Association of the TCF7L2 rs12255372 (G/T) variant with type 2 diabetes mellitus in an Iranian population

In various populations worldwide, common variants of the TCF7L2 (Transcription factor 7-like 2) gene are associated with the risk of type 2 diabetes mellitus (T2DM). The aim was to investigate the association between rs12255372 (G/T) polymorphism in the TCF7L2 gene and T2DM in an Iranian population. 236 unrelated patients with T2DM, and 255 normoglycemic controls without diabetes were studied. The PCR-RFLP method was used for genotyping rs12255372 (G/T) polymorphism, and the SPSS version 18.0 for Windows for statistical analysis. The minor T allele of TCF7L2 rs12255372 was found to significantly increase the risk of T2DM, with an allelic odds ratio (OR) of 1.458 (95% CI 1.108-1.918, p = 0.007). A significant difference in TT genotype was observed between T2DM patients and normoglycemic controls (OR 2.038, 95% CI 1.147-3.623; p = 0.014). On assuming dominant and recessive models, ORs of 1.52 [95% CI (1.05-2.21) p = 0.026)] and 1.74 [95% CI (1.01-3.00) p = 0.043] were obtained, respectively, thereby implying that the co-dominant model would best fit the susceptible gene effect. This study further confirms the TCF7L2 gene as enhancing susceptibility to the development of T2DM. © 2012, Sociedade Brasileira de Genética

Association of interleukin-1 gene cluster polymorphisms and haplotypes with multiple sclerosis in an Iranian population

Multiple sclerosis (MS) is a multi-factorial autoimmune disease of the central nervous system. The exact etiology of MS is still unknown. Due to the important roles that cytokines play as mediators in immune and inflammatory responses, we have evaluated the association of IL-1 gene cluster polymorphisms and haplotypes with MS susceptibility in 306 unrelated MS patients and 312 healthy matched controls. A significant association was found for the IL-1β + 3953 T allele [OR = 1.43, 95% CI (1.14-1.79), P value = 0.002, Pc= 0.01] and for IL-1β + 3953 T/T genotype and MS risk [OR = 1.92, 95% CI (1.25-2.96), P value = 0.005, Pc= 0.01]. Interestingly, the genotypes of the polymorphisms remained significant under recessive, co-recessive and dominant models. However, no significant differences were found between MS patients and controls in the genotype and allele frequencies of the IL-1β - 511, - 31 and IL-1Ra polymorphisms. Haplotype analysis for IL-1β - 31 and IL-1β - 511, with moderate linkage disequilibrium (LD), using the EM algorithm revealed a significant global association of haplotype differences between the two groups. Lower presence of two haplotypes (H3: C-T and H4: T-C) was observed in the MS patients than healthy controls. However, after applying Bonferroni's correction the differences were not significant. To our knowledge, this is the first study reporting the association of the IL-1β + 3953 gene polymorphism and MS susceptibility. © 2015 Elsevier B.V

Association of P1635 and P1655 polymorphisms in dysbindin (DTNBP1) gene with schizophrenia

Alizadeh F, Tabatabaiefar MA, Ghadiri M, Yekaninejad MS, Jalilian N, Noori-Daloii MR. Association of P1635 and P1655 polymorphisms in dysbindin (DTNBP1) gene with schizophrenia. Objectives: Schizophrenia (SCZ) is a severe psychiatric disorder with a lifetime prevalence of approximately 1 in most of the populations studied. SCZ is multifactorial with the contribution of multiple susceptibility genes that could act in conjunction with epigenetic processes and environmental factors. There is some evidence supporting the association between genetic variants in dysbindin (DTNBP1) gene and SCZ in populations. In this study, we investigated the association between polymorphisms P1635 and P1655 in dysbindin gene with SCZ. Methods: Totally, 115 unrelated patients with SCZ and 117 unrelated healthy volunteers were studied. Genomic DNA was extracted from blood. Genotyping was done with the PCR-RFLP method. The allele and genotype associations were analysed with �2 test. The Benjamini-Hochberg procedure was used to correct p values for multiple comparisons. Results: The results showed no significant difference between patients and controls in allelic frequencies or genotypic distributions of SNP P1635 (p = 0.809), but a significant difference between the case and control groups for SNP P1655 (p = 0.009) was found. We could also find a significant positive association between A-C haplotype and SCZ (OR = 1.7, 95 CI 1.18-2.42; p = 0.004, pc = 0.02) and a protective effect for A-G haplotype (p = 0.003, OR = 0.57, 95 CI 1.18-2.42; p = 0.003, pc = 0.02). Conclusion: This study may provide further support for the association between SNP polymorphisms in DTNBP1 and SCZ in the Iranian population. Studies with more markers and subjects for various populations will be necessary to understand the genetic contribution of the gene to the development of SCZ. © 2011 John Wiley & Sons A/S

Identification and Clinical Implications of a Novel MYO15A Variant in a Consanguineous Iranian Family by Targeted Exome Sequencing

BACKGROUND AND OBJECTIVES: Hereditary hearing loss (HL) is known by a very high genetic heterogeneity, which makes a molecular diagnosis problematic. Next-generation sequencing (NGS) is a new strategy that can overcome this problem. METHOD: A comprehensive family history was obtained, and clinical evaluations and pedigree analysis were performed in the family with 3 affected members. After excluding mutations in the GJB2 and 7 other most common autosomal recessive nonsyndromic HL genes via Sanger sequencing and genetic linkage analysis in the family, we applied the Otogenetics deafness NGS panel in the proband of this family. RESULTS: NGS results showed a novel rare variant (c.7720C>T) in the MYO15A gene. This nonsense variant in the exon 40 of the MYO15A gene fulfills the criteria of being categorized as pathogenic according to the American College of Medical Genetics and Genomics guideline. CONCLUSIONS: New DNA sequencing technologies could lead to identification of the disease causing variants in highly heterogeneous disorders such as HL

dy of P53 gene mutations in promoter and exons 2-4 and 9-11 in patient with gastric cancer by PCR-SSCP in Chaharmahal Va Bakhtiari province

Background: Gastric cancer is one of the most important diseases and after lung cancer, is the second cause of cancer death worldwide. Genetic factors including oncogenes and tumor suppressor genes are always contributed in progression of this cancer. The P53 tumor suppressor gene has a broad role in genomic stability and DNA repair. The aim of this study was to determine the P53 gene mutations in gastric cancer specimens in Chaharmahal Va Bakhtiari Province. Methods: In this descriptive-lab based study, we investigated the promoter, exons 2-4 and 9-11 of P53 gene mutations in 38 paraffin embedded gastric cancer specimens. DNA was extracted following the standard phenol chloroform protocol. The P53 gene mutations were determined using PCR-SSCP procedure. Results: Our study revealed no P53 gene mutation in promoter and exons 2-4 and 9-11 in the gastric cancer subjects studied. Conclusion: While P53 gene mutations have been reported as the most frequent genetic alterations and are found in about 50% of the human malignancies, no mutation was detected in this study. The reason may be due to small sample size or mutations on other genes or epigenetic factors

Mutations in GJB2 as Major Causes of Autosomal Recessive Non-Syndromic Hearing Loss: First Report of c.299-300delAT Mutation in Kurdish Population of Iran

Background and Objectives: : Autosomal recessive non-syndromic hearing loss (ARNSHL) with genetic origin is common (1/2000 births). ARNSHL can be associated with mutations in gap junction protein beta 2 (GJB2). To this end, this cohort investigation aimed to find the contribution of GJB2 gene mutations with the genotype-phenotype correlations in 45 ARNSHL cases in the Kurdish population. Subjects and Methods: : Genomic DNA was extracted from a total of 45 ARNSHL families. The linkage analysis with 3 short tandem repeat markers linked to GJB2 was performed on 45 ARNSHL families. Only 9 of these families were linked to the DFNB1 locus. All the 45 families who took part were sequenced for confirmation linkage analysis (to perform a large project). Results: : A total of three different mutations were determined. Two of which [c.35delG and c.-23+1G>A (IVS1+1G>A)] were previously reported but (c.299-300delAT) mutation was novel in the Kurdish population. The homozygous pathogenic mutations of GJB2 gene was observed in nine out of the 45 families (20%), also heterozygous genotype (c.35delG/N)+(c.-23+1G>A/c.-23+1G>A) were observed in 4/45 families (8.8%). The degree of hearing loss (HL) in patients with other mutations was less severe than patients with c.35delG homozygous mutation (p<0.001). Conclusions: : Our data suggest that GJB2 mutations constitute 20% of the etiology of ARNSHL in Iran; moreover, the c.35delG mutation is the most common HL cause in the Kurdish population. Therefore, these mutations should be included in the molecular testing of HL in this populatio

A novel mutation in the PAX3 gene causes Waardenburg syndrome type I in an Iranian family

Objectives: Sensorineural hearing impairment (HI) is one of the most frequent congenital defects, with a prevalence of 1 in 500 among neonates. Although there are over 400 syndromes involving HI, most cases of HI are nonsyndromic (70), 20 of which follow autosomal dominant mode of inheritance. Waardenburg syndrome (WS) ranks first among autosomal dominant syndromic forms of HI. WS is characterized by sensorineural hearing impairment, pigmentation abnormalities of hair and skin and hypoplastic blue eyes or heterochromia iridis. WS is subdivided into four major types, WS1-WS4. WS1 is diagnosed by the presence of dystopia canthorum and PAX3 is the only gene involved. This study aims to determine the pathogenic mutation in a large Iranian pedigree affected with WS1 in order to further confirm the clinical diagnosis. Methods: In the present study, a family segregating HI was ascertained in a genetic counseling center. Upon clinical inspection, white forelock, dystopia canthorum, broad high nasal root and synophrys, characteristic of WS1 were evident. In order to clarify the genetic etiology and confirm the clinical data, primers were designed to amplify exons and exon-intron boundaries of the responsible gene, PAX3 with 10 exons, followed by the Sanger DNA sequencing method. Results: Genetic analysis of PAX3 revealed a novel mutation in PAX3 (c.1024₁₀₄₀ del AGCACGATTCCTTCCAA). Our data provide genotype-phenotype correlation for the mutation in PAX3 and WS1 in the studied family, with implications for genetic counseling, which necessitates detailed clinical inspection of HI patients to distinguish syndromic HI from the more common non-syndromic cases. Conclusion: Our results reveal the value of phenotype-directed genetic analysis and could further expand the spectrum of PAX3 mutations. © 2015 Elsevier Ireland Ltd

Molecular and clinical characterization of Waardenburg syndrome type I in an Iranian cohort with two novel PAX3 mutations

Waardenburg syndrome (WS) is a disease of abnormal neural-crest derived melanocyte development characterized by hearing loss and pigmentary disturbances in hair, eyes and skin. WS is subdivided into four major types, WS1-WS4, where WS1 is recognized by the presence of dystopia canthorum, with PAX3 being the only known gene involved. This study aimed at investigating PAX3 mutations and clinical characteristics of WS1 in a group of Iranian patients. A total of 12 WS1 patients from four unrelated Iranian families were enrolled. Waardenburg consortium guidelines were used for WS1 diagnosis. A detailed family history was traced and a thorough clinical examination was performed for all participants. Furthermore, WS1 patients underwent screening for PAX3 mutations using PCR-sequencing.Dystopia canthorum, broad high nasal root and synophrys were observed in all patients. Early graying, hair discoloration, hypoplastic blue eyes (characteristic brilliant blue iris) and hearing loss were the most common features observed, while heterochromia iridis was the least frequently observed sign among the studied Iranian WS1 patients. Genetic analysis of PAX3 revealed four mutations including c.667C > T, c.784C > T, c.951delT and c.451 + 3A > C. Two of the four mutations reported here (c.951delT and c.451 + 3A > C) are being reported for the first time in this study.Our data provide insight into genotypic and phenotypic spectrum of WS1 in an Iranian series of patients. Our results expand the spectrum of PAX3 mutations and may have implications for the genetic counseling of WS in Iran. © 2015 Elsevier B.V