted to case reports or small cohorts. The Brazilian OI Network (BOIN) is a multicenter study collecting clinical OI treatment data from five reference centers in three regions of Brazil. To describe the molecular analysis of a large cohort of OI registered at BOIN. Targeted next-generation sequencing (NGS) was performed at a centralized laboratory with the Ion Torrent platform, covering 99.6 % of the coding regions of 18 OI-associated genes. Clinical information was obtained from a clinical database. We included 156 subjects in the molecular analyses. Variants were detected in 121 subjects: 65 (53.7 %) in COL1A1, 42 (34.7 %) in COL1A2, 2 (1.7 %) in IFITM5, one (0.8 %) in CRTAP, three (2.5 %) in P3H1, two (1.7 %) in PPIB, four (3.3 %) FKBP10, one (0.8 %) in SERPINH1, and one (0.8 %) in TMEM38B. Ninety-one distinct variants were identified, of which 26 were novel. Of the 107 variants identified in COL1A1 and COL1A2, 24.5 % cause mild OI, while the remaining 75.5 % cause moderate, severe, or lethal OI, of which 49.3 % are glycine to serine substitutions. A single variant in FKBP10 (c.179A>C; p.Gln60Pro) was found in three unrelated and non-consanguineous participants living in the same geographic area in Northeast Brazil, suggesting a possible founder effect. Consistent with the literature, 88.4 % of the subjects had a variant in the COL1A1 and COL1A2 genes, with 10 % inherited in an autosomal recessive manner. Notably, one variant in FKBP10 with a potential founder effect requires further investigation. Data from this large cohort improves our understanding of genotype-phenotype correlations for OI in Brazil. •This is the largest molecular analysis study of OI in Brazil.•The majority of cases a collagen I defect was found (88.4 %).•In 9.9 % an autosomal recessive gene play a role in OI.•A possible founder effect was identified in three cases with a variant in FKBP10.