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Novel mutation of RUNX2 gene in a patient with cleidocranial dysplasia.

ABSTRACT: Cleidocranial dysplasia is a rare hereditary skeletal disorder due to heterozygous loss of function mutations in the RUNX2 gene that encodes runt-related transcription factor 2 (RUNX2). Here we report a 52 year-old woman with cleidocranial dysplasia due to a novel RUNX2 mutation.A 52 year-old Han Chinese woman presented with short stature and skeletal dysplasia that was first noted during early childhood. She was 153 cm in height and 40 kg in weight. Her skull was deformed with hypertelorism, midface hypoplasia, protrusion of chin, and dental abnormalities. Radiological examination revealed shortened clavicles and depressed skull bone and that were consistent with the clinical diagnosis of cleidocranial dysplasia. There was no family history of a similar skeletal disorder. We sequenced the RUNX2 gene and discovered a novel heterozygous mutation in exon 3 (c.476 del G, p.G159fs175X) that is predicted to cause a frameshift and premature termination that leads to the loss of the final 347 amino acid residues. This severely truncated protein is expected to be inactive.RUNX2 gene controls osteoblast differentiation and chondrocyte maturation. Around 90 RUNX2 mutations have been discovered in patients with cleidocranial dysplasia.We identified a case of cleidocranial dysplasia due to a novel mutation of RUNX2 gene at exon 3 (c.476 del G).

SUBMITTER: Guo YW

PROVIDER: S-EPMC4348862 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Novel mutation of RUNX2 gene in a patient with cleidocranial dysplasia.

Guo Ya-Wun YW Chiu Chih-Yang CY Liu Chien-Lin CL Jap Tjin-Shing TS Lin Liang-Yu LY

International journal of clinical and experimental pathology 20150101 1

<h4>Background</h4>Cleidocranial dysplasia is a rare hereditary skeletal disorder due to heterozygous loss of function mutations in the RUNX2 gene that encodes runt-related transcription factor 2 (RUNX2). Here we report a 52 year-old woman with cleidocranial dysplasia due to a novel RUNX2 mutation.<h4>Case description</h4>A 52 year-old Han Chinese woman presented with short stature and skeletal dysplasia that was first noted during early childhood. She was 153 cm in height and 40 kg in weight. H ...[more]

PMID: 25755819

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Project description:ObjectivesCleidocranial dysplasia (CCD) is a skeletal disorder affecting cranial sutures, teeth, and clavicles, and is associated with the RUNX2 mutations. Although numerous patients have been described, a direct genotype-phenotype correlation for RUNX2 has been difficult to establish. Further cases must be studied to understand the clinical and genetic spectra of CCD. To characterize detailed phenotypes and identify variants causing CCD in five unrelated patients and their family members.MethodologyClinical and radiographic examinations were performed. Genetic variants were identified by exome and Sanger sequencing, data were analyzed by bioinformatics tools.ResultsThree cases were sporadic and two were familial. Exome sequencing successfully detected the heterozygous pathogenic RUNX2 variants in all affected individuals. Three were novel, comprising a frameshift c.739delA (p.(Ser247Valfs*)) in exon 6 (Patient-1), a nonsense c.901C>T (p.(Gln301*)) in exon 7 (Patient-2 and affected mother), and a nonsense c.1081C>T (p.(Gln361*)) in exon 8 (Patient-3). Two previously reported variants were missense: the c.673C>T (p.(Arg225Trp)) (Patient-4) and c.674G>A (p.(Arg225Gln)) (Patient-5) in exon 5 within the Runt homology domain. Patient-1, Patient-2, and Patient-4 with permanent dentition had thirty, nineteen, and twenty unerupted teeth, respectively; whereas Patient-3 and Patient-5, with deciduous dentition, had normally developed teeth. All patients exhibited typical CCD features, but the following uncommon/unreported phenotypes were observed: left fourth ray brachymetatarsia (Patient-1), normal clavicles (Patient-2 and affected mother), phalangeal malformations (Patient-3), and normal primary dentition (Patient-3, Patient-5).ConclusionsThe study shows that exome sequencing is effective to detect mutation across ethnics. The two p.Arg225 variants confirm that the Runt homology domain is vital for RUNX2 function. Here, we report a new CCD feature, unilateral brachymetatarsia, and three novel truncating variants, expanding the phenotypic and genotypic spectra of RUNX2 , as well as show that the CCD patients can have normal deciduous teeth, but must be monitored for permanent teeth anomalies.

Dataset Information

Novel mutation of RUNX2 gene in a patient with cleidocranial dysplasia.

Publications

Novel mutation of RUNX2 gene in a patient with cleidocranial dysplasia.

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