Dose matters: haploinsufficiency in osteogenesis imperfecta

Osteogenesis imperfecta is a common genetic disorder of syndromic bone fragility manifesting in types with variable skeletal and extraskeletal severity. Over the past decades, the deforming types have almost exclusively received all scientific attention, leaving large knowledge gaps about the prevalent osteogenesis imperfecta type 1. However, studies within the past 5 years reveal serious unrecognized aspects of disease burden in this large patient population that contrast with osteogenesis imperfecta type 1's widely adopted classification as mild osteogenesis imperfecta. These patients present distinct clinical and molecular features, necessitating personalized clinical approaches and dedicated research. To our knowledge, this Review addresses this distinct patient group by recognizing the diverse facets of clinical burden, genetic landscape, bone pathophysiology, disease models and emerging treatment options. Owing to their later diagnosis, disease invisibility, increased mobility and uncharted clinical course compared with patients who have other types of osteogenesis imperfecta, these patients and their treating physicians face distinct healthcare and diagnostic challenges. In contrast to other patients with osteogenesis imperfecta with broader genetic causes, they are primarily characterized by molecular uniformity in the form of collagen type I deficiency. The scarcity of animal and cell models has also contributed to the lack of initiatives to explore osteogenesis imperfecta type 1. This Review aims to break this vicious cycle of osteogenesis imperfecta type 1 obscurity by defining knowledge gaps that future investigations of this disease should aim to address.