Skeletal dysplasia

Gene: CTGF

Green List (high evidence)

The 'new-gene-name' tag was added as the HGNC approved gene name is CCN2.

Created: 15 Jan 2025, 6:45 p.m. | Last Modified: 15 Jan 2025, 6:45 p.m.

Panel Version: 7.8

Comment on list classification: There is sufficient evidence available (two unrelated cases and animal models) in support of the association of biallelic variants with kyphomelic dysplasia. However, there is only one family reported with monoallelic variants. Hence, the MOI was set to 'BIALLELIC, autosomal or pseudoautosomal'. It can be promoted to green rating in the next GMS update.

Created: 15 Jan 2025, 6:41 p.m. | Last Modified: 15 Jan 2025, 6:41 p.m.

Panel Version: 7.8

Biallelic phenotype:
As reviewed by Cassandra Smith, PMID:39506047 reported three patients from two unrelated families with two different homozygous CCN2 variants and with kyphomelic dysplasia. In addition, Ccn2-deficient mice reported in PMID:12736220 and CCN2 knockout in zebrafish models also exhibited skeletal phenotypes supporting the disease association.

Monoallelic phenotype:
PMID:39414788 reported a total of 14 affected patients from a four-generation family with a monoallelic variant in the signal peptide of CCN2 (p.Arg22Pro) and with spondyloepimetaphyseal dysplasia. Cell lines harbouring the variant showed impaired protein secretion. Zebrafish ccn2a knockout model and osteoblast lineage-specific Ccn2-deficient mice partially recapitulated the phenotypes. However, they would be more representative of recessive disease because they are null models.

This gene has not yet been associated with any relevant phenotypes in OMIM or in Gene2Phenotype.

Created: 15 Jan 2025, 6:36 p.m. | Last Modified: 15 Jan 2025, 6:36 p.m.

Panel Version: 7.5

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
kyphomelic dysplasia, MONDO:0008881; spondyloepimetaphyseal dysplasia, MONDO:0100510

Publications

• 12736220
• 39414788
• 39506047

Green List (high evidence)

New gene name CCN2

39506047: Two consanguineous families with three affected patients with reported kyphomelic dysplasia. Rare missense (Cys148Tyr )and novel frameshift variant (Pro260LeufsTer7). Zebrafish crispants show skeletal changes.

12736220: Knockout mice show a skeletal phenotype
Sources: Literature

Created: 10 Jan 2025, 6:56 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Publications

• 39506047
• 12736220