CCD_RUNX2
- Gene
- RUNX2
- Disease
- CCD
- Inheritance
- AD
- Classification
- Definitive
- Total Score
- 12
- Publications Reviewed
- 6
- Publication Span
- 28.17 years
- Last Updated
- 08/14/2025
- Curator(s)
- Macayla Weiner, Laurel Hiatt, Elbay Aliyev
Description
Cleidocranial dysplasia (CCD) is an autosomal dominant skeletal dysplasia caused by RUNX2 disruption. This curation focuses on the RUNX2 coding Q/A repeat region. Human repeat-specific evidence includes a Japanese sporadic CCD patient with a RUNX2 polyalanine expansion from 17A to 20A (+3Ala), a RUNX2/CBFA1 polyalanine expansion to 27 alanines segregating in family CCD-B with brachydactyly and minor CCD findings, and a familial RUNX2 polyglutamine insertion (27Q/17A; p.Q71_E72insQQQQ) in affected CCD individuals with reduced transactivation. Additional screening evidence reported low-range RUNX2 polyalanine expansions as secondary findings without reported CCD features, warranting curator review. Experimental evidence supports repeat-specific mechanisms involving RUNX2 Q/A repeat effects on coiled-coil structure, condensate behavior, aggregation/localization, co-activator partitioning, and transcriptional activity.
Genetic evidence
Total: 7.5
| Singular Evidence | Probands | PMID:26220009 | 3 | A Japanese sporadic CCD patient had a heterozygous RUNX2 c.181_189dupGCGGCGGCT variant, expanding the polyalanine tract from 17A to 20A (+3Ala), with severe short stature, cranial suture delay, dental abnormalities, mild brachydactyly, and mild clavicular hypoplasia. |
| Singular Evidence | Probands | PMID:40585427 | 0 | PMID:40585427 reports RUNX2 GCN/polyalanine expansions as secondary findings detected during reanalysis of WES/WGS data from neurologic probands. Using a pathogenic threshold of 20, the authors identified 3 probands with polyalanine expansions in RUNX2 with the lengths of 23, 21, and 20 repeats. The 21-repeat expansion was also verified in the proband's healthy mother. None of the probands or the healthy mother had reported CCD-related phenotype. The authors suggest incomplete penetrance within the low pathogenic range or the possibility that the pathogenic range may be longer than 23 repeats. |
| Singular Evidence | Probands | PMID:9182765 | 3 | Family CCD-B had an in-frame 30-bp RUNX2/CBFA1 polyalanine duplication expanding the tract from 17A to 27A, segregating with affected family members who had brachydactyly and minor clinical findings of CCD. |
| Collective Evidence | Computational | PMID:25852448 | 1.5 | RUNX2 contains a Q/A repeat domain with a wild-type 23Q/17A tract; the familial CCD variant expanded the glutamine tract to 27Q/17A (p.Q71_E72insQQQQ), consistent with repeat-slippage susceptibility of this locus. |
Experimental evidence
Total: 4.5
| Function | Biochemical function | PMID:32386547 | 0.5 | RUNX2 is a RUNT-family transcription factor controlling bone morphogenesis; the RUNX2 repeat-containing IDR drove phase separation in optoDroplet assays and formed liquid-like droplets. |
| Function | Biochemical function | PMID:24497578 | 1 | RUNX2 polyQ/polyA repeat peptides formed alpha-helical coiled-coil structures in vitro, with polyalanine length and coiled-coil stability promoting higher-order assembly. |
| Function | Regulatory impact | PMID:32386547 | 1 | The CCD-associated RUNX2 +10A alanine expansion enhanced homotypic phase separation, unblended from MED1 co-condensates, and significantly reduced IDR-driven luciferase reporter activity. |
| Functional Alteration | Non-patient cells | PMID:32386547 | 1 | In HEK293T and U2OS non-patient cell systems, the RUNX2 +10A IDR showed altered condensate/aggregate behavior and reduced MED1 recruitment compared with wild type. |
| Functional Alteration | Non-patient cells | PMID:24497578 | 1 | In HEK293 cells, polyA-expanded RUNX2(+12A) and coiled-coil-stabilized RUNX2 mutants mislocalized and aggregated; coiled-coil-disrupting mutations reduced aggregation and mislocalization. |
Note: Maximum score caps apply at evidence type, category, and supercategory levels, so section totals may be lower than the raw sum of row scores.