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Identification of RUNX2 variants associated with cleidocranial dysplasia.

ABSTRACT: Background:Cleidocranial dysplasia (CCD) is a rare autosomal dominant disorder mainly characterized by hypoplastic or absent clavicles, delayed closure of the fontanelles, multiple dental abnormalities, and short stature. Runt-related transcription factor 2 (RUNX2) gene variants can cause CCD, but are not identified in all CCD patients. Methods:In this study, we detected genetic variants in seven unrelated children with CCD by targeted high-throughput DNA sequencing or Sanger sequencing. Results:All patients carried a RUNX2 variant, totally including three novel pathogenic variants (c.722_725delTGTT, p.Leu241Serfs*8; c.231_232delTG, Ala78Glyfs*82; c.909C?>?G, p.Tyr303*), three reported pathogenic variants (c.577C?>?T, p.Arg193*; c.574G?>?A, p.Gly192Arg; c.673 C?>?T, p.Arg225Trp), one likely pathogenic variant (c.668G?>?T, p.Gly223Val). The analysis of the variant source showed that all variants were de novo except the two variants (c.909C?>?G, p.Tyr303*; c.668G?>?T, p.Gly223Val) inherited from the patient's father and mother with CCD respectively. Further bioinformatics analysis indicated that these variants could influence the structure of RUNX2 protein by changing the number of H-bonds or amino acids. The experimental result showed that the Gly223Val mutation made RUNX2 protein unable to quantitatively accumulate in the nucleus. Conclusions:The present study expands the pathogenic variant spectrum of RUNX2 gene, which will contribute to the diagnosis of CCD and better genetic counseling in the future.

SUBMITTER: Gao X

PROVIDER: S-EPMC6747736 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Identification of <i>RUNX2</i> variants associated with cleidocranial dysplasia.

Gao Xueren X Li Kunxia K Fan Yanjie Y Sun Yu Y Luo Xiaomei X Wang Lili L Liu Huili H Gong Zhuwen Z Wang Jianguo J Wang Yu Y Gu Xuefan X Yu Yongguo Y

Hereditas 20190916

<h4>Background</h4>Cleidocranial dysplasia (CCD) is a rare autosomal dominant disorder mainly characterized by hypoplastic or absent clavicles, delayed closure of the fontanelles, multiple dental abnormalities, and short stature. Runt-related transcription factor 2 (<i>RUNX2</i>) gene variants can cause CCD, but are not identified in all CCD patients.<h4>Methods</h4>In this study, we detected genetic variants in seven unrelated children with CCD by targeted high-throughput DNA sequencing or Sang ...[more]

PMID: 31548836

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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

Identification of RUNX2 variants associated with cleidocranial dysplasia.

Publications

Identification of <i>RUNX2</i> variants associated with cleidocranial dysplasia.

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