Trends of human brucellosis in Central Iran (2010-2018).

BACKGROUND: Brucellosis is one of the most common infectious diseases worldwide which is caused by direct contact with affected animals or their products. It puts a huge impact on the economy, society, and the environment. Iran is the fourth endemic country for brucellosis in the world. It has been described a new epidemiological feature of the disease and its trends in Isfahan province, as one of the endemic areas of brucellosis in Central Iran. MATERIALS AND METHODS: This is a cross-sectional, population-based study. Data collection was performed using epidemiological questionnaires through Epi-2006 software from the private and public sectors in 22 districts of Isfahan province over 9 years (2010-2018). The results were obtained by the description statistics using the SPSS Statistics software version 20 (SPSS Inc., Chicago, IL, USA). RESULTS: Altogether, 5751 new brucellosis patients were recorded over 9 years. About 70% of these cases were male. The majority of cases had occurred in the age group of 21-30 years. The average incidence of brucellosis over the 9 years was 14.1 cases/100,000 population including 8.8 in the urban versus 45.2 cases in the rural areas. During the 9-year study period, the incidence of brucellosis was increased between 2010 and 2014. From 2014 to 2017, the trend has been decreasing, but in the last year of the study, the trend has been increasing again. Seasonally, the incidence rate was variable between the lowest from October to January and the highest from June to July. CONCLUSION: According to the fluctuation of incidence trend of brucellosis during the 9-year study period in Central Iran, it seems some policy changes regarding to the control and prevention of brucellosis have a role, changes that should be fixed and corrected.

A novel pathogenic variant in the LRTOMT gene causes autosomal recessive non-syndromic hearing loss in an Iranian family.

BACKGROUND: Hearing loss (HL) is the most common sensorineural disorder with high phenotypic and genotypic heterogeneity, which negatively affects life quality. Autosomal recessive non-syndromic hearing loss (ARNSHL) constitutes a major share of HL cases. In the present study, Whole exome sequencing (WES) was applied to investigate the underlying etiology of HL in an Iranian patient with ARNSHL. METHODS: A proband from an Iranian consanguineous family was examined via WES, following GJB2 sequencing. WES was utilized to find possible genetic etiology of the disease. Various Bioinformatics tools were used to assess the pathogenicity of the variants. Co-segregation analysis of the candidate variant was carried out. Interpretation of variants was performed according to the American College of Medical Genetics and Genomics (ACMG) guidelines. RESULTS: WES results showed a novel frameshift (16 bp deletion) variant (p.Ala170Alafs*20) in the LRTOMT gene. This variant, which resides in exon 6, was found to be co-segregating in the family. It fulfils the criteria set by the ACMG guidelines of being pathogenic. CONCLUSION: Here, we report successful application of WES to identify the molecular pathogenesis of ARNSHL, which is a genetically heterogeneous disorder, in a patient with ARNSHL.

Whole exome sequencing identifies novel compound heterozygous pathogenic variants in the MYO15A gene leading to autosomal recessive non-syndromic hearing loss.

Autosomal recessive non-syndromic hearing loss (ARNSHL) is a highly heterogeneous disease, for which more than 70 genes have been identified. MYO15A mutations have been reported to cause congenital severe-to-profound HL. In this study, we applied the whole exome sequencing (WES) to find the cause of HL in an Iranian family. A proband from an Iranian non-consanguineous family with hearing impaired parents, was examined via WES, after excluding GJB2 mutations as the most common ARNSHL gene via Sanger sequencing. Co-segregation analysis of the candidate variant was done in the family members. Interpretation of variants was according to the American College of Medical Genetics and Genomics (ACMG) guidelines. WES results showed novel compound heterozygous variants (p.Arg1507Ter and p.Val2815Valfs*10) in the MYO15A gene. These two variants, residing in highly conserved regions, were found to be co-segregating in the family and fulfill the criteria of being categorized as pathogenic, according to the ACMG guidelines. Here, we report successful application of WES to identify the molecular pathogenesis of ARNSHL in a patient with ARNSHL, as an example of an extremely heterogeneous disease. In agreement with previous studies, MYO15A is regarded to be important in causing HL in Iran.

Epigenetics and Common Non Communicable Disease.

Common Non communicable diseases (NCDs), such as cardiovascular disease, cancer, schizophrenia, and diabetes, have become the major cause of death in the world. They result from an interaction between genetics, lifestyle and environmental factors. The prevalence of NCDs are increasing, and researchers hopes to find efficient strategies to predict, prevent and treat them. Given the role of epigenome in the etiology of NCDs, insight into epigenetic mechanisms may offer opportunities to predict, detect, and prevent disease long before its clinical onset.Epigenetic alterations are exerted through several mechanisms including: chromatin modification, DNA methylation and controlling gene expression by non-coding RNAs (ncRNAs). In this chapter, we will discuss about NCDs, with focus on cancer, diabetes and schizophrenia. Different epigenetic mechanisms, categorized into two main groups DNA methylation and chromatin modifications and non-coding RNAs, will be separately discussed for these NCDs.

Clinical characterizations and molecular genetic study of two co-segregating variants in PDZD7 and PDE6C genes leading simultaneously to non-syndromic hearing loss and achromatopsia.

BACKGROUND: Autosomal recessive non-syndromic hearing loss (NSHL) and cone dystrophies (CODs) are highly genetically and phenotypically heterogeneous disorders. In this study, we applied the whole exome sequencing (WES) to find the cause of HL and COD in an Iranian consanguineous family with three affected individuals. METHODS: Three members from an Iranian consanguineous family who were suffering from NSHL and visual impairment were ascertained in this study. Comprehensive clinical evaluations and genetic analysis followed by bioinformatic and co-segregation studies were performed to diagnose the cause of these phenotypes. Data were collected from 2020 to 2022. RESULTS: All cases showed congenital bilateral NSHL, decreased visual acuity, poor color discrimination, photophobia and macular atrophy. Moreover, cornea, iris and anterior vitreous were within normal limit in both eyes, decreased foveal sensitivity, central scotoma and generalized depression of visual field were seen in three cases. WES results showed two variants, a novel null variant (p.Trp548Ter) in the PDE6C gene causing COD type 4 (Achromatopsia) and a previously reported variant (p.Ile84Thr) in the PDZD7 gene causing NSHL. Both variants were found in the cis configuration on chromosome 10 with a genetic distance of about 8.3 cM, leading to their co-inheritance. However, two diseases could appear independently in subsequent generations due to crossover during meiosis. CONCLUSIONS: Here, we could successfully determine the etiology of a seemingly complex phenotype in two adjacent genes. We identified a novel variant in the PDE6C gene, related to achromatopsia. Interestingly, this variant could cooperatively cause visual disorders: cone dystrophy and cone-rod dystrophy.

A Novel Germline Pathogenic Variant of RECQL4 Gene in an Iranian Pedigree with Familial Squamous Cell Carcinoma: A Brief Report.

Squamous cell carcinoma (SCC) is the most common human solid tumor and the leading cause of cancer death. SCC of the breast is a very rare type of cancer that has not been well researched. Early identification of the genetic factors involved can lead to early diagnosis and targeted treatment. The present study was conducted in 2018 at Isfahan University of Medical Sciences (Isfahan, Iran). The proband was a 66-year-old woman with SCC of the breast and a positive family history of cancer. Blood DNA samples were used for whole-exome sequencing to identify germline pathogenic variants. Variant annotation and prioritization were done on variant call format files using bioinformatics software tools. The screened variants were confirmed using the Sanger sequencing method. Co-segregation analysis was performed on the blood DNA samples of the first- and second-degree relatives of the proband to assess the presence of the mutation. A novel germline pathogenic variant was identified in the RECQL4 gene of the family. RECQL4 is a known protein in DNA repair and replication. Considering its effect on other types of SCC, it may play an important role in SCC initiation and progression in the breast.

Novel in-frame duplication variant characterization in late infantile metachromatic leukodystrophy using whole-exome sequencing and molecular dynamics simulation.

Metachromatic leukodystrophy (MLD) is a neurodegenerative lysosomal storage disease caused by a deficiency in the arylsulfatase A (ARSA). ARSA deficiency leads to sulfatide accumulation, which involves progressive demyelination. The profound impact of early diagnosis on MLD treatment options necessitates the development of new or updated analysis tools and approaches. In this study, to identify the genetic etiology in a proband from a consanguineous family with MLD presentation and low ARSA activity, we employed Whole-Exome Sequencing (WES) followed by co-segregation analysis using Sanger sequencing. Also, MD simulation was utilized to study how the variant alters the structural behavior and function of the ARSA protein. GROMACS was applied and the data was analyzed by RMSD, RMSF, Rg, SASA, HB, atomic distance, PCA, and FEL. Variant interpretation was done based on the American College of Medical Genetics and Genomics (ACMG) guidelines. WES results showed a novel homozygous insertion mutation, c.109_126dup (p.Asp37_Gly42dup), in the ARSA gene. This variant is located in the first exon of ARSA, fulfilling the criteria of being categorized as likely pathogenic, according to the ACMG guidelines and it was also found to be co-segregating in the family. The MD simulation analysis revealed this mutation influenced the structure and the stabilization of ARSA and led to the protein function impairment. Here, we report a useful application of WES and MD to identify the causes of a neurometabolic disorder.

Whole exome sequencing identified a novel LAMA2 frameshift variant causing merosin-deficient congenital muscular dystrophy in a patient with cardiomyopathy, and autism-like behavior.

Muscular dystrophy (MD) is a group of multiple muscle diseases, which causes severely impaired motor ability, degeneration and dysfunctions in the musculoskeletal system, respiratory failure and feeding difficulties. LAMA2-related MD is caused by pathogenic variants in the LAMA2 gene, encoding laminin a2 chain, a component of the skeletal muscle extracellular matrix protein laminin-α2ß1γ1. We performed clinical examination and molecular genetic analysis in a patient with congenital MD (CMD), and autism-like phenotype. We performed whole exome sequencing (WES) to find possible genetic etiology of CMD in an Iranian non-consanguineous patient. The pathogenicity of the variants was assessed using various Bioinformatics tools. American College of Medical Genetics and Genomics (ACMG) guidelines were used to interpret the variant and Sanger sequencing in the patient and her family was applied for the confirmation of the variant. WES results showed a novel frameshift homozygous variant (p.Tyr1313LeufsTer4) in the LAMA2 gene leading to the CMD phenotype. This variant resides in a highly conserved region and was found to be co-segregating in the family. It fulfils the criteria of being pathogenic. We successfully identified a novel LAMA2 pathogenic variant in an Iranian patient suffering from CMD and autism using WES. Identification of disease-causing variant in autosomal recessive disorders such as CMD can be useful in genetic counseling, prenatal diagnosis, and predicting prognosis of the disease.

Whole-Exome Sequencing Identifies a Recurrent Small In-Frame Deletion in MYO15A Causing Autosomal Recessive Nonsyndromic Hearing Loss in 3 Iranian Pedigrees.

BACKGROUND: Hearing loss (HL) is the most prevalent and genetically heterogeneous sensory disabilities in humans throughout the world. METHODS: In this study, we used whole-exome sequencing (WES) to determine the variant causing autosomal recessive nonsyndromic hearing loss (ARNSHL) segregating in 3 separate Iranian consanguineous families (with 3 different ethnicities: Azeri, Persian, and Lur), followed by cosegregation analysis, computational analysis, and structural modeling using the I-TASSER (Iterative Threading ASSEmbly Refinement) server. Also, we used speech-perception tests to measure cochlear implant (CI) performance in patients. RESULTS: One small in-frame deletion variant (MYO15A c.8309_8311del (p.Glu2770del)), resulting in deletion of a single amino-acid residue was identified. We found it to be cosegregating with the disease in the studied families. We provide some evidence suggesting the pathogenesis of this variant in HL based on the American College of Medical Genetics (ACMG) and Genomics guidelines. Evaluation of auditory and speech performance indicated favorable outcome after cochlear implantation in our patients. CONCLUSIONS: The findings of this study demonstrate the utility of WES in genetic diagnostics of HL.