A novel intragenic microdeletion in RUNX2 in a Chinese family with cleidocranial dysplasia

Objective: Cleidocranial dysplasia (CCD) is a rare autosomal dominant skeletal dysplasia which is characterized by cranial, clavicular, and dental anomalies. Aberrations in the RUNX2 gene, which is considered to be responsible for CCD, were investigated in a Chinese family with CCD in this study. Methods: Genomic DNA was isolated from the blood samples of all 11 participants, including 3 patients in this family. Mutation analysis of RUNX2 was performed using amplified polymerase chain reaction and direct sequencing. To determine the copy number of the exon of RUNX2, real-time quantitative PCR was performed for all 3 patients and the 8 unaffected individuals. Results: A previously reported SNP (rs6921145) was found, but no causative mutation was detected in the coding regions of RUNX2 by direct sequencing analysis. Real-time quantitative PCR revealed a novel exon 4 to exon 7 intragenic deletion in RUNX2 in all 3 affected family members. Conclusions: Our findings suggest that the intragenic deletion from exon 4 to exon 7 in the RUNX2 gene is the cause of CCD in this family and most likely causes CCD by altering the protein structure of RUNX2, which then fails to regulate the transcription of RUNX2-regulated genes. We therefore highlight the importance of considering deletions and duplications in patients without a causative mutation identified by DNA sequencing.