Prevalence of dentinogenesis imperfecta and dental aberrations related to genetic findings in osteogenesis imperfecta

Sammanfattning: Osteogenesis imperfecta (OI) is a clinically and genetically heterogeneous connective tissue disorder, mainly caused by mutations in COL1A1 and COL1A2, the genes encoding collagen type I. The cardinal symptoms include bone fragility and varying degrees of growth retardation. Dental and craniofacial manifestations, with dentinogenesis imperfecta (DGI) being the major one, are common findings in OI. DGI exists in two forms, DGI type I – a collagenous manifestation associated with OI, and DGI type II – a non-collagenous disease caused by mutations in the DSPP gene. Clinically and radiographically the discrimination between the two is challenging. Study I of this thesis had two aims, to: (i) investigate the prevalence and incidence of DGI type II among Swedish children and adolescents and (ii) identify undiagnosed cases of DGI type I. We invited all specialist pediatric dental clinics (n=47) in Sweden to participate in the study. Pediatric dentists interviewed and examined patients regarding medical and dental aspects known to be associated with OI. The prevalence of DGI type II was estimated to be 0.0022% (95% CI: 0.00160.0029%) or 2.2 in 100,000 individuals. Clinical and radiographic findings raised a suspicion of undiagnosed OI in one individual, who was later diagnosed with OI type IV. Study II was a cohort study comprising 128 unrelated individuals with OI. Panoramic radiographs were analyzed regarding DGI, and congenitally missing teeth. Collagen I genes were Sanger sequenced in all individuals. Tooth agenesis was diagnosed in 17% (hypodontia 11%, oligodontia 6%) and was more frequent in those with DGI (p=0.016) and in those with OI type III, 47%, compared to those with OI types I, 12% (p=0.003) and IV, 13% (p=0.017). Seventy-five percent of the individuals with oligodontia harbored a mutation predicted to cause a qualitatively changed protein, but there was no association with type of OI, gender, or presence of DGI. Study III investigated the association between collagen I mutations and DGI, taurodontism, and retention of permanent second molars in a retrospective cohort of 152 unrelated children and adolescents with OI. DGI was diagnosed clinically and radiographically in 29% of the individuals (44/152) and through isolated histological findings in another 19% (29/152). In the individuals with a COL1A1 mutation, 70% (7/10) of those with a glycine substitution located C-terminal of p.Gly305 exhibited DGI in both dentitions while no individual (0/7) with a mutation N-terminal of this point exhibited DGI in either dentition (p=0.01). In the individuals with a COL1A2 mutation, 80% (8/10) of those with a glycine substitution located C-terminal of p.Gly211 exhibited DGI in both dentitions while no individual (0/5) with a mutation N-terminal of this point (p=0.007) exhibited DGI in either dentition. DGI was restricted to the deciduous dentition in 20 individuals. Taurodontism occurred in 18% of the lower permanent first molars and retention of permanent second molars in 31% of the adolescents. Study IV comprised 11 individuals with OI and hypodontia/oligodontia who were clinically examined and further genetically investigated with whole-genome sequencing. We detected a novel homozygous nonsense variant in CREB3L1, p.Tyr428', c.1284C>A in one boy previously diagnosed with OI type III. COL1A1 and COL1A2 were the only two genes with variants that could be detected in all individuals. However, we found rare variants of unknown significance in several other genes related to tooth development. Among those, a missense variant in AXIN2, segregating with tooth agenesis in an autosomal dominant manner in the family of a boy with OI type IV and oligodontia. Conclusions This thesis found that the prevalence of DGI type II in Sweden was significantly lower than previously reported, and points to the importance of excluding OI in children with DGI. Tooth agenesis is common in OI, and OI caused by a collagen I mutation predicted to induce a qualitatively changed protein is associated with oligodontia. Additive effects from other modifying or interacting genes may contribute to the severity of the expressed phenotype. Dental aberrations are more common in individuals with a qualitatively changed collagen type I. The varying expressivity of DGI is related to the location of the collagen I mutation.