Homozygosity for a missense variant in COMP gene associated with severe pseudoachondroplasia

Clin Genet. 2018 Jan;93(1):182-186. doi: 10.1111/cge.13091. Epub 2017 Nov 21.


The phenotypic spectrum associated with heterozygous mutations in cartilage oligomeric matrix protein gene (COMP) range from a mild form of multiple epiphyseal dysplasia (MED) to pseudoachondroplasia (PSACH). However, the phenotypic effect from biallelic COMP variants is unclear. We investigated a large consanguineous Pakistani family with a severe form of PSACH in 2 individuals. Another 14 family members presented with a mild PSACH phenotype similar to MED. Using exome sequencing and subsequent segregation analysis, we identified homozygosity for a COMP missense variant [c.1423G>A; p.(D475N)] in the 2 severely affected individuals, whereas family members with the mild PSACH phenotype were heterozygous. Our observations show for the first time that a biallelic COMP variant may be associated with pronounced and widespread skeletal malformations suggesting an additive effect of the 2 mutated alleles.

Keywords: COMP; PSACH; exome sequencing; homozygous; variant.

Publication types

  • Case Reports

MeSH terms

  • Achondroplasia / genetics*
  • Achondroplasia / pathology
  • Adolescent
  • Adult
  • Amino Acid Sequence
  • Base Sequence
  • Cartilage Oligomeric Matrix Protein / genetics*
  • Consanguinity
  • Exome Sequencing
  • Female
  • Genetic Predisposition to Disease / genetics*
  • Homozygote
  • Humans
  • Male
  • Mutation, Missense*
  • Pakistan
  • Pedigree
  • Phenotype
  • Sequence Homology, Amino Acid


  • COMP protein, human
  • Cartilage Oligomeric Matrix Protein

Supplementary concepts

  • Pseudoachondroplasia