Exome sequencing revealed a p.G299R mutation in the COMP gene in an Iranian family suffering from pseudoachondroplasia.

Background: Short-stature (SS) is multifactorial pathologic condition that originates from either genetic or environmental factors. The diagnosis is based on family history, clinical findings, radiological examination and genetic analysis. A variety of genes have been reported for SS, among which FGFR-3 was the main gene in achondroplasia and hypochondroplasia. In other forms of SS, the gene involved varies from one patient to another. Whole exome sequencing (WES) and comparative genomic hybridization (CGH) have recently introduced a growing body of genes annually. The present study performed a WES analysis on an Iranian family suffering from an inherited form of SS aiming to diagnose the causative gene. The father and all of his four sons were diagnosed as SS.

Methods: The blood samples were collected from the proband and his available family members. Genomic DNA was extracted using salting-out method. The DNA of the proband was analyzed using WES and confirmed through polymerase chain reaction (PCR)-sequencing. The WES-extracted variant was evaluated in silico using software aiming to determine whether this nucleotide change is pathogenic. The presence of the variant was traced in other affected family members using PCR-sequencing.

Results: Following segregation analysis, variant c.896 G>A of the COMP gene was found in all of the affected individuals in a heterozygous form. This variant resulted in substitution of glycine 299 with arginine and was previously predicted as pathogenic in the Human Gene Mutation Database dataset, although it represents the first report in Iran.

Conclusions: The findings of the present study suggest consideration of the c.896 G>A variant of the COMP gene with respect to the genetic counseling of inherited skeletal dysplasia in Iran.