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Homozygosity for a missense variant in COMP gene associated with severe pseudoachondroplasia
Author(s) -
Tariq M.,
Khan T.N.,
Lundin L.,
Jameel M.,
Lönnerholm T.,
Baig S.M.,
Dahl N.,
Klar J.
Publication year - 2018
Publication title -
clinical genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.543
H-Index - 102
eISSN - 1399-0004
pISSN - 0009-9163
DOI - 10.1111/cge.13091
Subject(s) - missense mutation , cartilage oligomeric matrix protein , disease gene identification , genetics , phenotype , osteochondrodysplasia , exome sequencing , allele , compound heterozygosity , biology , gene , medicine , pathology , alternative medicine , anatomy , osteoarthritis
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.