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