Locus CCD RUNX2

A condition that primarily affects the development of the bones and teeth. Characteristic features include underdeveloped or absent collarbones (clavicles); dental abnormalities; and delayed closing of the spaces between the skull bones (fontanels). Other features may include decreased bone density (osteopenia), osteoporosis, hearing loss, bone abnormalities of the hands, and recurrent sinus and ear infections¹.

Prevalence

All conditions 1/1,000,000 births (likely underdiagnosed); Utah population frequency 0.12/10,000. Found in many ethnic groups². TR expansions causative in 2 individuals³.

Age of Onset

0 (birth)⁴.

HPO Terms

HP:0000162 Glossoptosis HP:0000164 Abnormality of the dentition HP:0000175 Cleft palate HP:0000189 Narrow palate HP:0000218 High palate HP:0000239 Large fontanelles HP:0000242 Parietal bossing HP:0000246 Sinusitis HP:0000248 Brachycephaly HP:0000256 Macrocephaly HP:0000272 Malar flattening HP:0000303 Mandibular prognathia HP:0000316 Hypertelorism HP:0000337 Broad forehead HP:0000340 Sloping forehead HP:0000347 Micrognathia HP:0000364 Hearing abnormality HP:0000365 Hearing impairment HP:0000389 Chronic otitis media HP:0000431 Wide nasal bridge HP:0000670 Carious teeth HP:0000680 Delayed eruption of primary teeth HP:0000682 Abnormal dental enamel morphology HP:0000684 Delayed eruption of teeth HP:0000696 Delayed eruption of permanent teeth HP:0000772 Abnormal rib morphology HP:0000773 Short ribs HP:0000774 Narrow chest HP:0000882 Hypoplastic scapulae HP:0000891 Cervical ribs HP:0000894 Short clavicles HP:0000939 Osteoporosis HP:0001156 Brachydactyly HP:0001172 Abnormal thumb morphology HP:0001182 Tapered finger HP:0001810 Dystrophic toenail HP:0002007 Frontal bossing HP:0002098 Respiratory distress HP:0002205 Recurrent respiratory infections HP:0002643 Neonatal respiratory distress HP:0002644 Abnormal pelvic girdle bone morphology HP:0002645 Wormian bones HP:0002650 Scoliosis HP:0002652 Skeletal dysplasia HP:0002659 Increased susceptibility to fractures HP:0002684 Thickened calvaria HP:0002688 Absent frontal sinuses HP:0002689 Absent paranasal sinuses HP:0002700 Large foramen magnum HP:0002705 High, narrow palate HP:0002738 Hypoplastic frontal sinuses HP:0002757 Recurrent fractures HP:0002808 Kyphosis HP:0002812 Coxa vara HP:0002827 Hip dislocation HP:0002857 Genu valgum HP:0002866 Hypoplastic iliac wing HP:0003183 Wide pubic symphysis HP:0003298 Spina bifida occulta HP:0003302 Spondylolisthesis HP:0003304 Spondylolysis HP:0003396 Syringomyelia HP:0004209 Clinodactyly of the 5th finger HP:0004220 Short middle phalanx of the 5th finger HP:0004322 Short stature HP:0004331 Decreased skull ossification HP:0004474 Persistent open anterior fontanelle HP:0005107 Abnormal sacrum morphology HP:0005259 Abnormal facility in opposing the shoulders HP:0005280 Depressed nasal bridge HP:0005916 Abnormal metacarpal morphology HP:0005930 Abnormal epiphysis morphology HP:0006040 Long second metacarpal HP:0006297 Enamel hypoplasia HP:0006660 Aplastic clavicle HP:0008391 Dystrophic fingernails HP:0008788 Delayed pubic bone ossification HP:0008821 Hypoplastic inferior ilia HP:0008848 Moderately short stature HP:0009577 Short middle phalanx of the 2nd finger HP:0010230 Cone-shaped epiphyses of the phalanges of the hand HP:0010535 Sleep apnea HP:0010669 Hypoplasia of the zygomatic bone HP:0010751 Dimple chin HP:0010807 Open bite HP:0011001 Increased bone mineral density HP:0011069 Supernumerary tooth HP:0011219 Short face HP:0011800 Midface retrusion HP:0100864 Short femoral neck HP:0200021 Down-sloping shoulders HP:6000872 Aplasia/Hypoplasia of the calvaria HP:6000875 Wide sacroiliac joint

Association

Mendelian

Locus

hg19 chr6:45390487-45390538

hg38 chr6:45422750-45422801

t2t chr6:45257567-45257618

Details

A poly-alanine expansion. Benign range (4-17 repeats) established from gnomAD and primary literature; pathogenic ranges (20-27) reflect two clinical cases to date^5,6. Intermediate alleles (i.e., 18 repeats; 19 not reported) appear to not be associated with disease^7,6. The gene RUNX2 was previously called CBFA1, as reflected in some of the literature⁸. Pathogenic range alleles up to 23 repeats have been detected in asymptomatic individuals, indicating potential incomplete penetrance⁹. A polyglutamine (CAG) tract lies immediately adjacent to this polyalanine locus (hg38 chr6:45422678-45422747), forming the Q/A domain of RUNX2. One 27 CAG allele has been reported in a father and son with classic CCD, implicating this expansion as potentially pathogenic¹⁰. PolyQ expansions are not always associated with CCD, as 24Q and 30Q alleles have been reported in population and osteoporotic bone fracture cohorts with no CCD phenotype¹¹.

Mechanism

LoF

Polyalanine expansion leading to haploinsufficiency⁶.

Detection

Year

Causation identified in 2015⁶; clinical association found in 1997⁸

Location in Gene

Coding Exon 3

Gene Strand

Alleles

Ref. Motif

GCN

Ranges

Benign (ref.)

–

Benign (gene)

–

Pathogenic (ref.)

GCN

Pathogen. (gene)

GCN

Unknown (ref.)

–

Unknown (gene)

–

Interruption (ref.)

–

Interrup. (gene)

–

gnomAD

Pathogenic genotype frequency data is not displayed for this locus because a substantial number of large alleles failed manual review by the gnomAD team.

References

Direct supporting references for info on this page.

Ontology Lookup Service (OLS)

mondo:0007340

Vérification de la connexion...

orphanet:1452

Resources for Genetics Professionals — Genetic Disorders Caused by Nucleotide Repeat Expansions and Contractions

Stephanie E.,Wallace, Lora JH,Bean

GeneReviews® [Internet] · 2022-10-20

genereviews:NBK535148

Cleidocranial Dysplasia Spectrum Disorder

Keren,Machol, Roberto,Mendoza-Londono, Brendan,Lee

GeneReviews® · 1993-01-01

genereviews:NBK1513

gnomAD

gnomad:RUNX2

Characterisation of novel RUNX2 mutation with alanine tract expansion from Japanese cleidocranial dysplasia patient.

Akio,Shibata, Junichiro,Machida, Seishi,Yamaguchi, Masashi,Kimura, Tadashi,Tatematsu, Hitoshi,Miyachi, Masaki,Matsushita, Hiroshi,Kitoh, Naoki,Ishiguro, Atsuo,Nakayama, Yujiro,Higashi, Kazuo,Shimozato, Yoshihito,Tokita

Mutagenesis · 2015-07-28

pmid:26220009

RUNX2 analysis of Danish cleidocranial dysplasia families.

L,Hansen, A K,Riis, A,Silahtaroglu, H,Hove, E,Lauridsen, H,Eiberg, S,Kreiborg

Clinical genetics · 2011-03-01

pmid:20560987

Mutations involving the transcription factor CBFA1 cause cleidocranial dysplasia.

S,Mundlos, F,Otto, C,Mundlos, J B,Mulliken, A S,Aylsworth, S,Albright, D,Lindhout, W G,Cole, W,Henn, J H,Knoll, M J,Owen, R,Mertelsmann, B U,Zabel, B R,Olsen

Cell · 1997-05-30

pmid:9182765

Reanalysis of Next-Generation Sequencing Data to Detect Tandem Repeat Expansions in 1,106 Czech Probands With Neurologic Disease.

Alena,Musilova, Petra,Lassuthova, Anna,Uhrova Meszarosova, Barbora,Straka, Jana,Krejcikova, Anna,Berounska, Marketa,Vlckova, Zuzana,Musova, Dana,Safka Brozkova

Neurology. Genetics · 2025-06-25

pmid:40585427

A Glutamine Repeat Variant of the RUNX2 Gene Causes Cleidocranial Dysplasia.

Masaki,Mastushita, Hiroshi,Kitoh, Asli,Subasioglu, Fatma,Kurt Colak, Munis,Dundar, Kenichi,Mishima, Yoshihiro,Nishida, Naoki,Ishiguro

Molecular syndromology · 2015-01-29

pmid:25852448

Alleles of RUNX2/CBFA1 gene are associated with differences in bone mineral density and risk of fracture.

Tanya,Vaughan, Julie A,Pasco, Mark A,Kotowicz, Geoff C,Nicholson, Nigel A,Morrison

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research · 2002-08-01

pmid:12162506

Additional Literature

Additional literature related to this locus.

Raw PubMed search results
(All PubMed results returned by searching for this gene, tandem repeats, and disease, in medline format)

DPHD from

Nittaya,Boonmuen, Moe Moe,Paing, Nareerat,Sutjarit, Pakpoom,Kheolamai, Sirikul,Manochantr, Chairat,Tantrawatpan, Waraluck,Chaichompoo, Apichart,Suksamrarn, Duangrat,Tantikanlayaporn

ACS omega · 2026-05-18

pmid:42255595

Novel RUNX1/2 fusions in unclassified cystic squamous salivary gland tumors: Possible expansion of the keratocystoma family.

Justin A,Bishop, Masato,Nakaguro, Doreen,Palsgrove, Anna,Trzcinska, Anne C,McLean, Jeffrey,Gagan, Junji,Shibahara, Toshitaka,Nagao

Annals of diagnostic pathology · 2025-12-26

pmid:41468806

Effects of G-CSF on hPDLSC proliferation and osteogenic differentiation in the LPS-induced inflammatory microenvironment.

Hui,Yu, Pengcheng,Wang, Haibin,Lu, Jiurong,Guan, Fang,Yao, Tianyi,Zhang, Qiuxu,Wang, Zuomin,Wang

BMC oral health · 2023-06-26

pmid:37365568

Osmolarity modulates the de-differentiation of horse articular chondrocytes during cell expansion in vitro: implications for tissue engineering in cartilage repair.

Elena,De Angelis, Amelia,Barilli, Roberta,Saleri, Bianca Maria,Rotoli, Francesca,Ravanetti, Francesca,Ferrari, Luca,Ferrari, Paolo,Martelli, Valeria,Dall'Asta, Paolo,Borghetti

Veterinary research communications · 2023-05-19

pmid:37202645

Unblending of Transcriptional Condensates in Human Repeat Expansion Disease.

Shaon,Basu, Sebastian D,Mackowiak, Henri,Niskanen, Dora,Knezevic, Vahid,Asimi, Stefanie,Grosswendt, Hylkje,Geertsema, Salaheddine,Ali, Ivana,Jerković, Helge,Ewers, Stefan,Mundlos, Alexander,Meissner, Daniel M,Ibrahim, Denes,Hnisz

Cell · 2020-05-07

pmid:32386547

Association of polyalanine and polyglutamine coiled coils mediates expansion disease-related protein aggregation and dysfunction.

Ilaria,Pelassa, Davide,Corà, Federico,Cesano, Francisco J,Monje, Pier Giorgio,Montarolo, Ferdinando,Fiumara

Human molecular genetics · 2014-02-04

pmid:24497578

Glutamine repeat variants in human RUNX2 associated with decreased femoral neck BMD, broadband ultrasound attenuation and target gene transactivation.

Nigel A,Morrison, Alexandre A,Stephens, Motomi,Osato, Patsie,Polly, Timothy C,Tan, Namiko,Yamashita, James D,Doecke, Julie,Pasco, Nicolette,Fozzard, Graeme,Jones, Stuart H,Ralston, Philip N,Sambrook, Richard L,Prince, Geoff C,Nicholson

PloS one · 2012-08-13

pmid:22912713

Runx2 contributes to murine Col10a1 gene regulation through direct interaction with its cis-enhancer.

Feifei,Li, Yaojuan,Lu, Ming,Ding, Dobrawa,Napierala, Sam,Abbassi, Yuqing,Chen, Xiangyun,Duan, Siying,Wang, Brendan,Lee, Qiping,Zheng

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research · 2011-12-01

pmid:21887706

The polycystic kidney disease 1 (Pkd1) gene is required for the responses of osteochondroprogenitor cells to midpalatal suture expansion in mice.

Bo,Hou, Elona,Kolpakova-Hart, Naomi,Fukai, Kimberly,Wu, Bjorn R,Olsen

Bone · 2009-03-02

pmid:19264154