Genotype-phenotype correlation study in 364 osteogenesis imperfecta Italian patients

Margherita Maioli, Maria Gnoli, Manila Boarini, Morena Tremosini, Anna Zambrano, Elena Pedrini, Marina Mordenti, Serena Corsini, Patrizia D'Eufemia, Paolo Versacci, Mauro Celli, Luca Sangiorgi, Margherita Maioli, Maria Gnoli, Manila Boarini, Morena Tremosini, Anna Zambrano, Elena Pedrini, Marina Mordenti, Serena Corsini, Patrizia D'Eufemia, Paolo Versacci, Mauro Celli, Luca Sangiorgi

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.

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

References

    1. Forlino A, Marini JC. Osteogenesis imperfecta. Lancet. 2016;387:1657–71. doi: 10.1016/S0140-6736(15)00728-X.
    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.
    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.
    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.
    1. Van Dijk FS, Byers PH, Dalgleish R, Malfait F, Maugeri A, Rohrbach M, et al. EMQN best practice guidelines for the laboratory diagnosis of Osteogenesis Imperfecta. Eur J Hum Genet. 2012;20:11–9. doi: 10.1038/ejhg.2011.141.
    1. Dalgleish R . Accessed 13 September 2017.
    1. Marini JC, Forlino A, Cabral WA, Barnes AM, San Antonio JD, Milgrom S, et al. Consortium of osteogenesis imperfecta mutations in the helical domain of type I collagen: regions rich in lethal mutations align with collagen binding sites for integrins and proteoglicans. Hum Mutat. 2007;28:209–21. doi: 10.1002/humu.20429.
    1. Rauch F, Lalic L, Roughley P, Glorieux FH. Genotype-phenotype correlations in nonlethal osteogenesis imperfecta caused by mutations in the helical domain of collagen type I. Eur J Hum Genet. 2010;18:642–7. doi: 10.1038/ejhg.2009.242.
    1. Ben Amor IM, Glorieux FH, Rauch F. Genotype-phenotype correlations in autosomal dominant osteogenesis imperfecta. J Osteoporos. 2011;2011:540178.
    1. Lin HY, Chuang CK, Su YN, Chen MR, Chiu HC, Niu DM, et al. Genotype and phenotype analysis of Taiwanese patients with osteogenesis imperfecta. Orphanet J Rare Dis. 2015;10:152. doi: 10.1186/s13023-015-0370-2.
    1. Lindahl K, Åström E, Rubin CJ, Grigelioniene G, Malmgren B, Ljunggren Ouml, et al. Genetic epidemiology, prevalence, and genotype-phenotype correlations in the Swedish population with osteogenesis imperfecta. Eur J Hum Genet. 2015;23:1042–50. doi: 10.1038/ejhg.2015.81.
    1. Sangiorgi Luca, Mordenti Marina. TELe-Health. Cham: Springer International Publishing; 2017. Disease Registry: A Tool for European Cross-Border Medicine; pp. 141–152.
    1. Allanson JE, Cunniff C, Hoyme HE, McGaughran J, Muenke M, Neri G. Elements of morphology: standard terminology for the head and face. Am J Med Genet A. 2009;149A:6–28. doi: 10.1002/ajmg.a.32612.
    1. Zoghbi WA, Enriquez-Sarano M, Foster E, Grayburn PA, Kraft CD, Levine RA, et al. Recommendations for evaluation of the severity of native valvular regurgitation with two-dimensional and Doppler echocardiography. J Am Soc Echocardiogr. 2003;16:777–802. doi: 10.1016/S0894-7317(03)00335-3.
    1. Dwan K, Phillipi CA, Steiner RD, Basel D. Bisphosphonate therapy for osteogenesis imperfecta. Cochrane Database Syst Rev. 2016;10:CD005088.
    1. Nagy E, Maquat LE. A rule for termination-codon position within intron-containing genes: when nonsense affects RNA abundance. Trends Biochem Sci. 1998;23:198–9. doi: 10.1016/S0968-0004(98)01208-0.
    1. Symoens S, Hulmes DJ, Bourhis JM, Coucke PJ, De Paepe A, Malfait F. Type I procollagen C-propeptide defects: study of genotype-phenotype correlation and predictive role of crystal structure. Hum Mutat. 2014;35:1330–41.
    1. Malfait F, Symoens S, Goemans N, Gyftodimou Y, Holmberg E, López-González V, et al. Helical mutations in type I collagen that affect the processing of the amino-propeptide result in an Osteogenesis Imperfecta/Ehlers-Danlos Syndrome overlap syndrome. Orphanet J Rare Dis. 2013;8:78. doi: 10.1186/1750-1172-8-78.
    1. Lee KS, Song HR, Cho TJ, Kim HJ, Lee TM, Jin HS, et al. Mutational spectrum of type I collagen genes in Korean patients with osteogenesis imperfecta. Hum Mutat. 2006;27:599. doi: 10.1002/humu.9423.
    1. Zhang ZL, Zhang H, Ke YH, Yue H, Xiao WJ, Yu JB, et al. The identification of novel mutations in COL1A1, COL1A2, and LEPRE1 genes in Chinese patients with osteogenesis imperfecta. J Bone Miner Metab. 2012;30:69–77. doi: 10.1007/s00774-011-0284-6.
    1. Venturi G, Tedeschi E, Mottes M, Valli M, Camilot M, Viglio S, et al. Osteogenesis imperfecta: clinical, biochemical and molecular findings. Clin Genet. 2006;70:131–9. doi: 10.1111/j.1399-0004.2006.00646.x.
    1. Prockop DJ, Constantinou CD, Dombrowski KE, Hojima Y, Kadler KE, Kuivaniemi H, et al. Type I procollagen: the gene-protein system that harbors most of the mutations causing osteogenesis imperfecta and probably more common heritable disorders of connective tissue. Am J Med Genet. 1989;34:60–7. doi: 10.1002/ajmg.1320340112.
    1. Fang Y, Bateman JF, Mercer JF, Lamandé SR. Nonsense-mediated mRNA decay of collagen -emerging complexity in RNA surveillance mechanisms. J Cell Sci. 2013;126(Pt 12):551–60.
    1. Lund AM, Müller J, Skovby F. Anthropometry of patients with osteogenesis imperfecta. Arch Dis Child. 1999;80:524–8. doi: 10.1136/adc.80.6.524.
    1. Kovero O, Pynnönen S, Kuurila-Svahn K, Kaitila I, Waltimo-Sirén J. Skull base abnormalities in osteogenesis imperfecta: a cephalometric evaluation of 54 patients and 108 control volunteers. J Neurosurg. 2006;105:361–70. doi: 10.3171/jns.2006.105.3.361.
    1. Semler O, Cheung MS, Glorieux FH, Rauch F. Wormian bones in osteogenesis imperfecta: Correlation to clinical findings and genotype. Am J Med Genet A. 2010;152A:1681–7. doi: 10.1002/ajmg.a.33448.
    1. Lund AM, Jensen BL, Nielsen LA, Skovby F. Dental manifestations of osteogenesis imperfecta and abnormalities of collagen I metabolism. J Craniofac Gen Dev Biol. 1998;18:30–7.
    1. Andersson K, Dahllöf G, Lindahl K, Kindmark A, Grigelioniene G, Åström E, et al. Mutations in COL1A1 and COL1A2 and dental aberrations in children and adolescents with osteogenesis imperfecta - a retrospective cohort study. PLoS ONE. 2017;12:e0176466. doi: 10.1371/journal.pone.0176466.
    1. Ashournia H, Johansen FT, Folkestad L, Diederichsen AC, Brixen K. Heart disease in patients with osteogenesis imperfecta - a systematic review. Int J Cardiol. 2015;196:149–57. doi: 10.1016/j.ijcard.2015.06.001.
    1. Folkestad L. Mortality and morbidity in patients with osteogenesis imperfecta in Denmark. Dan Med J. 2018;65:pii: B5454.
    1. Migliaccio S, Barbaro G, Fornari R, Di Lorenzo G, Celli M, Lubrano C, et al. Impairment of diastolic function in adult patients affected by osteogenesis imperfecta clinically asymptomatic for cardiac disease: casuality or causality? Int J Cardiol. 2009;131:200–3. doi: 10.1016/j.ijcard.2007.10.051.
    1. Iung B, Vahanian A. Epidemiology of valvular heart disease in the adult. Nat Rev Cardiol. 2011;8:162–72. doi: 10.1038/nrcardio.2010.202.
    1. Chandrasekhar J, Dangas G, Mehran R. Valvular heart disease in women, differential remodeling, and response to new therapies. Curr Treat Options Cardiovasc Med. 2017;19:74. doi: 10.1007/s11936-017-0573-z.
    1. Dolk H, Loane M, Garne E. The prevalence of congenital anomalies in Europe. Adv Exp Med Biol. 2010;686:349–64. doi: 10.1007/978-90-481-9485-8_20.

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