Structural Variants in COL1A1 and COL1A2 in Osteogenesis Imperfecta

Osteogenesis Imperfecta (OI) is a heterogeneous skeletal dysplasia characterized by bone fragility, skeletal deformities, and short stature. Most commonly, it is caused by autosomal dominant variants in the type I collagen genes, COL1A1 or COL1A2. Type I collagen is the main protein of the extracellular matrix in the skeleton and changes in its structure or quantity may lead to OI. 85%-90% of OI cases occur due to sequence variants in type I collagen genes, while OI caused by structural abnormalities in type I collagen genes is less common. In most cases, haploinsufficiency of type I collagen is associated with a milder OI phenotype. Large genomic deletions often involve several genes within the same chromosomal region, leading to microdeletion syndromes with OI features. Here, we report eight Swedish patients from five unrelated families with OI due to structural variants in the COL1A1 and COL1A2 genes. One patient with OI type III had a complex rearrangement with a deletion and duplication event in COL1A2, leading to reduced COL1A2 expression. Three other patients from two different families with OI type I had whole gene deletions involving COL1A1. In one family, three affected individuals with OI type I had a small intragenic deletion of exons 11-12 in COL1A2. One patient had a 2.1 Mb de novo deletion encompassing COL1A1 and DLX3 genes and features of OI and tricho-dento-osseous syndrome. Overall, this study highlights the importance of investigating gene dosage abnormalities in patients with OI and further delineates clinical and genetic variability of OI caused by structural variants in type I collagen genes.