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

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.