Publications by authors named "Mohammad Amin Tabatabaiefar"

83 Publications

Molecular diagnosis of -related hereditary hearing loss in a group of patients from two provinces of Iran.

Intractable Rare Dis Res 2021 Feb;10(1):23-30

Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.

The gene has been described as the second gene involved in most cases of autosomal recessive non-syndromic hearing loss (ARNSHL), after . Over 500 different mutations have been reported, with each ethnic population having its own distinctive mutations. Here, we aimed to determine the frequency and mutation profile of the gene from two different provinces (center and west) of Iran. This study included 50 nuclear families with two or more siblings segregating presumed ARNSHL. All affected tested negative for mutations in at the DFNB1 locus and were therefore screened for autozygosity by descent using short tandem repeat polymorphisms (STRPs) of DFNB4. Sanger sequencing was performed to screen the 20 exons of the gene for the families linked to this locus. analyses were also performed using available software tools. Four out of 25 (16%) and 3 of 25 (12%) studied families of Isfahan and Hamedan provinces, respectively. were linked to DFNB4. Sanger sequencing led to the identification of six different mutations, one of which (c.919-2A>G) was recurrent and accounted for 31% of all mutant alleles. One out of 7 (14.3%) families with mutations were confirmed to be Pendred syndrome (PS). The mutations have a high carrying rate in ARNSHL Iranian patients. The identification of a disease causing mutation can be used to establish a genotypic diagnosis and provide important information to the patients and their families.
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http://dx.doi.org/10.5582/irdr.2020.03090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882080PMC
February 2021

Molecular Genetic Study in a Cohort of Iranian Families Suspected to Maturity-Onset Diabetes of the Young, Reveals a Recurrent Mutation and a High-Risk Variant in the Gene.

Adv Biomed Res 2020 27;9:25. Epub 2020 Jun 27.

Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.

Background: Diabetes mellitus (DM) is a group of metabolic disorders in the body, accompanied with increasing blood sugar levels. Diabetes is classified into three groups: Type 1 DM (T1DM), Type 2 DM (T2DM), and monogenic diabetes. Maturity-onset diabetes of the young (MODY) is a monogenic diabetes that is frequently mistaken for T1D or T2D. The aim of this study was to diagnose MODY and its subtype frequency in a diabetic population in Iran.

Materials And Methods: In this study among ten diabetic families that were highly suspected to MODY by nongenetic biomarkers and without any pathogenic mutation in and genes, two patients from two unrelated families were examined via whole-exome sequencing (WES) in order to detect the causative gene of diabetes. Co-segregation analysis of the identified variant was performed using Sanger sequencing.

Results: In this study, no pathogenic variant was found in and genes (MODY2 and MODY3), while these two types of MODY were introduced as the most frequent in other studies. By using WES, a pathogenic variant (p.I488T) was found in one of the patients in gene causing MODY8 that its frequency is very rare in other studied populations. A high-risk variant associated with diabetes was found in another patient.

Conclusion: WES was applied in this study to reveal the cause of MODY in 1 family. This pathogenic mutation was previously reported as a disease causing mutation.
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http://dx.doi.org/10.4103/abr.abr_18_20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7532821PMC
June 2020

Next-generation sequencing reveals a novel pathogenic variant in the gene.

Int J Neurosci 2021 Jan 24:1-5. Epub 2021 Jan 24.

Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.

Introduction: Ataxia telangiectasia (A-T) is a rare autosomal recessive, multisystemic disease. Patients with the A-T syndrome present a broad spectrum of disease phenotypes. The (ataxia telangiectasia mutated) gene, the only causative gene for A-T.

Method: A patient of Persian origin presenting with typical A-T was referred to our genetics centre for specialized genetic counselling and testing. Targeted next-generation sequencing (NGS) was applied. Sanger sequencing was used to confirm the candidate variant. Modelling was performed using the SWISS-MODEL server.

Results: A homozygous stop-gain variant c.829G > T (p.E277*) was found in the gene. This variant was confirmed by Sanger sequencing and modelling of native structure, and truncated structure was performed.

Conclusion: To date, very few pathogenic variants of the gene have been reported from the Iranian population. The finding has implications in molecular diagnostic for A-T in Iran.
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http://dx.doi.org/10.1080/00207454.2020.1826944DOI Listing
January 2021

A pathogenic variant in the transforming growth factor beta I () in four Iranian extended families segregating granular corneal dystrophy type II: A literature review.

Iran J Basic Med Sci 2020 Aug;23(8):1020-1027

Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.

Objectives: Granular and lattice corneal dystrophies (GCDs & LCDs) are autosomal dominant inherited disorders of the cornea. Due to genetic heterogeneity and large genes, unraveling the mutation is challenging.

Materials And Methods: Patients underwent comprehensive clinical examination, and targeted next-generation sequencing (NGS) was used for mutation detection. Co-segregation and analysis was accomplished.

Results: Patients suffered from GCD. NGS disclosed a known pathogenic variant, c.371G>A (p.R124H), in exon 4 of . The variant co-segregated with the phenotype in the family. Homozygous patients manifested with more severe phenotypes. Variable expressivity was observed among heterozygous patients.

Conclusion: The results, in accordance with previous studies, indicate that the c.371G>A in TGFBI is associated with GCD. Some phenotypic variations are related to factors such as modifier genes, reduced penetrance and environmental effects.
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http://dx.doi.org/10.22038/ijbms.2020.36763.8757DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7478261PMC
August 2020

Upregulation of MTOR, RPS6KB1, and EIF4EBP1 in the whole blood samples of Iranian patients with multiple sclerosis compared to healthy controls.

Metab Brain Dis 2020 12 18;35(8):1309-1316. Epub 2020 Aug 18.

Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Poursina St., Tehran, 14155-6447, Iran.

Various genetic and epigenetic mechanisms have been suggested to play roles as the underlying pathophysiology of Multiple Sclerosis (MS). Changes in different parts of the mTOR signaling pathway are among the potential suggested mechanisms based on the specific roles of this pathway in CNS. MTOR, RPS6KB1, and EIFEBP1 genes are among important genes in the mTOR pathway, responsible for the proper function of acting proteins in this signaling pathway. This study aimed to investigate the relative expression levels of these genes in the blood samples of relapsing-remitting MS (RRMS) patients compared to healthy controls. In this case-control study blood samples were collected from 30 newly diagnosed RRMS patients and 30 age and sex-matched healthy controls. mRNA level of MTOR, RPS6KB1, and EIFEBP1 genes were assessed using Real-Time PCR. The expression of MTOR, RPS6KB1, and EIF4EBP1 genes was up regulated in MS patients compared to healthy controls (p < 0.001 for all mentioned genes). Considering gender differences, expression of the mentioned genes was increased among female patients (all P < 0.001). However, no statistically significant changes were observed among male patients. Based on the receiver operating characteristic, MTOR gene had the highest diagnostic value followed by EIF4EBP1 and RPS6KB1 genes in differentiating RRMS patients from controls. In conclusion, we found the simultaneous upregulation of MTOR, RPS6KB1, and EIF4EBP1 genes among RRMS patients. MTOR showed to have the highest diagnostic value compared to other 2 genes in differentiating RRMS patients. Further studies evaluating the importance of these findings from pharmacological and prognostic perspectives are necessary.
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http://dx.doi.org/10.1007/s11011-020-00590-7DOI Listing
December 2020

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

Mol Biol Rep 2020 Jul 4;47(7):5355-5364. Epub 2020 Jul 4.

Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.

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.
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http://dx.doi.org/10.1007/s11033-020-05618-wDOI Listing
July 2020

Genetic polymorphisms of Y-chromosome short tandem repeats (Y-STRs) in a male population from Golestan province, Iran.

Mol Biol Res Commun 2020 Apr;9(1):11-16

Iranian Legal Medicine Research Center, Legal Medicine Organization, Tehran, Iran.

Short Tandem Repeats (STRs), which are located out of pseudo-autosomal parts of the human Y chromosome and passed-down from fathers to the male offspring in a non-recombinant form, are regarded as appropriate markers for forensic purposes and evolutionary investigations. Few studies concerned the genotyping of Y chromosome short tandem repeats (Y-STRs) among the ethnic groups of the north of Iran, especially the province of Golestan which is a multiethnic region of Iran. Thus, in this work we investigated the frequency of Y-STR haplotypes among the male population from Golestan province, to elucidate their identity and kinship patterns. A total number of 106 unrelated male individuals participated in this study. Genomic DNA was extracted from blood samples and the multiplex polymerase chain reaction was employed to amplify DNA fragments. Genotyping was performed using capillary electrophoresis and, finally, allele polymorphisms, haplotype diversity (HD) and haplotype discrimination capacity (DC) were determined using GenAlEXv6.5 and Arlequin v5.3.2 software and compared to other regions of Iran. A total number of 87 unique haplotypes were determined. The highest and least allelic polymorphism was observed for the DYS385b and DYS391 loci, respectively. HD and DC were 0.9962 and 0.8207, respectively. In the case of locus with the least allelic variation, we didn't observe any difference between the Gilan and Golestan but there was a difference between the Golestan and Mazandaran provinces. Our results indicated the efficiency of Y-STRs to be used as genetic markers for forensic medicine, and also the evolutionary comparison of different ethnic groups of Golestan, Iran. Also, a low genetic distance between the population of Golestan with other northern provinces was noticed.
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http://dx.doi.org/10.22099/mbrc.2020.35547.1462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275825PMC
April 2020

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

BMC Med Genet 2020 06 9;21(1):127. Epub 2020 Jun 9.

Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.

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.
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http://dx.doi.org/10.1186/s12881-020-01061-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7285524PMC
June 2020

A Novel Cadherin 23 Variant for Hereditary Hearing Loss Reveals Additional Support for a DFNB12 Nonsyndromic Phenotype of CDH23.

Audiol Neurootol 2020 2;25(5):258-262. Epub 2020 Jun 2.

Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran,

Background And Objectives: Identification of the pathogenic mutations underlying hereditary hearing loss (HL) is difficult, since causative mutations in 60 different genes have so far been reported.

Methods: A comprehensive clinical and pedigree examination was performed on a multiplex family suffering from HL. Direct sequencing of GJB2 and genetic linkage analysis of 5 other most common recessive nonsyndromic HL (ARNSHL) genes were accomplished. Next-generation sequencing (NGS) was utilized to reveal the possible genetic etiology of the disease.

Results: NGS results showed a novel rare variant c.2977G>A (p.Asp993Asn) in the CDH23 gene. The variant, which is a missense in exon 26 of the CDH23 gene, fulfills the criteria of being categorized as pathogenic according to the American College of Medical Genetics and Genomics (ACMG) guideline. Electroretinography rejects the Usher syndrome in the family.

Conclusions: The present study shows that an accurate molecular diagnosis based on NGS technologies largely improves molecular-diagnostic outcome and thus genetic counseling, and helps to clarify the recurrence risk in deaf families.
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http://dx.doi.org/10.1159/000506500DOI Listing
June 2020

Correction to: Clinical and genetic analysis of two wolfram syndrome families with high occurrence of wolfram syndrome and diabetes type II: a case report.

BMC Med Genet 2020 03 20;21(1):58. Epub 2020 Mar 20.

Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Following publication of the original article [1], the authors flagged that the name of 'Asal Hojjat' was misspelled; the name had been spelled as 'Asal Hojat'.
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http://dx.doi.org/10.1186/s12881-020-0980-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7082902PMC
March 2020

Clinical and genetic analysis of two wolfram syndrome families with high occurrence of wolfram syndrome and diabetes type II: a case report.

BMC Med Genet 2020 01 14;21(1):13. Epub 2020 Jan 14.

Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Background: Mutations of the WFS1 gene are responsible for most cases of Wolfram syndrome (WS), a rare, recessively inherited neurodegenerative disorder characterized by juvenile-onset non-autoimmune diabetes mellitus and optic atrophy. Variants of WFS1 are also associated with non-syndromic hearing loss and type-2 diabetes mellitus (T2DM). Our study adds to literature significant associations between WS and T2DM.

Case Presentation: In this study, we analyzed the clinical and genetic data of two families with high prevalence of WS and T2DM. Genetic linkage analysis and DNA sequencing were exploited to identify pathogenic variants. One novel pathogenic variant (c.2243-2244insC) and one known pathogenic (c.1232_1233delCT) (frameshift) variant were identified in exon eight of WFS1 gene.

Conclusions: The mutational and phenotypic spectrum of WS is broadened by our report of novel WFS1 mutation. Our results reveal the value of molecular analysis of WFS1 in the improvement of clinical diagnostics for WS. This study also confirms the role of WFS1 in T2DM.
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http://dx.doi.org/10.1186/s12881-020-0950-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6961406PMC
January 2020

Screening of 10 DFNB Loci Causing Autosomal Recessive Non-Syndromic Hearing Loss in Two Iranian Populations Negative for Mutations.

Iran J Public Health 2019 Sep;48(9):1704-1713

Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.

Background: Autosomal recessive non-syndromic hearing loss (ARNSHL), one of the global public health concerns, is marked by a high degree of genetic heterogeneity. The role of as the most common cause of ARNSHL, is only <20% in the Iranian population. Here, we aimed to determine the relative contribution of several apparently most common loci in a cohort of ARNSHL Iranian families that were negative for the mutations.

Methods: Totally, 80 Iranian ARNSHL families with 3 or more affected individuals from Isfahan and Hamedan provinces, Iran were enrolled in 2017. After excluding mutations in the gene via Sanger sequencing, 60 negative samples (30 families from each province) were analyzed using homozygosity mapping for 10 ARNSHL loci.

Results: Fourteen families were found to be linked to five different known loci, including DFNB4 (5 families), DFNB2 (3 families), DFNB7/11 (1 family), DFNB9 (2 families) and DFNB3 (3 families).

Conclusion: Despite the high heterogeneity of ARNSHL, the genetic causes were determined in 23.5% of the studied families using homozygosity mapping. This data gives an overview of the ARNSHL etiology in the center and west of Iran, used to establish a diagnostic gene panel including most common loci for hearing loss diagnostics.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825662PMC
September 2019

A Patient with Trisomy 4p and Monosomy 10q

Arch Iran Med 2019 07 1;22(7):414-417. Epub 2019 Jul 1.

Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.

Translocations are the most common structural abnormality in the human genome. Carriers of balanced chromosome rearrangements exhibit increased risk of abortion or a chromosomally-unbalanced child. The present study was carried out in 2017 at the Iranian Blood Transfusion Research Center. This study reported a rare chromosomal disorder with 4p duplication and 10q distal deletion syndrome which is associated with various complications at birth. Defects included the following characteristics: dysmorphic facial characteristic, hand or foot anomalies, growth retardation, developmental delay, strabismus, heart defects and renal anomalies. Cytogenetic analysis and array CGH were performed and, for the first time, we reported a patient with trisomy 4p16.3p12 and monosomy 10q26.3. The patient was found to have: arr 4p16.3p12 (37,152-45,490,207) x3, 10q26.3 (134,872,562-135,434,149) x1 genomic imbalances.
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July 2019

Genetic Study of Hepatocyte Nuclear Factor 1 Alpha Variants in Development of Early-Onset Diabetes Type 2 and Maturity-Onset Diabetes of the Young 3 in Iran.

Adv Biomed Res 2019 23;8:55. Epub 2019 Sep 23.

Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.

Background: Maturity-onset diabetes of the young (MODY) is a clinically and genetically heterogeneous group of diabetes characterized by noninsulin-dependent, autosomal-dominant disorder with strong familial history, early age of onset, and pancreatic beta-cell dysfunction. Mutations in at least 14 different genes are responsible for various MODY subtypes. Heterozygous mutations in the hepatocyte nuclear factor 1 alpha () gene are responsible for the MODY3 subtype, which is a common subtype of MODY in different studied populations. To date, more than 450 different variants of this gene have been reported as disease causing for MODY3. This study was carried out to evaluate mutations in Iranian diabetic families fulfilling MODY criteria.

Materials And Methods: Polymerase chain reaction and Sanger sequencing were performed. All the ten exons of the gene were sequenced in ten families, followed by cosegregation analysis and evaluation. Computational protein modeling was accomplished for the identified mutation.

Results: MODY3 was confirmed in two large families by detecting a mutation (p.G253E) in coding regions of . Compound heterozygous state for two common variants in (p.I27 L and p.S487N) was detected in affected members of 5 families, and in one family, a rare benign variant in the coding sequence for Kozak sequence was detected. Two new nonpathogenic variants were found in noncoding regions of .

Conclusion: It seems that mutations are a common cause of MODY in Iranian diabetic patients. Identified common variants in heterozygous state can cause diabetes Type II in earlier ages. The role of rare variant rs3455720 is unknown, and more investigation is needed to uncover the function of this variant.
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http://dx.doi.org/10.4103/abr.abr_54_19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777141PMC
September 2019

A Novel Pathogenic Variant in the CABP2 Gene Causes Severe Nonsyndromic Hearing Loss in a Consanguineous Iranian Family.

Audiol Neurootol 2019 29;24(5):258-263. Epub 2019 Oct 29.

Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran,

Background And Objectives: Hereditary hearing loss (HL) can originate from mutations in one of many genes involved in the complex process of hearing. CABP2 mutations have been reported to cause moderate HL. Here, we report the whole exome sequencing (WES) of a proband presenting with prelingual, severe HL in an Iranian family.

Methods: A comprehensive family history was obtained, and clinical evaluations and pedigree analysis were performed in the family with 2 affected members. After excluding mutations in the GJB2 gene and 7 other most common autosomal recessive nonsyndromic HL (ARNSHL) genes via Sanger sequencing and genetic linkage analysis in the family, WES was utilized to find the possible etiology of the disease.

Results: WES results showed a novel rare variant (c.311G>A) in the CABP2gene.This missense variant in the exon 4 of the CABP2gene meets the criteria of being pathogenic according to the American College of Medical Genetics and Genomics (ACMG) interpretation guidelines.

Conclusions: Up to now, 3 mutations have been reported for the CABP2gene to cause moderate ARNSHL in different populations. Our results show that CABP2variantsalso cause severe ARNSHL, adding CABP2to the growing list of genes that exhibit phenotypic heterogeneity. Expanding our understanding of the mutational spectrum of HL genes is an important step in providing the correct clinical molecular interpretation and diagnosis for patients.
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http://dx.doi.org/10.1159/000502251DOI Listing
May 2020

Evidence for expression of promoterless GFP cassette: Is GFP an ideal reporter gene in biotechnology science?

Res Pharm Sci 2019 Aug;14(4):351-358

Isfahan Cardiovascular Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, I.R. Iran.

Green fluorescent protein (GFP) has played an important role in biochemistry and cell biology as a reporter gene. It has been used to assess the potency of promoters for recombinant protein production. This investigation reveals evidences suggesting that the gene () could be expressed without the promoter. In a study, a pLenti-F/GFP vector was constructed with the purpose to allow GFP expression in transduced cells but not in packaging cells; however, after transfecting the HEK293T cell line, was expressed, compared to pLOX/CW-transfected cells showed expression lag, lower levels and reduced percentage of GFP expression in the cells. This unexpected result could be due to auto transduction in packaging cell, possible retrotransposon activity in the cell line, possible contamination of pLenti-F/GFP with the pLOX/CWgfp and possible presence of a promoter within backbone of the vector. All the possibilities were ruled out. To exclude the possibility that a sequence within the region might act as a promoter, the fragment to be transfected was minimized to a region containing "from the start of the gene to 5'LTR R". The gene was again expressed. Therefore, our findings suggest the does not need promoter for expression. This should appeal to the researchers designing GFP based assays to evaluate the potency of promoters, since possible aberrant expression may have a potential to influence on the results of a planned experiment.
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http://dx.doi.org/10.4103/1735-5362.263559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6714119PMC
August 2019

Epigenetics and Common Non Communicable Disease.

Adv Exp Med Biol 2019 ;1121:7-20

Genetics Department, Erythron Pathobiology and Genetics lab, Isfahan, Iran.

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.
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http://dx.doi.org/10.1007/978-3-030-10616-4_2DOI Listing
August 2019

Clinical and molecular assessment of 13 Iranian families with Wolfram syndrome.

Endocrine 2019 11 16;66(2):185-191. Epub 2019 Jul 16.

Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Poursina Ave, 16 Azar St. Keshavarz BLVD, Tehran, 1417613151, Iran.

Purpose: Wolfram syndrome (WS) is a rare genetic disorder described by a pattern of clinical manifestations such as diabetes mellitus, diabetes insipidus, optic nerve atrophy, sensorineural hearing loss, urinary tract abnormalities, and psychiatric disorders. WFS1 and WFS2 loci are the main genetic loci associated with this disorder.

Methods: In the current study, we investigated associations between these loci and WS via STR markers and homozygosity mapping in 13 Iranian families with WS. All families were linked to WFS1 locus.

Results: Mutation analysis revealed four novel mutations (Q215X, E89X, S168Del, and E391Sfs*51) in the assessed families. Bioinformatics tools confirmed the pathogenicity of the novel mutations. Other identified mutations were previously reported in other populations for their pathogenicity.

Conclusions: The current study adds to the mutation repository of WS and shows a panel of mutations in Iranian population. Such panel would facilitate genetic counseling and prenatal diagnosis in families with WS cases.
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http://dx.doi.org/10.1007/s12020-019-02004-wDOI Listing
November 2019

Homozygosity mapping and direct sequencing identify a novel pathogenic variant in the CISD2 gene in an Iranian Wolfram syndrome family.

Acta Diabetol 2020 Jan 15;57(1):81-87. Epub 2019 Jul 15.

Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, 81746-73461, Iran.

Aims: Wolfram syndrome (WS) is a rare recessive neurodegenerative disorder characterized by diabetes mellitus and optic atrophy. Mortality and morbidity rate of the disease is high in adulthood due to neurological and respiratory defects. So far, two WS genes, WFS1 (more than 90% of cases) and CISD2, have been identified. In the present study, we aimed to determine the role of WFS2 in a group of Iranian WS families.

Methods: We recruited 27 families with the clinical diagnosis of WS. Homozygosity mapping was implemented using short tandem repeat polymorphic markers and bi-directional sequencing of the CISD2 gene in families negative for WFS1 mutations. The candidate variant was checked among family members. In silico analysis and protein modeling were applied to assess the pathogenic effect of the variant. Tetra-primers ARMS PCR was set up for checking the variant in 50 ethnic-matched controls.

Results: One family showed homozygosity by descent at WFS2. A novel missense variant, c.310T > C (p.S104P), was found in exon 2 of the CISD2 gene. Computational predictions revealed its pathogenic effect on protein structure, function, and stability. Parents and his healthy brother were heterozygous for the variant. The variant was not observed in the control group.

Conclusions: This is the first study that elucidates the role of the CISD2 gene among Iranian WS families with a novel disease-causing missense variant. Next-generation sequencing could unravel disease-causing genes in remained families to expand genetic heterogeneity of WS.
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http://dx.doi.org/10.1007/s00592-019-01381-yDOI Listing
January 2020

A pathogenic variant in is associated with Pendred syndrome in a consanguineous Iranian family.

Int J Audiol 2019 10 12;58(10):628-634. Epub 2019 Jun 12.

Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences , Shahrekord , Iran.

Hearing loss (HL) is a common sensory deficit with high phenotypic and genotypic heterogeneity. A large Iranian family with HL was genetically assessed in this study. A proband from a consanguineous multiplex HL family from Iran was examined via Targeted Next-Generation Sequencing (TNGS). Sanger sequencing allowed the segregation analysis of the variant of interest and the investigation of its presence in a cohort of 50 ethnicity-matched healthy control individuals. The gene was previously associated with HL. Therefore, to determine whether the variant was specifically associated with Pendred Syndrome (PDS) or DFNB4, biochemical analyses, PTA, thyroid scans by Tc99m, perchlorate discharge test and high-resolution CT scan of the temporal bone were carried out on the affected family members. Ten members of a large multiplex Iranian family with HL were recruited in this study. In addition, 50 unrelated healthy controls of the same ethnic group were randomly selected to genotype the variant. A homozygous missense variant (NM_000441.1: c.1211C > T/p.Thr404Ile) in exon 10 was found segregating in the family. Based on the ACMG's guidelines, the variant was classified as pathogenic. This study expands the spectrum of pathogenic variants in hearing loss.
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http://dx.doi.org/10.1080/14992027.2019.1619945DOI Listing
October 2019

Next-generation sequencing reveals a novel pathological mutation in the TMC1 gene causing autosomal recessive non-syndromic hearing loss in an Iranian kindred.

Int J Pediatr Otorhinolaryngol 2019 Sep 21;124:99-105. Epub 2019 May 21.

Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran. Electronic address:

Objectives: Hearing loss (HL) is the most common sensory-neural disorder with excessive clinical and genetic heterogeneity, which negatively affects life quality. Autosomal recessive non-syndromic hearing loss (ARNSHL) is the most common form of the disease with no specific genotype-phenotype correlation in most of the cases. Whole exome sequencing (WES) is a powerful tool to overcome the problem of finding mutations in heterogeneous disorders.

Methods: A comprehensive clinical and pedigree examination was performed on a multiplex family from Khuzestan province suffering from hereditary HL. Direct sequencing of GJB2 and genetic linkage analysis of DFNB1A/B was accomplished. WES was utilized to find possible genetic etiology of the disease. Co-segregation analysis of the candidate variant was done. High resolution melting analysis was applied to detect variant status in 50 healthy matched controls.

Results: Clinical investigations suggested ARNSHL in the pedigree. The family was negative for DFNB1A/B. WES revealed a novel nonsense mutation, c.256G > T (p.Glu86*), in TMC1 segregating with the phenotype in the pedigree. The variant was absent in the controls.

Conclusion: Here, we report successful application of WES to identify the molecular pathogenesis of ARNSHL in a large family. The novel nonsense TMC1 variant meets the criteria of being pathogenic according to the ACMG-AMP variant interpretation guideline.
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http://dx.doi.org/10.1016/j.ijporl.2019.05.023DOI Listing
September 2019

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

Audiol Neurootol 2019 3;24(1):25-31. Epub 2019 Apr 3.

Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran,

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.
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http://dx.doi.org/10.1159/000498843DOI Listing
February 2020

Engineered zinc-finger nuclease to generate site-directed modification in the KLF1 gene for fetal hemoglobin induction.

J Cell Biochem 2018 Dec 16. Epub 2018 Dec 16.

Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.

Elevation of hemoglobin F (HbF) ameliorates symptoms of β-thalassemia, as a common autosomal recessive disorder. In this study, the ability of an engineered zinc-finger nuclease (ZFN) system was assesed to disrupt the KLF1 gene to inhibit the γ to β hemoglobin switching in K562 cells. This study was performed using a second generation integration-deficient lentiviral vector assigned to transient gene targeting. The sequences coding for zinc finger protein arrays were designed and subcloned in TDH plus as a transfer vector. Transduction of K562 cells was performed with the integrase minus lentivirus containing ZFN. The indel percentage of the transducted cells with lentivirus containing ZFN was about 29%. Differentiation of K562 cell line into erythroid cell lineage was induced with cisplatin concentration of 15 µg/mL. After differentiation, γ-globin and HbF expression were evaluated using real-time reverse-transcription polymerase chain reaction and hemoglobin electrophoresis methods. The levels of γ-globin messenger RNA were nine-fold higher in the ZFN treated cells compared with untreated cells 5 days after differentiation. Hemoglobin electrophoresis method showed the same results for HbF level measurement. Application of the ZFN tool to induce KLF1 gene mutation in adult erythroid progenitors might be a candidate to stimulate HbF expression in β-thalassemia patients.
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http://dx.doi.org/10.1002/jcb.28130DOI Listing
December 2018

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.

J Audiol Otol 2019 Jan 7;23(1):20-26. Epub 2018 Dec 7.

Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, 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 population.
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http://dx.doi.org/10.7874/jao.2018.00185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6348308PMC
January 2019

Applying Two Different Bioinformatic Approaches to Discover Novel Genes Associated with Hereditary Hearing Loss via Whole-Exome Sequencing: ENDEAVOUR and HomozygosityMapper.

Adv Biomed Res 2018 31;7:141. Epub 2018 Oct 31.

Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.

Background: Hearing loss (HL) is a highly prevalent heterogeneous deficiency of sensory-neural system with involvement of several dozen genes. Whole-exome sequencing (WES) is capable of discovering known and novel genes involved with HL.

Materials And Methods: Two pedigrees with HL background from Khuzestan province of Iran were selected. Polymerase chain reaction-sequencing of and homozygosity mapping of 16 DFNB loci were performed. One patient of the first and two affected individuals from the second pedigree were subjected to WES. The result files were analyzed using tools on Ubuntu 16.04. Short reads were mapped to reference genome (hg19, NCBI Build 37). Sorting and duplication removals were done. Variants were obtained and annotated by an online software tool. Variant filtration was performed. In the first family, ENDEAVOUR was applied to prioritize candidate genes. In the second family, a combination of shared variants, homozygosity mapping, and gene expression were implemented to launch the disease-causing gene.

Results: sequencing and linkage analysis established no homozygosity-by-descent at any DFNB loci. Utilizing ENDEAVOUR, : C.C857G (.A286G), and : C.C5557T (.R1853C) were put forward, but none of the variants co-segregated with the phenotype. Two genes, and , were prioritized in the homozygous regions detected by HomozygosityMapper.

Conclusion: WES is regarded a powerful approach to discover molecular etiology of Mendelian inherited disorders, but as it fails to enrich GC-rich regions, incapability of capturing noncoding regulatory regions and limited specificity and accuracy of copy number variations detection tools from exome data, it is assumed an insufficient procedure.
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http://dx.doi.org/10.4103/abr.abr_80_18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6233028PMC
October 2018

A Comprehensive Genetic and Clinical Evaluation of Waardenburg Syndrome Type II in a Set of Iranian Patients.

Int J Mol Cell Med 2018 27;7(1):17-23. Epub 2018 Mar 27.

Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Waardenburg syndrome (WS) is a neurocristopathy with an autosomal dominant mode of inheritance, and considerable clinical and genetic heterogeneity. WS type II is the most common type of WS in many populations presenting with sensorineural hearing impairment, heterochromia iridis, hypoplastic blue eye, and pigmentary abnormalities of the hair and skin. To date, mutations of , , and have been implicated in the pathogenesis of WS2. Although different pathogenic mutations have been reported in many ethnic groups, the data on Iranian WS2 patients is insufficient. 31 WS2 patients, including 22 men and 9 women from 14 families were included. Waardenburg consortium guidelines were employed for WS2 diagnosis. WS2 patients underwent screening for , , and mutations using direct sequencing and MLPA analysis. Clinical evaluation revealed prominent phenotypic variability in Iranian WS2 patients. Sensorineural hearing impairment and heterochromia iridis were the most common features (67% and 45%, respectively), whereas anosmia was the least frequent phenotype. Molecular analysis revealed a heterozygous c.640C>T (p.R214X) in and a heterozygous gross deletion in the study population. Our data help illuminate the phenotypic and genotypic spectrum of WS2 in an Iranian series of patients, and could have implications for the genetic counseling of WS in Iran.
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http://dx.doi.org/10.22088/IJMCM.BUMS.7.1.17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6134422PMC
March 2018

Molecular genetic study of glutaric aciduria, type I: Identification of a novel mutation.

J Cell Biochem 2019 03 11;120(3):3367-3372. Epub 2018 Sep 11.

Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.

Glutaric acidemia type I (GA-1) is an inborn error of metabolism due to deficiency of glutaryl-CoA dehydrogenase (GCDH), which catalyzes the conversion of glutaryl-CoA to crotonyl-CoA. GA-1 occurs in about 1 in 100 000 infants worldwide. The GCDH gene is on human chromosome 19p13.2, spans about 7 kb and comprises 11 exons and 10 introns. Tandem mass spectrometry (MS/MS) was used for clinical diagnosis in a proband from Iran with GA-1. Sanger sequencing was performed using primers specific for coding exons and exon-intron flanking regions of the GCDH gene in the proband. Cosegregation analysis and in silico assessment were performed to confirm the pathogenicity of the candidate variant. A novel homozygous missense variant c.1147C > A (p.Arg383Ser) in exon 11 of GCDH was identified. Examination of variant through in silico software tools determines its deleterious effect on protein in terms of function and stability. The variant cosegregates with the disease in family. In this study, the clinical and molecular aspects of GA-1 were investigated, which showed one novel mutation in the GCDH gene in an Iranian patient. The variant is categorized as pathogenic according to the the guideline of the American College of Medical Genetics and Genomics (ACMG) for variant interpretation. This mutation c.1147C > A (p.Arg383Ser) may also be prevalent among Iranian populations.
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http://dx.doi.org/10.1002/jcb.27607DOI Listing
March 2019

A novel variant of SLC26A4 and first report of the c.716T>A variant in Iranian pedigrees with non-syndromic sensorineural hearing loss.

Am J Otolaryngol 2018 Nov - Dec;39(6):719-725. Epub 2018 Jul 27.

Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran. Electronic address:

The autosomal recessive non-syndromic hearing loss (ARNSHL) can be associated with variants in solute carrier family 26, member 4 (SLC26A4) gene and is the second most common cause of ARNSHL worldwide. Therefore, this study aims to determine the contribution of the SLC26A4 genotype in the hearing loss (HL) of 40 ARNSHL pedigrees in Iran. A cohort of the 40 Iranian pedigrees with ARNSHL, having no mutation in the GJB2 gene, was selected. The linkage analysis with five short tandem repeat (STR) markers linked to SLC26A4 was performed for the 40 ARNSHL pedigrees. Then, two out of the 40 pedigrees with ARNSHL that linked to DFNB4 locus were further screened to determine the variants in all exons of SLC26A4 gene by direct DNA sequencing. The 21 exons of SCL26A4 were analyzed for the two pedigrees. A known variant (c.716T>A homozygote), it is the first reported incidence in Iran, a novel variant (c.493A>C homozygote) were detected in the two pedigrees and pathogenesis of c.493A>C confirmed in this study with review 100 hearing ethnically matched controls by PCR-RFLP analysis. The present study suggests that the SLC26A4 gene plays a crucial role in the HL occurring in Iranian pedigrees. Also, the results probably support the specificity and unique spectrum of SLC26A4 variants among Iranian HL patients. Molecular study of SLC26A4 gene may lead to elucidation of the profile of the population-specific variants which has importance in diagnostics of HL.
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http://dx.doi.org/10.1016/j.amjoto.2018.07.022DOI Listing
February 2019

A novel pathogenic variant in the MARVELD2 gene causes autosomal recessive non-syndromic hearing loss in an Iranian family.

Genomics 2019 07 9;111(4):840-848. Epub 2018 May 9.

Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran. Electronic address:

Background And Aims: Hearing loss (HL) is the most common sensorineural disorder and one of the most common human defects. HL can be classified according to main criteria, including: the site (conductive, sensorineural and mixed), onset (pre-lingual and post-lingual), accompanying signs and symptoms (syndromic and non-syndromic), severity (mild, moderate, severe and profound) and mode of inheritance (Autosomal recessive, autosomal dominant, X-linked and mitochondrial). Autosomal recessive non-syndromic HL (ARNSHL) forms constitute a major share of the HL cases. In the present study, next-generation sequencing (NGS) was applied to investigate the underlying etiology of HL in a multiplex ARNSHL family from Khuzestan province, southwest Iran.

Methods: In this descriptive study, 20 multiplex ARNSHL families from Khuzestan province, southwest of Iran were recruited. After DNA extraction, genetic linkage analysis (GLA) was applied to screen for a panel of more prevalent loci. One family, which was not linked to these loci, was subjected to Otogenetics deafness Next Generation Sequencing (NGS) panel.

Results: NGS results showed a novel deletion-insertion variant (c.1555delinsAA) in the MARVELD2 gene. The variant which is a frameshift in the seventh exon of the MARVELD2 gene fulfills the criteria of being categorized as pathogenic according to the American College of Medical Genetics and Genomics (ACMG) guideline.

Conclusion: NGS is very promising to identify the molecular etiology of highly heterogeneous diseases such as HL. MARVELD2 might be important in the etiology of HL in this region of Iran.
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http://dx.doi.org/10.1016/j.ygeno.2018.05.008DOI Listing
July 2019

A novel missense mutation in GIPC3 causes sensorineural hearing loss in an Iranian family revealed by targeted next-generation sequencing.

Int J Pediatr Otorhinolaryngol 2018 May 31;108:8-11. Epub 2018 Jan 31.

Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran. Electronic address:

Background: Recent studies have confirmed the utility of targeted next-generation sequencing (NGS), providing a remarkable opportunity to find variants in known disease genes, especially in genetically heterogeneous disorders such as hearing loss (HL).

Methods: After excluding mutations in the most common autosomal recessive non-syndromic HL (ARNSHL) genes via Sanger sequencing and genetic linkage analysis, we performed NGS in the proband an Iranian family with ARNSHL. The NimbleGen sequence capture array captures codingsequences (CDSs) and 100 bp of the flanking sequence of 129 common deafness genes (cat# Oto-DA3). NGSwas performed on the IlluminaHiSeq2000. BWA, SAMtools, Picard, GATK, Variant Tools, ANNOVAR, and IGV were applied for Bioinformatics analyses. Data filtering with allele frequencies (<5% in the 1000 Genomes Project and 5400 NHLBI exomes) and PolyPhen2/SIFTscores (>0.95) prioritized 1indel (insertions/deletions) and 3 missense variants in this family. Eventually, Sanger sequencing, segregation pattern, the frequency in 50 healthy matched normal controls, and evolutionary conservation of amino acid residues revealed the pathogenic variant.

Results: We identified a novel missenseGIPC3 mutation, c.472G > A (p.Glu158 Lys). The pathogenicity of GIPC3c.472G > A was supported by its absence in the population databases and the healthy-matched controls.Sanger sequencing confirmed co-segregation of the mutation with HL.

Conclusions: This study is the first report of the contribution of theGIPC3 gene to HL in the Iranian population.Targeted NGS allows easier detection of mutations in relatively uncommon deafness genes in families with ARNSHL.
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http://dx.doi.org/10.1016/j.ijporl.2018.01.006DOI Listing
May 2018