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

• Published in: Clinical genetics 2018-01, Vol.93 (1), p.182-186
• Main Authors: Tariq, M., Khan, T.N., Lundin, L., Jameel, M., Lönnerholm, T., Baig, S.M., Dahl, N., Klar, J.
• Format: Article
• Language: English
• Subjects: Achondroplasia - genetics; Achondroplasia - pathology; Adolescent; Adult; Amino Acid Sequence; Base Sequence; Cartilage; Cartilage oligomeric matrix protein; Cartilage Oligomeric Matrix Protein - genetics; COMP; Consanguinity; Dysplasia; exome sequencing; Female; Genetic Predisposition to Disease - genetics; Genotype & phenotype; Homozygote; homozygous; Humans; Male; Matrix protein; Mutation; Mutation, Missense; Pakistan; Pedigree; Phenotype; PSACH; Pseudoachondroplasia; Sequence Homology, Amino Acid; variant; Whole Exome Sequencing
• ISSN: 0009-9163; 1399-0004; 1399-0004
• DOI: 10.1111/cge.13091

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.