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. 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. 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.

中文翻译：

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COL1A1/A2 和 CREB3L1 的突变与成骨不全症中的少牙相关。

成骨不全症 (OI) 是一种异质性结缔组织疾病，其特征是终生骨折倾向增加。COL1A1 和 COL1A2 的常染色体显性 (AD) 突变在大约 85% 的病例中是致病原因。近年来，在参与胶原蛋白加工的基因中发现了隐性变异。先前曾在 OI 患者中报告过牙体不足（< 6 颗缺失恒牙）和少牙症（≥ 6 颗恒牙缺失）。本横断面研究的目的是调查患有 OI、少牙和缺牙的儿童和青少年是否也存在其他基因的变异，这些变异对牙齿发育有潜在影响。该队列包括 10 个人 (7.7-19. 9 岁）具有已知的 COL1A1/A2 变体，我们对其进行临床和放射学检查，并通过全基因组测序进一步进行基因评估。所有研究参与者都在斯德哥尔摩卡罗林斯卡大学医院的 Astrid Lindgren 儿童医院（瑞典国家多学科儿科 OI 团队）接受治疗。我们评估了一组与非综合征性和综合征性缺牙或少牙相关的基因，以及在动物模型中发现与牙齿发育有关的基因。我们在一个先前被诊断为 OI 型 III 的男孩中检测到 CREB3L1、p.Tyr428*、c.1284C > A 中的纯合无义变体。COL1A1 和 COL1A2 是 9 个携带致病突变的个体中仅有的两个基因。我们在与牙齿发育相关的其他几个基因中发现了具有未知意义的罕见变异。我们的研究结果表明，COL1A1、COL1A2 和 CREB3L1 的突变可能导致 OI 中的缺牙和少牙。这些发现不能排除其他可能导致表达表型严重程度的修饰或相互作用基因的附加效应。需要更大的队列和进一步的功能研究。