Whole-exome sequencing reveals a rare missense variant in DTNA in an Iranian pedigree with early-onset atrial fibrillation.

Atrial fibrillation (AF) is a morbid and heritable irregular cardiac rhythm that affects about 2%-3% of the population. Patients with early-onset AF have a strong genetic association with the disease; nonetheless, the exact underlying mechanisms need clarification. We herein present our evaluation of a 2-generation Iranian pedigree with early-onset AF. Whole-exome sequencing was applied to elucidate the genetic predisposition. Direct DNA sequencing was utilized to confirm and screen the variants in the proband and his available family members. The pathogenicity of the identified nucleotide variations was scrutinized via either segregation analysis in the family or in silico predictive software. The comprehensive variant analysis revealed a missense variant (c.G681C, p.E227D, rs1477078144) in the human α-dystrobrevin gene (DTNA), which is rare in genetic databases. Most in silico analyses have predicted this variant as a disease-causing variant, and the variant is co-segregated with the disease phenotype in the family. Previous studies have demonstrated the association between the DTNA gene and left ventricular noncompaction cardiomyopathy. Taken together, we provide the first evidence of an association between a nucleotide variation in the DTNA gene and early-onset AF in an Iranian family. However, the genetic testing of AF in the Iranian population is still limited. This finding not only further confirms the significant role of genetics in the incidence of early-onset AF but also expands the spectrum of the gene variations that lead to AF. Additionally, it may have further implications for the treatment and prevention of AF.

Endothelial nitric oxide synthase Asp298Glu (894G/T) gene polymorphism as a possible risk factor for the coronary slow flow phenomenon among Iranians.

BACKGROUND: Mounting evidence indicates an association between endothelial dysfunction and the coronary slow flow phenomenon (CSFP). In the present study, we aimed to evaluate the possible role of endothelial nitric oxide synthase (eNOS) 894G/T and interleukin-1ß (IL-1ß) 315C/T polymorphisms as possible risk factors for CSFP. METHODS: This prospective study enrolled patients with CSFP and individuals with normal coronary arteries. Genotypes were assessed using regular polymerase chain reaction and direct Sanger-sequencing techniques. RESULTS: The study population consisted of 267 individuals: 180 patients with CSFP (49 women [27.2%]) at a median age of 55 (48-62) years and 87 controls with normal coronary arteries (56 women [64.4%]) at a median age of 47 (41-58) years. The allelic distribution of eNOS 894G/T was significantly associated with CSFP (odds ratio [OR], 1.58; 95% confidence interval (CI), 1.04-2.42; P = 0.03). This polymorphism increased the risk of CSFP under the dominant model (OR 1.73; 95% CI I.02-2.95; P = 0.04). However, the allelic frequencies (1.05; 95% CI 0.68-1.59; P = 0.83) and genotypic frequencies (0.88; 95% CI 0.52-1.49; P = 0.63) of the IL-1ß 315C/T polymorphism were not associated with the incidence of CSFP in the Iranian population. CONCLUSIONS: The CSFP and control groups were statistically different regarding the eNOS 894G/T polymorphism. Our findings also demonstrated that the IL-1ß 315C/T polymorphism was not a risk factor for CSFP.