Abstract
Cleidocranial dysplasia (CCD) is mainly attributable to a variant of runt-related transcription factor 2 (RUNX2) on chromosome 6p21. CCD is an autosomal dominant skeletal disorder characterized by open/delayed closure of fontanels, clavicular hypoplasia, retention of deciduous teeth, and supernumerary permanent teeth. The aim of this study was to investigate potentially pathogenic mutations in 2 Chinese families. Genomic DNA was obtained from peripheral blood lymphocytes, and whole exome sequencing and Sanger sequencing were performed to detect gene variants. Real-time quantitative PCR was performed to determine the mRNA expression level of RUNX2 in the proband of family 1. Silico algorithms and conservation analyses were used to evaluate the functional impact. We identified a novel initiation codon mutation (c.2T>C) and a previously reported mutation (c.569G>A). Familial co-segregation verified an autosomal-dominant inheritance pattern. Our findings demonstrated that the novel mutation c.2T>C causes CCD. Quantitative real-time PCR suggested that downregulated RUNX2 levels and haploinsufficiency in RUNX2 lead to CCD. These results extend the spectrum of RUNX2 mutations in CCD patients and can be used for genetic consultation and prenatal diagnosis.