Abstract
BackgroundCleidocranial 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.MethodsIn this study, we detected genetic variants in seven unrelated children with CCD by targeted high-throughput DNA sequencing or Sanger sequencing.ResultsAll 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.ConclusionsThe 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.
Highlights
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
The Runt-related transcription factor 2 (RUNX2) gene is located on chromosome 6p21.1 and encodes a transcription factor with a highly conserved Runt domain [4, 5]
Genomic DNA extraction and genetic testing A total of seven unrelated children with CCD ranging in age from 1 month to 12 years were enrolled for genetic evaluation (Table 1)
Summary
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. Cleidocranial dysplasia (CCD; OMIM #119600) is a rare autosomal dominant disorder mainly characterised by hypoplastic or absent clavicles, delayed closure of fontanelles, multiple dental abnormalities, and short stature [1,2,3]. DNA motif (TGT/CGGT sequence) in the promoter region of its target genes and heterodimerization with CBFB (core-binding factor subunit beta) [6,7,8]. The former participates in regulating the transcription of multiple genes. The last five amino acids (VWRPY) of RUNX2 protein compose a conserved motif in all runt proteins, and functions as a transcriptional repression domain [9, 11]
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