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.

Exome sequencing found a novel homozygous deletion in ADCK3 gene involved in autosomal recessive spinocerebellar ataxia.

Autosomal recessive cerebellar ataxia is heterogeneous inherited neurodegenerative disorders with more than 70 involved genes. The development of next generation sequencing opens a new window in rapid diagnosis of such heterogeneous condition in medical genetics laboratories. Here, we present ADCK3; del.CD (229-230) mutation in an Iranian consanguineous family with three cerebellar ataxic boys using whole exome sequencing. The mutation was predicted pathogenic and all the affected individuals were homozygous for the variant. Although, the ADCK3 was previously reported as one of the master genes of ARSC, our mutation was novel as has been not previously reported in dbSNP or literature.

The influence of combined genotypes of the HLADRB1*1501 and CD24 single nucleotide polymorphism on disease severity of Iranian multiple sclerosis patients.

Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. It is a clinically heterogeneous disorder especially in terms of disease severity. Current investigations suggest that genes and gene-gene interactions not only influence on susceptibility to MS but also affect the disease severity. In this study, we investigated the contribution of the HLADRB1*1501 allele and single nucleotide polymorphism (SNP) in CD24 gene and also combined genotypes of the HLADRB1*1501 and CD24 SNP to disease severity in Iranian MS patients. We have reported previously that the HLA- DRB1*1501 allele and the CD24v/v genotype associated with disease susceptibility and some other studies proposed that HLA-DRB1*1501 allele be associated with MS severity. In this study, the results showed a significant difference in the Multiple Sclerosis Severity Score (MSSS) of the nine different genotypes (F=2.838, P=0.007). Subsequent analysis revealed a statistically significant difference in the MSSS between the MS patients who were carriers of HLA-DRB1*1501/1501 and those who were not carriers of HLA-DRB1*1501/1501 genotypes (P=0.04). Moreover, the MS patients carrying combined genotypes of the HLA- DRB1*1501/x-CD24 v/v had statistically severe disease than the patients who did not carry the HLA- DRB1*1501- CD24 v/v (P=0.047). In conclusion, our findings suggest that, HLA-DRB1*1501/1501 and bigenic genotypes of the HLA- DRB1*1501/x- CD24 v/v may influence on disease severity in Iranian MS patients.

Investigation of CD24 and its expression in Iranian relapsing-remitting multiple sclerosis.

CD24 is a glycosylphosphatidylinositol (GPI)-linked cell surface glycoprotein expressed in central nervous system cells. Recent investigations have suggested that CD24 participates in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). However, a limited number of studies have been published regarding the contribution of CD24 to the risk and severity of MS in humans. We investigated the contribution of a CD24 single nucleotide polymorphism (SNP) to MS disease risk and severity. We also studied mRNA expression of the CD24 gene in Iranian MS patients using quantitative real-time polymerase chain reaction (PCR). Our findings showed that the CD24(v/v) genotype was significantly more frequent in MS patients compared with controls (p(c) = .004). Moreover, a statistically significant difference in the Multiple Sclerosis Severity Score (MSSS) was found between MS patients carrying CD24(a/a) and CD24(v/v) genotypes (p = .008). The results also indicated that the expression of CD24 mRNA was 1.7 times more in MS patients compared with controls. In conclusion, our results suggest that the CD24(v/v) genotype influences both MS disease risk and severity in Iranian MS patients, and the high disease severity in CD24(v/v) patients may indicate that they require more aggressive treatment than do patients carrying CD24(a/a).

Intragenic DNA polymorphism analysis of DMD/BMD dystrophy gene for carrier and prenatal diagnosis in 60 Iranian healthy individuals.

Duchenne and Becker muscular dystrophies (DMD/BMD) are allelic, x-linked neuromuscular disease resulting from mutations in dystrophin gene. DMD is the most severe and frequent inherited but still incurable disease in males. About two-third of such patients have large deletions or duplications that can be identified by multiplex polymerase chain reaction (PCR). In one-third of remaining cases, a linkage analysis that involves DNA markers of intragenic dystrophic gene is considered a rapid and simple method for carrier detection and prenatal diagnosis. In the present study, we investigated frequency and heterozygosity of three polymorphic restriction sites and also four highly polymorphic (CA)(n) repeat microsatellites loci within hot spots region of human dystrophin gene in 60 healthy Iranian populations. Our findings indicated that the allele frequencies of pERT87-8/TaqI, pERT87-15/BamHI, and pERT87-15/XmnI were 0.23/0.77, 0.221/0.779, and 0.239/0.761, respectively. Among these three polymorphic sites, pERT78-15/XmnI locus had the highest heterozygosity with frequency of 47.17%. We also found that STR49 had the highest heterozygosity among four polymorphic microsatellites. These findings are useful in linkage analysis of Iranian DMD families in both carrier detection and prenatal diagnosis.