Genotype–phenotype correlation study in 364 osteogenesis imperfecta Italian patients

Abstract

Osteogenesis imperfecta (OI) is a rare genetic disorder of the connective tissue and 90% of cases are due to dominant mutations in COL1A1 and COL1A2 genes. To increase OI disease knowledge and contribute to patient follow-up management, a homogeneous Italian cohort of 364 subjects affected by OI types I–IV was evaluated. The study population was composed of 262 OI type I, 24 type II, 39 type III, and 39 type IV patients. Three hundred and nine subjects had a type I collagen affecting function mutations (230 in α1(I) and 79 in α2(I)); no disease-causing changes were noticed in 55 patients. Compared with previous genotype–phenotype OI correlation studies, additional observations arose: a new effect for α1- and α2-serine substitutions has been pointed out and heart defects, never considered before, resulted associated to quantitative mutations (P = 0.043). Moreover, some different findings emerged if compared with previous literature; especially, focusing the attention on the lethal form, no association with specific collagen regions was found and most of variants localized in the previously reported “lethal clusters” were causative of OI types I–IV. Some discrepancies have been highlighted also considering the “50–55 nucleotides rule,” as well as the relationship between specific collagen I mutated region and the presence of dentinogenesis imperfecta and/or blue sclera. Despite difficulties still present in defining clear rules to predict the clinical outcome in OI patients, this study provides new pieces for completing the puzzle, also thanks to the inclusion of clinical signs never considered before and to the large number of OI Italian patients.

Inter‐ and Intrafamilial Phenotypic Variability in Individuals with Collagen‐Related Osteogenesis Imperfecta

“…In general, DN collagen type I pathogenic variants are associated with more severe OI (types II, III, and IV), whereas LOF pathogenic variants mainly cause mild OI forms (type I). 5,7,8 However, interconnections between phenotype and genotype are much more complicated than presented above. The severity of the phenotype depends on the location of the pathogenic variant, changes in amino acid properties, and currently unknown modifying factors.…”

“…Similarly to the previous report, our results show that the degree of variability depends on the affected gene and the type of collagen defect. 8 The correlation between the degree of variability and the affected gene might be explained by a lack of LOF variants in the COL1A2 gene, as compared with the COL1A1 gene, and a dominating number of Gly substitutions. COL1A1/2 LOF pathogenic variants are associated with less variable phenotypes compared with DN pathogenic variants.…”

Novel Compound Heterozygous Mutations in CRTAP Cause Rare Autosomal Recessive Osteogenesis Imperfecta

“…Among them, 425 conditions are shown to be associated with pathogenic variants in one or more of 437 different genes. Mutations in different loci within one gene can cause distinct types of skeletal disorders, while mutations in different genes can lead to the same disease (Foldynova-Trantirkova et al, 2012;Maioli et al, 2019). Therefore, genetic testing is indispensable in conjunction with clinical examination and radiographs for diagnostic confirmation.…”

Diagnóstico molecular de osteogênese imperfeita através do sequenciamento paralelo em larga escala de 15 genes candidatos

“…Nove estudos prévios principais publicados a partir de 2015 buscaram identificar o diagnóstico molecular de OI em coortes de diferentes países (Patel et al, 2015;Lindahl et al, 2015;Bardai et al, 2016;Liu et al, 2017;Caparros-Martin et al, 2017;Mrosk et al, 2018;Mohd Nawawi et al, 2018;Li et al, 2019;Maioli et al, 2019 BMP1,COL1A1,COL1A2,CREB3L1,CRTAP,FKBP10,IFITM5,P3H1,PLOD2,PPIB,SERPINF1,SERPINH1,SP7,TMEM38B,WNT1 *20 casos sem consanguinidade foram analisados por painel, e 22 casos com consanguinidade foram analisados por Sanger; **Foram realizados exoma e painel em alguns casos, mas o estudo não deixa claro em quantos casos Figura 7 -Panorama da distribuição diagnóstica de OI em diferentes contextos Representação da distribuição dos defeitos moleculares identificados nos estudos detalhados na Tabela 13, agrupados de acordo com mecanismo fisiopatológico. Dentro de cada estudo, a intensidade da cor de fundo da célula é proporcional à prevalência relativa dos genes identificados.…”

“…Historicamente, a literatura sugere que 85 a 90% dos casos de OI sejam relacionados a defeitos nesses genes (Forlino & Marini, 2016). De fato, nos estudos de Lindahl et al, Bardai et al, e Maioli et al, realizados, respectivamente, nas populações sueca, canadense e italiana, e que empregaram predominantemente como método de análise molecular o sequenciamento Sanger de COL1A1 e COL1A2, as proporções diagnósticas de defeitos no colágeno 1 ficaram entre 85 e 88% (Lindahl et al, 2015;Bardai et al, 2016;Maioli et al, 2019).…”