New Genetic Variants of IRUNX2/I in Mexican Families Cause Cleidocranial Dysplasia

Cleidocranial dysplasia is a rare disease, manifested by anomalies in the skull, face, teeth, thorax, clavicle, extremities, and short stature. The disease is caused by mutations in the RUNX2 gene, which is involved in the differentiation of cells that give rise and formation of bones. In this study, the genetic material of four patients and their families was analyzed, with the purpose of identifying changes in the sequence of the RUNX2 gene, finding three new changes and one change already reported in the literature. One patient presented cataract and damage to the retina of the eye, and data were not reported in other patients. A bioinformatic analysis of the RUNX2 protein was carried out with the aim of predicting mechanisms, such as the function, stability, and conformation of the protein, and of trying to understand its relationship with the variable presentation of signs and symptoms in this condition. These results can be useful in the genetic counselling of patients. Cleidocranial dysplasia (CCD) is an autosomal dominant skeletal dysplasia characterized by persistent open skull sutures with bulging calvaria, hypoplasia, or aplasia of clavicles permitting abnormal opposition of the shoulders; wide public symphysis; short middle phalanx of the fifth fingers; and vertebral, craniofacial, and dental anomalies. It is a rare disease, with a prevalence of 1–9/1,000,000, high penetrance, and variable expression. The gene responsible for CCD is the Runt-related transcription factor 2 (RUNX2) gene. We characterize the clinical, genetic, and bioinformatic results of four CCD cases: two cases within Mexican families with six affected members, nine asymptomatic individuals, and two sporadic cases with CCD, with one hundred healthy controls. Genomic DNA analyses of the RUNX2 gene were performed for Sanger sequencing. Bioinformatics tools were used to predict the function, stability, and structural changes of the mutated RUNX2 proteins. Three novel heterozygous mutations (c.651_652delTA; c.538_539delinsCA; c.662T>A) and a previously reported mutation (c.674G>A) were detected. In silico analysis showed that all mutations had functional, stability-related, and structural alterations in the RUNX2 protein. Our results show novel mutations that enrich the pool of RUNX2 gene mutations with CCD. Moreover, the proband 1 presented clinical data not previously reported that could represent an expanded phenotype of severe expression.