Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 2019 Jul;27(7):1090-1100.
doi: 10.1038/s41431-019-0373-x. Epub 2019 Mar 18.

Genotype-phenotype correlation study in 364 osteogenesis imperfecta Italian patients

Margherita Maioli  1 , Maria Gnoli  2 , Manila Boarini  3 , Morena Tremosini  2 , Anna Zambrano  4 , Elena Pedrini  2 , Marina Mordenti  3 , Serena Corsini  2 , Patrizia D'Eufemia  4 , Paolo Versacci  5 , Mauro Celli  4 , Luca Sangiorgi  6
Affiliations
Clinical Trial

Genotype-phenotype correlation study in 364 osteogenesis imperfecta Italian patients

Margherita Maioli et al. Eur J Hum Genet. 2019 Jul.

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.

PubMed Disclaimer

Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
Relationship between OI types I–IV and the type of genetic mutation (qualitative or quantitative). The frequency has been reported for each class
Fig. 2
Fig. 2
Glycine substitutions distribution along the α1- (a) and α2-chains (b) in relationship with the clinical outcome. Each symbol corresponds to a patient
Fig. 3
Fig. 3
a Stature distribution in OI types I, III, and IV. b Relationship between OI clinical classes and the presence/absence of cardiac defects
Fig. 4
Fig. 4
Dentinogenesis imperfecta (DGI) and scleral hue matching to the position of glycine mutations in COL1A1-A2 genes. BS + = blue, BS − = gray/white; gray sclera is shown by dashed lines
See this image and copyright information in PMC

References

    1. Forlino A, Marini JC. Osteogenesis imperfecta. Lancet. 2016;387:1657–71. doi: 10.1016/S0140-6736(15)00728-X. - DOI - PMC - PubMed
    1. Steiner RD, Adsit J, Basel D. COL1A1/2-related osteogenesis imperfecta. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, et al., editors. GeneReviews®[Internet]. Seattle (WA): University of Washington; 2005. p. 1993–2019 [updated 14 February 2013].
    1. Van Dijk FS, Sillence DO. Osteogenesis imperfecta: clinical diagnosis, nomenclature and severity assessment. Am J Med Genet A. 2014;164A:1470–81. doi: 10.1002/ajmg.a.36545. - DOI - PMC - PubMed
    1. Sillence DO, Senn A, Danks DM. Genetic heterogeneity in osteogenesis imperfecta. J Med Genet. 1979;16:101–16. doi: 10.1136/jmg.16.2.101. - DOI - PMC - PubMed
    1. Gentile FV, Zuntini M, Parra A, Battistelli L, Pandolfi M, Pals G, et al. Validation of a quantitative PCR-high-resolution melting protocol for simultaneous screening of COL1A1 and COL1A2 point mutations and large rearrangements: application for diagnosis of osteogenesis imperfecta. Hum Mutat. 2012;33:1697–707. doi: 10.1002/humu.22146. - DOI - PubMed

Publication types