Molecular Genetics of Cleidocranial Dysplasia.

BACKGROUND: Cleidocranial dysplasia (CCD) is a genetic disorder with an autosomal dominant inheritance pattern. CCD characterized by abnormal clavicles, patent sutures and fontenelles, supernumerary teeth and short stature. Approximately 60-70% of CCD patients have mutations in the RUNX2 gene. The RUNX2 gene is an essential transcription factor for chondrocyte maturation, osteoblast differentiation and bone formation. Runx2 regulates mesenchymal cell proliferation in sutures and suture closure by inducing the signaling pathways of the genes of Fgf, Pthlh, hedgehog and Wnt. Material and Methods: We summarized molecular genetics aspects of CCD. Result: Approximately 94% of CCD patients have dental anomalies, the most common of which are supernumerary tooth. Dental anomalies are not determined solely by gene mutations of RUNX2, but are also affected by modifier genes, environmental factors, epigenetic factors and copy number variations. Conclusion: a definite diagnosis of CCD should include the patient's clinical history, symptoms and signs, as well as genetic analyses.

Identification of a Novel Splice Site Mutation in RUNX2 Gene in a Family with Rare Autosomal Dominant Cleidocranial Dysplasia.

Background: Pathogenic variants of RUNX2, a gene that encodes an osteoblast-specific transcription factor, have been shown as the cause of Cleidocranial dysplasia (CCD), which is a rare hereditary skeletal and dental disorder with dominant mode of inheritance and a broad range of clinical variability. Due to the relative lack of clinical complications resulting in CCD, the medical diagnosis of this disorder is challenging, which leaves it underdiagnosed. Methods: : In this study, nine healthy and affected members of an Iranian family were investigated. PCR and sequencing of all exons and exon-intron boundaries of runt-related transcription factor 2 (RUNX2; NM_001024630) gene was performed on proband. Co-segregation analysis was conducted in the other family members for the identified variant. Additionally, a cohort of 100 Iranian ethnicity-matched healthy controls was screened by Amplification Refractory Mutation System PCR method. Results: The novel splice site variant (c.860-2A>G), which was identified in the intron 6 of RUNX2 gene, co-segregated with the disease in the family, and it was absent in healthy controls. Pathogenicity of this variant was determined by several software, including , human splicing finder, which predicts the formation or disruption of splice donor sites, splice acceptor sites, exonic splicing silencer sites, and exonic splicing enhancer sites. In silico analysis predicted this novel variant to be disease causing. Conclusion: The identified variant is predicted to have an effect on splicing, which leads to exon skipping and producing a truncated protein via introducing a premature stop codon.