Osteoporosis International

, Volume 28, Issue 7, pp 2095–2101 | Cite as

Molecular diagnosis in children with fractures but no extraskeletal signs of osteogenesis imperfecta

  • G. Bardai
  • L. M. Ward
  • P. Trejo
  • P. Moffatt
  • F. H. Glorieux
  • F. RauchEmail author
Original Article



In 26 of 94 individuals (28%) below 21 years of age who had a significant fracture history but did not have extraskeletal features of osteogenesis imperfecta (OI), we detected disease-causing mutations in OI-associated genes.


In children who have mild bone fragility but do not have extraskeletal features of OI, it can be difficult to establish a diagnosis on clinical grounds. Here, we assessed the diagnostic yield of genetic testing in this context, by sequencing a panel of genes that are associated with OI.


DNA sequence analysis was performed on 94 individuals below 21 years of age who had a significant fracture history but had white sclera and no signs of dentinogenesis imperfecta.


Disease-causing variants were detected in 28% of individuals and affected 5 different genes. Twelve individuals had mutations in COL1A1 or COL1A2, 8 in LRP5, 4 in BMP1, and 2 in PLS3.


DNA sequence analysis of currently known OI-associated genes identified disease-causing variants in more than a quarter of individuals with a significant fracture history but without extraskeletal manifestations of OI.


Children Fractures Mutations Next-generation sequencing Osteogenesis imperfecta 



FR received salary support from the Chercheur-Boursier Clinicien program of the Fonds de Recherche du Québec—Santé. LMW is supported by the Research Chair program at the University of Ottawa and the Departments of Pediatrics and Surgery, Children’s Hospital of Eastern Ontario. This study was supported by the Shriners of North America.

Web resources

Exome Aggregation Consortium (ExAC) Browser:

Online Mendelian Inheritance in Man (OMIM),

Osteogenesis Imperfecta Variant Database:

UCSC database, version hg19:

Authors’ contributions

GB performed analyses; LMW, PT and FHG contributed patient information; PM and FHG reviewed sequencing data; and FR conceptualized the project, contributed patient information, finalized the report, and accepts responsibility for the integrity of the data analysis. All authors have read and approved of the final version of the manuscript.

Compliance with ethical standards

Ethics statement

The study was approved by the Institutional Review Board of McGill University and the Research Ethics Board at the Children’s Hospital of Eastern Ontario.

Conflicts of interest


Supplementary material

198_2017_4031_MOESM1_ESM.docx (63 kb)
ESM 1 (DOCX 63 kb).


  1. 1.
    Rauch F, Neu C, Manz F, Schoenau E (2001) The development of metaphyseal cortex--implications for distal radius fractures during growth. J Bone Miner Res 16:1547–1555CrossRefPubMedGoogle Scholar
  2. 2.
    Farr JN, Amin S, Melton LJ 3rd, Kirmani S, McCready LK, Atkinson EJ, Muller R, Khosla S (2014) Bone strength and structural deficits in children and adolescents with a distal forearm fracture resulting from mild trauma. J Bone Miner Res 29:590–599CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Ward LM, Konji VN, Ma J (2016) The management of osteoporosis in children. Osteoporos Int 27:2147–2179CrossRefPubMedGoogle Scholar
  4. 4.
    Trejo P, Rauch F (2016) Osteogenesis imperfecta in children and adolescents-new developments in diagnosis and treatment. Osteoporos Int 27:3427–3437CrossRefPubMedGoogle Scholar
  5. 5.
    Forlino A, Marini JC (2016) Osteogenesis imperfecta. Lancet 387:1657–1671CrossRefPubMedGoogle Scholar
  6. 6.
    Bardai G, Moffatt P, Glorieux FH, Rauch F (2016) DNA sequence analysis in 598 individuals with a clinical diagnosis of osteogenesis imperfecta: diagnostic yield and mutation spectrum. Osteoporos Int 27:3607–3613CrossRefPubMedGoogle Scholar
  7. 7.
    Rauch F, Lalic L, Roughley P, Glorieux FH (2010) Genotype-phenotype correlations in nonlethal osteogenesis imperfecta caused by mutations in the helical domain of collagen type I. Eur J Hum Genet 18:642–647CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Lindahl K, Astrom E, Rubin CJ, Grigelioniene G, Malmgren B, Ljunggren O, Kindmark A (2015) Genetic epidemiology, prevalence, and genotype-phenotype correlations in the Swedish population with osteogenesis imperfecta. Eur J Hum Genet 23:1042–1050CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Rauch F, Plotkin H, Dimeglio L, Engelbert RH, Henderson RC, Munns C, Wenkert D, Zeitler P (2008) Fracture prediction and the definition of osteoporosis in children and adolescents: the ISCD 2007 pediatric official positions. J Clin Densitom 11:22–28CrossRefPubMedGoogle Scholar
  10. 10.
    Rauch F, Glorieux FH (2004) Osteogenesis imperfecta. Lancet 363:1377–1385CrossRefPubMedGoogle Scholar
  11. 11.
    Ogden CL, Kuczmarski RJ, Flegal KM, Mei Z, Guo S, Wei R, Grummer-Strawn LM, Curtin LR, Roche AF, Johnson CL (2002) Centers for Disease Control and Prevention 2000 growth charts for the United States: improvements to the 1977 National Center for Health Statistics version. Pediatrics 109:45–60CrossRefPubMedGoogle Scholar
  12. 12.
    Kalkwarf HJ, Zemel BS, Yolton K, Heubi JE (2013) Bone mineral content and density of the lumbar spine of infants and toddlers: influence of age, sex, race, growth, and human milk feeding. J Bone Miner Res 28:206–212CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Zemel BS, Kalkwarf HJ, Gilsanz V et al (2011) Revised reference curves for bone mineral content and areal bone mineral density according to age and sex for black and non-black children: results of the bone mineral density in childhood study. J Clin Endocrinol Metab 96:3160–3169CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Kumar P, Henikoff S, Ng PC (2009) Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc 4:1073–1081CrossRefPubMedGoogle Scholar
  15. 15.
    Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR (2010) A method and server for predicting damaging missense mutations. Nat Methods 7:248–249CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Pollard KS, Hubisz MJ, Rosenbloom KR, Siepel A (2010) Detection of nonneutral substitution rates on mammalian phylogenies. Genome Res 20:110–121CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Lek M, Karczewski KJ, Minikel EV et al (2016) Analysis of protein-coding genetic variation in 60,706 humans. Nature 536:285–291CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Richards S, Aziz N, Bale S et al (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17:405–424CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Fahiminiya S, Al-Jallad H, Majewski J, Palomo T, Moffatt P, Roschger P, Klaushofer K, Glorieux FH, Rauch F (2015) A polyadenylation site variant causes transcript-specific BMP1 deficiency and frequent fractures in children. Hum Mol Genet 24:516–524CrossRefPubMedGoogle Scholar
  20. 20.
    Fahiminiya S, Majewski J, Al-Jallad H, Moffatt P, Mort J, Glorieux FH, Roschger P, Klaushofer K, Rauch F (2014) Osteoporosis caused by mutations in PLS3: clinical and bone tissue characteristics. J Bone Miner Res 29:1805–1814CrossRefPubMedGoogle Scholar
  21. 21.
    Korvala J, Juppner H, Makitie O et al (2012) Mutations in LRP5 cause primary osteoporosis without features of OI by reducing Wnt signaling activity. BMC Med Genet 13:26CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Dawson PA, Kelly TE, Marini JC (1999) Extension of phenotype associated with structural mutations in type I collagen: siblings with juvenile osteoporosis have an alpha2(I)Gly436 --> Arg substitution. J Bone Miner Res 14:449–455CrossRefPubMedGoogle Scholar
  23. 23.
    Baron R, Kneissel M (2013) WNT signaling in bone homeostasis and disease: from human mutations to treatments. Nat Med 19:179–192CrossRefPubMedGoogle Scholar
  24. 24.
    Scotti MM, Swanson MS (2016) RNA mis-splicing in disease. Nat Rev Genet 17:19–32CrossRefPubMedGoogle Scholar
  25. 25.
    Ben Amor IM, Roughley P, Glorieux FH, Rauch F (2013) Skeletal clinical characteristics of osteogenesis imperfecta caused by haploinsufficiency mutations in COL1A1. J Bone Miner Res 28:2001–2007CrossRefPubMedGoogle Scholar
  26. 26.
    Rauch F, Travers R, Parfitt AM, Glorieux FH (2000) Static and dynamic bone histomorphometry in children with osteogenesis imperfecta. Bone 26:581–589CrossRefPubMedGoogle Scholar
  27. 27.
    Brunetti G, Papadia F, Tummolo A et al (2016) Impaired bone remodeling in children with osteogenesis imperfecta treated and untreated with bisphosphonates: the role of DKK1, RANKL, and TNF-alpha. Osteoporos Int 27:2355–2365CrossRefPubMedGoogle Scholar
  28. 28.
    Hendrickx G, Boudin E, Van Hul W (2015) A look behind the scenes: the risk and pathogenesis of primary osteoporosis. Nat Rev Rheumatol 11:462–474CrossRefPubMedGoogle Scholar
  29. 29.
    Rivadeneira F, Makitie O (2016) Osteoporosis and bone mass disorders: from gene pathways to treatments. Trends Endocrinol Metab 27:262–281CrossRefPubMedGoogle Scholar
  30. 30.
    Hartikka H, Makitie O, Mannikko M, Doria AS, Daneman A, Cole WG, Ala-Kokko L, Sochett EB (2005) Heterozygous mutations in the LDL receptor-related protein 5 (LRP5) gene are associated with primary osteoporosis in children. J Bone Miner Res 20:783–789CrossRefPubMedGoogle Scholar
  31. 31.
    Joiner DM, Ke J, Zhong Z, Xu HE, Williams BO (2013) LRP5 and LRP6 in development and disease. Trends Endocrinol Metab 24:31–39CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Mao W, Wordinger RJ, Clark AF (2011) Functional analysis of disease-associated polymorphism LRP5.Q89R. Mol Vis 17:894–902PubMedPubMedCentralGoogle Scholar
  33. 33.
    Saarinen A, Mayranpaa MK, Lehesjoki AE, Makitie O (2010) Low-density lipoprotein receptor-related protein 5 (LRP5) variation in fracture prone children. Bone 46:940–945CrossRefPubMedGoogle Scholar
  34. 34.
    Franceschi R, Vincenzi M, Camilot M, Antoniazzi F, Freemont AJ, Adams JE, Laine C, Makitie O, Mughal MZ (2015) Idiopathic juvenile osteoporosis: clinical experience from a single centre and screening of LRP5 and LRP6 genes. Calcif Tissue Int 96:575–579CrossRefPubMedGoogle Scholar

Copyright information

© International Osteoporosis Foundation and National Osteoporosis Foundation 2017

Authors and Affiliations

  • G. Bardai
    • 1
  • L. M. Ward
    • 2
  • P. Trejo
    • 1
  • P. Moffatt
    • 1
  • F. H. Glorieux
    • 1
  • F. Rauch
    • 1
    Email author
  1. 1.Shriners Hospital for Children and McGill UniversityMontrealCanada
  2. 2.Children’s Hospital of Eastern OntarioOntarioCanada

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