RUNX2 – Cleidocranial Dysplasia 1

Cleidocranial dysplasia 1 (CCD1) is an autosomal dominant skeletal dysplasia caused by heterozygous mutations in the osteoblast‐specific transcription factor RUNX2. Patients present with hypoplastic or absent clavicles, patent fontanelles, short stature and dental anomalies, reflecting combined defects in intramembranous and endochondral ossification (PMID:9207800). The association between RUNX2 and Cleidocranial Dysplasia 1 is supported by multiple reports of segregating variants in familial and sporadic cases.

Inheritance is autosomal dominant with high penetrance. Segregation analyses demonstrate the same heterozygous RUNX2 variant in affected family members, with examples such as an Italian pedigree showing a splice‐site mutation c.580+1G>A segregating in three individuals (PMID:21131390). Case series have identified 42 unrelated patients with RUNX2 mutations (PMID:10521292) and a cohort of 31 index patients across 20 families (PMID:16222673), confirming robust genetic evidence.

The variant spectrum is broad, including missense changes in the Runt domain and loss‐of‐function alleles such as frameshifts and splice‐site mutations. A recurrent missense variant c.673C>T (p.Arg225Trp) is reported in multiple ethnicities (PMID:28738062). We selected one example: c.673C>T (p.Arg225Trp).

Functional studies demonstrate that missense mutations in the Runt homology domain abolish DNA binding and transactivation of osteoblast target genes, consistent with a haploinsufficiency mechanism. In vitro assays show impaired nuclear localization and dominant‐negative effects for variants such as p.Gly192Arg (PMID:16244783). Mouse models heterozygous for Runx2 null alleles recapitulate CCD phenotypes, including delayed ossification and open sutures, providing concordant in vivo evidence.

While most RUNX2 variants are pathogenic, an 18-bp in‐frame deletion (c.243-260del) was identified as a benign population polymorphism, highlighting the importance of segregation and functional data to distinguish pathogenic alleles from neutral variation (PMID:29960047). No significant refuting evidence for a CCD association has been reported.

Overall, genetic and experimental data together conclusively establish RUNX2 haploinsufficiency as the cause of autosomal dominant cleidocranial dysplasia. Identification of RUNX2 mutations enables molecular diagnosis, informs genetic counseling, and supports early intervention strategies to manage skeletal and dental manifestations.

References

• Nature Genetics | 1997 | Missense mutations abolishing DNA binding of the osteoblast‐specific transcription factor OSF2/CBFA1 in cleidocranial dysplasia PMID:9207800
• American Journal of Human Genetics | 1999 | Mutation analysis of core binding factor A1 in patients with cleidocranial dysplasia PMID:10521292
• American Journal of Medical Genetics Part A | 2005 | Cleidocranial dysplasia: molecular genetic analysis and phenotypic-based description of a Middle European patient group PMID:16222673
• Journal of Human Genetics | 2005 | Functional analysis of a novel RUNX2 missense mutation found in a family with cleidocranial dysplasia PMID:16244783
• PLoS One | 2017 | Analysis of novel RUNX2 mutations in Chinese patients with cleidocranial dysplasia PMID:28738062
• European Journal of Medical Genetics | 2019 | An 18 bps in-frame deletion mutation in RUNX2 gene is a population polymorphism rather than a pathogenic variant PMID:29960047

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