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Mutations in the CDC14A (Cell Division-Cycle 14A) gene, which encodes a conserved dual-specificity protein tyrosine phosphatase, have been identified as a cause of autosomal recessive non-syndromic hearing loss (DFNB32) and hearing impairment infertility male syndrome (HIIMS). We used next-generation sequencing to screen six deaf probands from six families segregating sensorineural moderate-to-profound hearing loss. Data analysis and variant prioritization were completed using a custom bioinformatics pipeline. We identified three homozygous loss of function variants (p.Arg345Ter, p.Arg376Ter, and p.Ala451Thrfs*43) in the CDC14A gene, segregating with deafness in each family. Of the six families, four segregated the p.Arg376Ter mutation, one family segregated the p.Arg345Ter mutation and one family segregated a novel frameshift (p.Ala451Thrfs*43) mutation. In-depth phenotyping of affected individuals ruled out secondary syndromic findings. This study implicates the p.Arg376Ter mutation might be as a founder mutation in the Iranian population. It also provides the first semen analysis for deaf males carrying mutations in exon 11 of CDC14A and reveals a genotype–phenotype correlation that delineates between DFNB32 and HIIMS. The clinical results from affected males suggest the NM_033313.2 transcript alone is sufficient for proper male fertility, but not for proper auditory function. We conclude that DFNB32 is a distinct phenotypic entity in males.

Iran, despite its size, geographic location and past cultural influence, has largely been a blind spot for human population genetic studies. With only sparse genetic information on the Iranian population available, we pursued its genome-wide and geographic characterization based on 1021 samples from eleven ethnic groups. We show that Iranians, while close to neighboring populations, present distinct genetic variation consistent with long-standing genetic continuity, harbor high heterogeneity and different levels of consanguinity, fall apart into a cluster of similar groups and several admixed ones and have experienced numerous language adoption events in the past. Our findings render Iran an important source for human genetic variation in Western and Central Asia, will guide adequate study sampling and assist the interpretation of putative disease-implicated genetic variation. Given Iran's internal genetic heterogeneity, future studies will have to consider ethnic affiliations and possible admixture.

Background: Mitochondrial DNA (mtDNA) is a valuable marker for population studies and forensic investigations. Recent advancements in massively parallel sequencing technologies enable whole mitochondrial genome sequencing. This study collected blood samples from unrelated Iranian participants from four ethnic groups: Persian, Kurd, Lur, and Azeri. We mapped mtDNA haplogroups according to genetic ancestry and investigated the ethnic similarities within the Iranian population. Methods: Complete mtDNA sequences were generated with targeted mtDNA sequencing method and haplogroups were determined on the base of mitogenome polymorphisms. Additionally, we used data from the whole exome sequencing (WES) of the current samples to compare the variants identified by two different mitochondrial testing methods. Principal component analysis (PCA) calculations were performed using the R software to determine diversity between unrelated individuals of various ethnicities. Results: A total of 129 sub-haplogroups were identified in 15 main haplogroups. The findings revealed high frequencies of haplogroups U and H (22.4% and 20.3%, respectively) in the Iranian population. The PCA scatter plots revealed overlapping diversity, with no distinct trends separating the groups in these four groups within the Iranian population. In the present samples, the WES method identified only 57.8% of the variants detected by the targeted mtDNA sequencing method. Conclusion: Variant studies do not show much difference, which indicate a small genetic difference between the central ethnic groups of Iran. Furthermore, comparing the targeted whole mitochondrial genome to mitochondrial data from WES in our study samples highlights the notion that targeted entire mitochondrial genome is a gold standard method for variant detection.

Coronary artery disease (CAD) is the leading cause of mortality in many parts of the world. Genome-wide association studies (GWAS) have identified several genetic variants associated with CAD in Low-density lipoprotein receptor (LDLR) locus. This study was evaluated the possible association of genetic markers at LDLR locus with CAD irrespective to lipid profile and as well as the association of these SNPs with severity of CAD in Iranian population. Sequencing of 2 exons in LDLR gene (Exon 2, 12) and part of intron 30 of SMARCA4 gene include rs1122608, was performed in 170 Iranian patients angiographically confirmed CAD and 104 healthy controls by direct sequencing. Sullivan's scoring system was used for determining the severity of CAD in cases. Our results showed that homozygote genotypes of rs1122608 (P<0.0001), rs4300767 (P<0.005) and rs10417578 (p<0.007) SNPs have strong protective effects on the CAD. In addition, we found that rs1122608 (GT or TT) was at higher risk of three vessel involvement compared to single vessels affecting (P=0.01).

Background: Hearing loss (HL) is the most common sensory deficit in humans, and genetic factors contribute to about half of the cases. With 112 causative genes identified so far and a disproportionate share of the genes within different ethnic groups, HL has proven to be quite heterogeneous.Methods: Twenty Iranian families having at least 2 children with hereditary HL were initially verified to be GJB2-negative and were then subjected to whole exome sequencing (WES). Sanger sequencing was used to confirm segregation of the variant identified in each family.Results: In 3 families, WES revealed 3 novel variants in KCNQ4, LHFPL5 and COCH genes. The KCNQ4 gene (DFNA2A) encodes a potassium channel (KV7.4) and the heterozygous variant identified (c.1647C>G, p.F549L) resulted in the substitution of Phe549 residing in the KV7.4 cytoplasmic region. The homozygous variant (c.34A>T, p.K12X) was identified in the LHFPL5 gene (DFNB67) which encodes a transmembrane protein, and another variant in a homozygous state (c.116T>A, p.L39X) was identified in the COCH gene which encodes a secretory protein. Pathogenic variants in the COCH gene are associated with late onset autosomal dominant hearing loss (DFNA9) but the affected individuals displayed early onset HL with a recessive mode of inheritance.Conclusions: The 16% contribution of GJB2 to HL in the Iranian population necessitates the discovery of the remaining causal factors. This study is the first to report KCNQ4 and COCH related HL in the Iranian population and the second study, globally, to report HL due to biallelic inactivation of the COCH gene.

Genetic analysis of non-syndromic hearing loss (NSHL) has been challenged due to marked clinical and genetic heterogeneity. Today, advanced next-generation sequencing (NGS) technologies, such as exome sequencing (ES), have drastically increased the efficacy of gene identification in heterogeneous Mendelian disorders. Here, we present the utility of ES and re-evaluate the phenotypic data for identifying candidate causal variants for previously unexplained progressive moderate to severe NSHL in an extended Iranian family. Using this method, we identified a known heterozygous nonsense variant in exon 26 of the DIAPH1 gene (MIM: 602121), which led to \"Deafness, autosomal dominant 1, with or without thrombocytopenia; DFNA1\" (MIM: 124900) in this large family in the absence of GJB2 disease-causing variants and also OtoSCOPE-negative results. To the best of our knowledge, this nonsense variant (NM_001079812.3):c.3610C>T (p.Arg1204Ter) is the first report of the DIAPH1 gene variant for autosomal dominant non-syndromic hearing loss (ADNSHL) in Iran.

Background: The study of Y-chromosomal variations provides valuable insights into male susceptibility in certain diseases like cardiovascular disease (CVD). In this study, we analyzed paternal lineage in different Iranian ethnic groups, not only to identify developing medical etiology, but also to pave the way for gender-specific targeted strategies and personalized medicine in medical genetic research studies. Methods: The diversity of eleven Iranian ethnic groups was studied using 27 Y-chromosomal short tandem repeat (Y-STR) haplotypes from Y-filer® Plus kit. Analysis of molecular variance (AMOVA) based on pair-wise RST along with multidimensional scaling (MDS) calculation and Network phylogenic analysis was employed to quantify the differences between 503 unrelated individuals from each ethnicity. Results: Results from AMOVA calculation confirmed that Gilaks and Azeris showed the largest genetic distance (RST=0.35434); however, Sistanis and Lurs had the smallest considerable genetic distance (RST=0.00483) compared to other ethnicities. Although Azeris had a considerable distance from other ethnicities, they were still close to Turkmens. MDS analysis of ethnic groups gave the indication of lack of similarity between different ethnicities. Besides, network phylogenic analysis demonstrated insignificant clustering between samples. Conclusion: The AMOVA analysis results explain that the close distance of Azeris and Turkmens may be the effect of male-dominant expansions across Central Asia that contributed to historical and demographics of populations in the region. Insignificant differences in network analysis could be the consequence of high mutation events that happened in the Y-STR regions over the years. Considering the ethnic group affiliations in medical research, our results provided an understanding and characterization of Iranian male population for future medical and population genetics studies.

Background : Ménière’s disease (MD) is a common inner ear disorder which is characterized by recurrent attacks of vertigo, fluctuating sensorineural hearing loss (SNHL), tinnitus, and a sense of fullness in the affected ear. MD is a complex disorder; although six genes have been linked to familial autosomal dominant form of the disease, in many cases, the exact genetic etiology remains elusive. Methods : To elucidate the genetic causes of MD in an Iranian family, we performed exome sequencing on all members of the family: consanguineous parents and four children (two affected and two unaffected). Variant filtering was completed using a customized workflow keeping variants based on segregation with MD in autosomal recessive (AR) inheritance pattern, minor allele frequency (MAF), and in-silico prediction of pathogenicity. Results : Analysis revealed that in this family, 970 variants co-segregated with MD in AR pattern, out of which eight variants (one intergenic, four intronic, and three exonic) were extremely rare. The exonic variants included a synonymous substitution in USP3 gene, an in-frame deletion in ZBED2 gene, and a rare, highly conserved deleterious missense alteration in LSAMP gene. Conclusion : The phenotype observed in the proband described here, i.e. vertigo, poor sense of smell, tinnitus, and borderline hearing ability, may originate from aberrant changes in the cerebellum and limbic system due to a deleterious mutation in the LSAMP gene; hence, LSAMP mutation is a possible candidate for the etiology of MD in this family.

Background: Complete SARS-CoV-2 genome sequencing in the early phase of the outbreak in Iran showed two independent viral entries. Subsequently, as part of a genome surveillance project, we aimed to characterize the genetic diversity of SARS-CoV-2 in Iran over one year after emerging. Methods: We provided 319 SARS-CoV-2 whole-genome sequences used to monitor circulating lineages in March 2020-May 2021 time interval. Results: The temporal dynamics of major SARS-CoV-2 clades/lineages circulating in Iran is comparable to the global perspective and represent the 19A clade (B.4) dominating the first disease wave, followed by 20A (B.1.36), 20B (B.1.1.413), 20I (B.1.1.7), leading the second, third and fourth waves, respectively. We observed a mixture of circulating B.1.36, B.1.1.413, B.1.1.7 lineages in winter 2021, paralleled in a fading manner for B.1.36/B.1.1.413 and a growing rise for B.1.1.7, prompting the fourth outbreak. Entry of the Delta variant, leading to the fifth disease wave in summer 2021, was detected in April 2021. This study highlights three lineages as hallmarks of the SARS-CoV-2 outbreak in Iran; B4, dominating early periods of the epidemic, B.1.1.413 (B.1.1 with the combination of [D138Y-S477N-D614G] spike mutations) as a characterizing lineage in Iran, and the co-occurrence of [I100T-L699I] spike mutations in half of B.1.1.7 sequences mediating the fourth peak. It also designates the renowned combination of G and GR clades’ mutations as the top recurrent mutations. Conclusion: In brief, we provided a real-time and comprehensive picture of the SARS-CoV-2 genetic diversity in Iran and shed light on the SARS-CoV-2 transmission and circulation on the regional scale.

Colorectal cancer (CRC) is the second leading cause of cancer-related deaths worldwide. Engineered biomolecules can be used as a targeted tool to deliver drugs directly to tumors that reduce the adverse effects of conventional treatments. We aimed to prepare non-targeted oxaliplatin-loaded chitosan nanoparticles (OXPT-CS NPs) and targeted OXPT-CS NPs decorated with cetuximab single-chain variable fragment (scFv) to send both NPs to epidermal growth factor receptor (EGFR) overexpressing HCT 116 cells, a human colorectal carcinoma cell line, for comparing their cytotoxicity. In this experimental study, OXPT-CS NPs were synthesized using a fluid system. Encapsulation efficiency percentage (EE%) and oxaliplatin release rate were evaluated. Western blot and cell-based ELISA confirmed scFv production and its binding ability to EGFR, respectively. The Fourier transform infrared spectroscopy (FTIR) determined the conjugation of scFv to OXPT-CS NPs. The NPs were characterized, and their toxicity against the HCT 116 cells was evaluated using 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) and flow cytometry assays. The EE% of OXPT-CS NPs was 93%, and the average diameters were 75.85 ± 8.81 nm and 92.48 ± 9.51 before and after scFv conjugation, respectively. The scFv was purified via affinity chromatography. The western blot method and cell-based ELISA revealed successful purification of scFv and its attachment to EGFR on HCT 116 cells. The FTIR analysis determined the interactions between the scFv and OXPT-CS NPs. According to MTT and flow cytometry results, the targeted delivery system significantly reduced HCT 116 cancer cell viability and increased apoptosis induction up to 99.8%. The scFv-OXPT-CS NPs demonstrated an increased cytotoxic function due to the presence of scFv in its formulation. This delivery system offers a promising method for delivering chemotherapy drugs to cancer cells. More research is needed on the best strategies for improving treatment efficacy by targeting cancer cells.