Mutations in COL1A1/A2 and CREB3L1 are associated with oligodontia in osteogenesis imperfecta

Abstract

Background: Osteogenesis imperfecta (OI) is a heterogeneous connective tissue disorder characterized by an increased tendency for fractures throughout life. Autosomal dominant (AD) mutations in COL1A1 and COL1A2 are causative in approximately 85% of cases. In recent years, recessive variants in genes involved in collagen processing have been found. Hypodontia (< 6 missing permanent teeth) and oligodontia (≥ 6 missing permanent teeth) have previously been reported in individuals with OI. The aim of the present cross-sectional study was to investigate whether children and adolescents with OI and oligodontia and hypodontia also present with variants in other genes with potential effects on tooth development. The cohort comprised 10 individuals (7.7-19.9 years of age) with known COL1A1/A2 variants who we clinically and radiographically examined and further genetically evaluated by whole-genome sequencing. All study participants were treated at the Astrid Lindgren Children's Hospital at Karolinska University Hospital, Stockholm (Sweden's national multidisciplinary pediatric OI team). We evaluated a panel of genes that were associated with nonsyndromic and syndromic hypodontia or oligodontia as well as that had been found to be involved in tooth development in animal models. Results: We detected a 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 among 9 individuals which carried a pathogenic mutation. We found rare variants with unknown significance in several other genes related to tooth development. Conclusions: Our findings suggest that mutations in COL1A1, COL1A2, and CREB3L1 may cause hypodontia and oligodontia in OI. The findings cannot exclude additive effects from other modifying or interacting genes that may contribute to the severity of the expressed phenotype. Larger cohorts and further functional studies are needed.

Abnormalities in Tooth Formation after Early Bisphosphonate Treatment in Children with Osteogenesis Imperfecta

“…The Malmgren et al [ 4 ] study found hypodontia in 11% and oligodontia in 6% of their patients with OI. In that study, treatment with BPs was not considered; instead, the very high prevalence of hypodontia and oligodontia prompted the group to investigate whether mutations in genes other than those earlier associated with OI ( COL1A1 , COL1A2 , and CREB3L1 ) were responsible for the disturbances [ 27 ]. Except for the known variants, we were unable to identify any other mutual variant related to collagen type I that could explain the phenotype of OI associated with hypodontia/oligodontia.…”

An Unusual Presentation of Osteogenesis Imperfecta

“…It is a missense mutation that is likely benign as predicted by software modeling. Other variants in this gene are associated with OI type III and are believed to be causal agents of the clinical features that are associated with this subtype, including dentinogenesis imperfecta 17,18 .…”

Emerging Landscape of Osteogenesis Imperfecta Pathogenesis and Therapeutic Approaches

“…Hearing loss is a recognized extra-skeletal symptom of OI, most commonly observed in individuals with OI types I through IV. The assumed mechanism involves altered genes related to COL1A1 / COL1A2 , resulting in abnormal inner ear mineralization and otosclerosis . Hearing loss in people with OI is categorized into three types: conductive, sensorineural, and mixed.…”