Abstract
Osteogenesis imperfecta (OI) type I is usually caused by COL1A1 stop or frameshift mutations, leading to COL1A1 haploinsufficiency. Here we report on 12 individuals from 5 families who had OI type I due to an unusual cause—heterozygous deletions of the entire COL1A1 gene. The deletions were initially detected by semiconductor-based sequencing of genomic DNA and confirmed by quantitative PCR. Array comparative genomic hybridization in DNA of the index patient in each family showed that deletion size varied from 18.5 kb to 2.23 Mb between families, encompassing between 1 and 47 genes (COL1A1 included). The skeletal phenotype of the affected individuals was similar to that of patients with haploinsufficiency caused by COL1A1 stop or frameshift mutations. However, one individual with a deletion that included also DLX3 and DLX4 had tooth discoloration and bone fragility. Three individuals from 2 families had deletions that included also CACNA1G, and these individuals had learning disabilities. These features are not usually observed in COL1A1 haploinsufficiency, but are in accordance with previously described individuals in whom deletions included the same genes. In summary, we found deletions of COL1A1 in 5 out of 161 families (3 %) with OI type I that were evaluated. Deletions encompassing not only COL1A1 but also neighboring genes can lead to contiguous gene syndromes that may include dental involvement and learning disability.
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Acknowledgments
We thank Mark Lepik for preparation of the figures. FR received support from the Chercheur-Boursier Clinicien program of the Fonds de recherche du Québec—Santé. This study was supported by the Shriners of North America and the Fonds de recherche du Québec—Santé.
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Frank Rauch received support from the Chercheur-Boursier Clinicien program of the Fonds de Recherche du Québec—Santé and has received consultancy fees from Genzyme Inc and Alexion Inc. Francis H Glorieux has received consultancy fees from Novartis Inc, Amgen Inc, and Alexion Inc. Ghalib Bardai, Emmanuelle Lemyre, Pierre Moffatt, Telma Palomo, Joanna Tung, and Leanne Ward declare no conflict of interest.
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All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from study participants or the legal guardians.
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Bardai, G., Lemyre, E., Moffatt, P. et al. Osteogenesis Imperfecta Type I Caused by COL1A1 Deletions. Calcif Tissue Int 98, 76–84 (2016). https://doi.org/10.1007/s00223-015-0066-6
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DOI: https://doi.org/10.1007/s00223-015-0066-6