ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000006.11) (NC_000006.12)

Haploinsufficiency phenotype comments:

A single mutation in COL9A1 has been associated with multiple epiphyseal dysplasia (MED), an autosomal dominantly inherited chondrodysplasia that is clinically heterogeneous. Czarny-Ratajczak et al (2001) (PMID: 11565064) identified a heterozygous insertion of a T at the donor splice site of IVS8+3 in the COL9A1 gene in two patients from a family with multiple epiphyseal dysplasia. Since COL9A1 contains six additional exons coding for the longer NC4 domain compared with the two other collagen IX genes, exon 9 of COL9A1 corresponds to exon 3 in the others. The insertion of a T at the donor splice site of IVS8+3 did not result in skipping of exon 9. It led to a complex splice pattern involving mainly exons 8 and 10 was not in itself surprising, however, since mutations at donor splice sites have been shown to lead to variable splice forms. From GeneReviews: "The pathologic effect of mutations in COL9A1, COL9A2, and COL9A3 is not well understood and a number of mechanisms have been proposed for these mutations including the degradation of mRNA from the mutant allele [Holden et al 1999, Spayde et al 2000], an accumulation of abnormal type IX collagen ?-chains in the rER of chondrocytes [Bonnemann et al 2000], and/or the degradation of abnormal ?-chains [van Mourik et al 1998]. However, the remarkable clustering of all COL9A1, COL9A2, and COL9A3 MED-causing mutations, which result in the in-frame deletion of equivalent regions of the COL3 domain of type IX collagen, led to the hypothesis that the deletion of these specific amino acids was a significant contributing factor to the development of the disease [Briggs & Chapman 2002]. Recent studies have confirmed that a COL9A3 mutation indeed abolishes binding of type IX collagen to matrilin-3 and type II collagen, thus identifying for the first time a molecular consequence of these mutations [Fresquet et al 2007]." No reported CNV losses in the DGV database. Mutations in COL9A1 have also been reported in association with an autosomal recessive form of Stickler syndrome.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

Note: DGV database reports CNV gains encompassing COL9A1 (nsv830683 and nssv1445434 (Wong et al., 2007); nsv524328 and nssv700234 (Shaikh et al 2009)).