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Web End = Calcif Tissue Int (2016) 98:7684
DOI 10.1007/s00223-015-0066-6
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Web End = Osteogenesis Imperfecta Type I Caused by COL1A1 Deletions
Ghalib Bardai1 Emmanuelle Lemyre2 Pierre Moffatt1 Telma Palomo1
Francis H. Glorieux1 Joanna Tung3 Leanne Ward3 Frank Rauch1
Received: 21 August 2015 / Accepted: 26 September 2015 / Published online: 19 October 2015 Springer Science+Business Media New York 2015
Abstract Osteogenesis imperfecta (OI) type I is usually caused by COL1A1 stop or frameshift mutations, leading to COL1A1 haploinsufciency. Here we report on 12 individuals from 5 families who had OI type I due to an unusual causeheterozygous deletions of the entire COL1A1 gene. The deletions were initially detected by semiconductor-based sequencing of genomic DNA and conrmed 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 to2.23 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 haploinsufciency 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 haploinsufciency, 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.
Keywords Copy number variation Deletion
Osteogenesis imperfecta Sequencing
Introduction
Osteogenesis imperfecta (OI) is a heritable connective tissue disorder that is typically characterized by bone fractures, tooth abnormalities (dentinogenesis imperfecta), and blue or gray sclera. It is usually transmitted in an autosomal dominant fashion but recessive OI also occurs [1]. Mutations in at least 12 different genes are known to cause OI,...