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    Molecular spectrum and differential diagnosis in patients referred with sporadic or autosomal recessive osteogenesis imperfecta

    265925.pdf (125.6Kb)
    Access Status
    Open access
    Authors
    Caparrós-Martín, Jose
    Aglan, M.
    Temtamy, S.
    Otaify, G.
    Valencia, M.
    Nevado, J.
    Vallespin, E.
    Del Pozo, A.
    Prior de Castro, C.
    Calatrava-Ferreras, L.
    Gutierrez, P.
    Bueno, A.
    Sagastizabal, B.
    Guillen-Navarro, E.
    Ballesta-Martinez, M.
    Gonzalez, V.
    Basaran, S.
    Buyukoglan, R.
    Sarikepe, B.
    Espinoza-Valdez, C.
    Cammarata-Scalisi, F.
    Martinez-Glez, V.
    Heath, K.
    Lapunzina, P.
    Ruiz-Perez, V.
    Date
    2017
    Type
    Journal Article
    
    Metadata
    Show full item record
    Citation
    Caparrós-Martín, J. and Aglan, M. and Temtamy, S. and Otaify, G. and Valencia, M. and Nevado, J. and Vallespin, E. et al. 2017. Molecular spectrum and differential diagnosis in patients referred with sporadic or autosomal recessive osteogenesis imperfecta. Molecular Genetics And Genomic Medicine. 5 (1): pp. 28-39.
    Source Title
    Molecular Genetics And Genomic Medicine
    DOI
    10.1002/mgg3.257
    ISSN
    2324-9269
    School
    School of Pharmacy and Biomedical Sciences
    URI
    http://hdl.handle.net/20.500.11937/67904
    Collection
    • Curtin Research Publications
    Abstract

    Background: Osteogenesis imperfecta (OI) is a heterogeneous bone disorder characterized by recurrent fractures. Although most cases of OI have heterozygous mutations in COL1A1 or COL1A2 and show autosomal dominant inheritance, during the last years there has been an explosion in the number of genes responsible for both recessive and dominant forms of this condition. Herein, we have analyzed a cohort of patients with OI, all offspring of unaffected parents, to determine the spectrum of variants accounting for these cases. Twenty patients had nonrelated parents and were sporadic, and 21 were born to consanguineous relationships. Methods: Mutation analysis was performed using a next-generation sequencing gene panel, homozygosity mapping, and whole exome sequencing (WES). Results: Patients offspring of nonconsanguineous parents were mostly identified with COL1A1 or COL1A2 heterozygous changes, although there were also a few cases with IFITM5 and WNT1 heterozygous mutations. Only one sporadic patient was a compound heterozygote for two recessive mutations. Patients offspring of consanguineous parents showed homozygous changes in a variety of genes including CRTAP, FKBP10, LEPRE1, PLOD2, PPIB, SERPINF1, TMEM38B, and WNT1. In addition, two patients born to consanguineous parents were found to have de novo COL1A1 heterozygous mutations demonstrating that causative variants in the collagen I structural genes cannot be overlooked in affected children from consanguineous couples. Further to this, WES analysis in probands lacking mutations in OI genes revealed deleterious variants in SCN9A, NTRK1, and SLC2A2, which are associated with congenital indifference to pain (CIP) and Fanconi–Bickel syndrome (FBS). Conclusion: This work provides useful information for clinical and genetic diagnosis of OI patients with no positive family history of this disease. Our data also indicate that CIP and FBS are conditions to be considered in the differential diagnosis of OI and suggest a positive role of SCN9A and NTRK1 in bone development.

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