A Novel 4.2 kb deletion of the 3′UTR of RUNX2 Gene Causes Cleidocranial Dysplasia: Further Delineation of the Role of yhe 3′UTR

Cleidocranial dysplasia is a rare autosomal dominant skeletal dysplasia. We present the first case in the literature involving a deletion of the 3′UTR of RUNX2 gene associated with a cleidocranial dysplasia spectrum disorder, along with the diagnostic odyssey that preceded the establishment of this diagnosis.

We describe a female patient with a classical phenotype of cleidocranial dysplasia, followed by a clinical geneticist since the neonatal period. Whole genome sequencing revealed a suspected deletion encompassing the 3′UTR of RUNX2 gene, initially classified as a variant of uncertain significance. This deletion was subsequently confirmed using a custom-designed qPCR assay and reclassified as likely pathogenic, thus considered causative for the disease. The diagnosis of cleidocranial dysplasia due to RUNX2 gene dysfunction is supported by a clear phenotype–genotype correlation, the de novo origin of the variant, and functional studies underscoring the importance of the 3′UTR for RUNX2 gene function.

Our case report provides new evidence supporting the functional significance of the 3′UTR of RUNX2 gene, whose haploinsufficiency, due to a small novel deletion of 4.2 kb, results in the classical phenotype of cleidocranial dysplasia. As well, our case illustrates that whole genome sequencing is advantageous for detecting copy number variants.