Abstract
Cleidocranial dysplasia (CCD; MIM 119600) is a rare autosomal dominant disorder characterized by facial, dental, and skeletal malformations. To date, rearrangement and mutations involving RUNX2, which encodes a transcription factor required for osteoblast differentiation on 6p21, has been the only known molecular etiology for CCD. However, only 70% patients were found to have point mutations, 13% large/contiguous deletion but the rest of 17% remains unknown. We ascertained a family consisted of eight affected individuals with CCD phenotypes. Direct sequencing analysis revealed no mutations in the RUNX2. Real time quantitative PCR were performed which revealed an exon 2 to exon 6 intragenic deletion in RUNX2. Our patients not only demonstrated a unique gene change as a novel mechanism for CCD, but also highlight the importance of considering "deletion" and "duplication" in suspected familial cases before extensive effort of gene hunting be carried.
Highlights
Cleidocranial dysplasia (CCD; MIM 119600) is a rare autosomal dominant human skeletal disorder
RUNX2 is one of the three mammalian homologs of the Drosophila runt gene, which encodes a transcription factor required for osteoblast differentiation
The work presented here described the first large intragenic microdeletion: exons 2–6 were deleted in the three generation CCD family
Summary
Cleidocranial dysplasia (CCD; MIM 119600) is a rare autosomal dominant human skeletal disorder. The clinical features of CCD include facial and dental malformations characterized by delayed closure frontanelles, frontal bossing, absent clavicles, short stature, late eruption, and supernumerary permanent teeth and other skeletal anomalies (Mundlos 1999). There is considerable phenotypic variation for CCD, even within families (Chitayat et al 1992). Mutations in the runt-related transcription factor 2 gene (RUNX2, known as CBFA1, PEBP2aA, and AML3) located on chromosome 6p21 (Mundlos et al 1997) have been identified as the cause of CCD. RUNX2 is one of the three mammalian homologs of the Drosophila runt gene, which encodes a transcription factor required for osteoblast differentiation.
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