Identification of a novel RUNX2 gene mutation in an Italian family with cleidocranial dysplasia

Cleidocranial dysplasia (CCD) is a rare, well-defined skeletal disorder with autosomal dominant inheritance and complete penetrance. Although it involves the whole skeletal system, the main clinical manifestations of CCD are malformations of the skull and clavicles, which lead to a typical appearance of the face and shoulders. Dental aspects are particularly evident and often eruption difficulties are the first indication for the patient, who does not present any other problem. It has been established that insufficiency of the RUNX-related transcription factor, the core-binding factor alpha 1 (CBFA1) protein, causes CCD. This protein is essential in skeletal development by regulating osteoblast differentiation and chondrocyte maturation. CBFA1 protein is encoded by the RUNX2 gene located on chromosome 6p21. The molecular characterization of the novel RUNX2 gene mutation c.580 + 1G > A in an Italian family (a 27-year-old female, her 54-year-old mother and 24-year-old sister) affected by the typical CCD phenotype, which was proven to alter splicing of the RUNX2 messenger RNA, underscoring the contribution of novel altered splicing mechanism to the aetiology of this disease is presented.