Publications by authors named "Mohammad Reza Pourreza"

10 Publications

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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

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

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

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

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

GJB2 mutations causing autosomal recessive non-syndromic hearing loss (ARNSHL) in two Iranian populations: Report of two novel variants.

Int J Pediatr Otorhinolaryngol 2018 Apr 31;107:121-126. Epub 2018 Jan 31.

Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran; Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Noncommunicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran. Electronic address:

Objective: Hereditary hearing loss (HL) is a noticeable concern in medicine all over the world. On average, 1 in 166 babies born are diagnosed with HL in Iran, which makes it a major public health issue. Autosomal recessive non-syndromic HL (ARNSHL) is the most prevalent form of HL. Although over 60 genes have been identified for ARNSHL, GJB2 mutations are the most prevalent causes of ARNSHL in many populations. Previous studies have estimated the average frequency of GJB2 mutations to be between 16 and 18% in Iran, but would vary among different ethnic groups. In the present study, we aimed to determine the frequency and mutation profile of 70 deaf patients from two different provinces (center and west) of Iran.

Methods: We enrolled 70 Iranian deaf patients with ARNSHL from Isfahan (40 family) and Hamedan (30 family) provinces. After extraction of genomic DNA, the entire coding region of GJB2 was directly sequenced in all patients. Multiplex PCR was used for detection of del(GJB6-D13S1830) and del(GJB6-D13S1854) in the GJB6 gene. In silico analyses were also performed by available software tools.

Results: A total of eleven different mutations were detected, nine of which were previously reported and the other two (c.130T > G and c.178T > G) were novel. Homozygous GJB2 mutations were observed in 22.5% and 20% of all the subjects from Isfahan and Hamedan provinces, respectively. c.35delG was the most frequent mutation. One compound heterozygous genotype (c.358_360delGAG/c.35delG) was observed for c.35delG. Screening for the two GJB6 deletions did not reveal any positive sample among heterozygous or GJB2 negative samples.

Conclusions: The present study suggests that mutations in the GJB2 gene specially c.35delG are important causes of ARNSHL in the center and west of Iran. Totally, 15% of the patients were heterozygous carriers. Further investigation is needed to detect the genetic cause of HL in the patients with monoallelic GJB2 mutations.
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http://dx.doi.org/10.1016/j.ijporl.2018.01.012DOI Listing
April 2018

A Novel Pathologic Variant in OTOF in an Iranian Family Segregating Hereditary Hearing Loss.

Otolaryngol Head Neck Surg 2018 06 27;158(6):1084-1092. Epub 2018 Feb 27.

6 Department of Medical Genetics, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.

Objective Hearing loss (HL) is the most common sensory-neural defect and the most heterogeneous trait in humans, with the involvement of >100 genes, which make a molecular diagnosis problematic. Next-generation sequencing (NGS) is a new strategy that can overcome this problem. Study Design Descriptive experimental study. Setting Diagnostic laboratory. Subjects and Methods A comprehensive family history was obtained, and clinical evaluations and pedigree analysis were performed in a family with multiple individuals with HL. As the first tier, GJB2 was sequenced, and genetic linkage analysis of DFNB1A/B was performed to rule out the most common cause of the disease. Targeted NGS was used to unravel the molecular etiology of the disease in the HL-associated genes in the proband. Two homozygous variants remained in OTOF after proper filtration. Cosegregation and in silico analysis were done. Preimplantation genetic diagnosis (PGD) was accomplished via linkage analysis and direct sequencing of the pathogenic variant. Results Clinical evaluations suggested autosomal recessive nonsyndromic HL. Two homozygous variants, c.367G>A (p.Gly123Ser) and c.1392+1G>A, were identified in cis status. c.1392+1G>A met the criteria for being pathogenic according to the variant interpretation guideline of the American College of Medical Genetics and Genomics. PGD was successfully performed to prevent the recurrence of the disease in the related family. Conclusion A novel OTOF mutation causing HL was identified. Here, we report the effectiveness of the combined application of targeted NGS and PGD in diagnosis and prevention of hereditary HL.
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http://dx.doi.org/10.1177/0194599818759007DOI Listing
June 2018

A Report of a Novel Mutation in Human Prostacyclin Receptor Gene in Patients Affected with Migraine.

Iran J Psychiatry 2017 Jul;12(3):219-222

Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Non-Communicable Diseases, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran; Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.

The human prostacyclin receptor gene encodes the human prostacyclin receptor, which is a part of the vasodilator system, during migraine attacks and almost certainly plays an important role in the mechanism of this disease. The present study aimed at determining any variants in PTGIR gene by means of PCR and direct sequencing. Blood samples were taken from the patients, and genomic DNA was extracted. Polymerase chain reaction was performed on the extracted DNA. The PCR products were then sequenced using the Sanger method. When reviewing the familial and clinicopathological history of the 2 patients, we found that both had symptoms of migraine with visual aura and that their mothers were also suffering from migraine. Their parents were not relatives prior to marriage. Direct sequencing of Exon 2 of the PTGIR gene showed the presence of 2 mutations. These mutations were heterozygous and made the following changes: g.1626T>A, c.754T>A, cDNA.867T>A, and p.S252T for the first mutation, and c.753C>T, cDNA866C>T, g.1625C>T, and p.C251C for the second mutation. The first mutation altered the amino acid and was a novel mutation. The second change was a conservative mutation that has already been reported. The prediction results of silico studies indicated that the c.754T>A change would negatively affect the protein's function and seemed to cause the disease. However, functional analysis is required to confirm the association between the variant and the disease.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5640585PMC
July 2017

Genetic study of the BRAF gene reveals new variants and high frequency of the V600E mutation among Iranian ameloblastoma patients.

J Oral Pathol Med 2018 Jan 7;47(1):86-90. Epub 2017 Nov 7.

Department of Oral and Maxillofacial Pathology, School of Dentistry, Isfahan University of Medical Sciences, Isfahan, Iran.

Background: Ameloblastoma is a benign, slow-growing and locally invasive tumor. It is one of the most prevalent odontogenic tumors, with an incidence rate of 1% of all oral tumors and approximately 18% of odontogenic tumors. A group of genes have been investigated in patients with ameloblastoma. The BRAF V600E mutation has been implicated as the most common mutation in ameloblastoma. The presence or absence of this mutation has been associated with several clinicopathological properties, including location, age at diagnosis, histology, and prognosis. Although some populations have been investigated so far, little data are available on the Iranian population. The current research was launched to study the BRAF V600E mutation among a cohort of Iranian patients with ameloblastoma.

Methods: In this clinicopathological and molecular biology study, a total of 19 formalin-fixed, paraffin-embedded tissues were studied. DNA extraction was performed, followed by PCR-sequencing of exons 10 and 15 of the BRAF gene to identify mutations. In silico analysis was performed for the identified variants. Results were analyzed by T test, Chi-square, and Fisher's exact test.

Results: Totally, 12 of 19 samples (63%) harbored the p. V600E hotspot mutation. In addition, we identified several variants, two of which were novel. The c.1769T>G (p. V590G) and c.1751C>T (p.L584F) as the novel variants showed a possible damaging effect by in silico analysis. No variant was found within exon 10.

Conclusions: Our study confirms the role of BRAF mutations in ameloblastoma in the Iranian patients studied.
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http://dx.doi.org/10.1111/jop.12610DOI Listing
January 2018

A novel pathogenic variant in the FZD6 gene causes recessive nail dysplasia in a large Iranian kindred.

J Dermatol Sci 2017 Oct 13;88(1):134-138. Epub 2017 May 13.

Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran; Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran. Electronic address:

Background: Nail disorder nonsyndromic congenital (NDNC) is a very rare clinically and genetically heterogeneous disease inherited both in recessive or dominant modes. FZD6 is a component of Wnt-FZD signaling pathway in which recessive loss-of-function variants in the corresponding genes could lead to nail anomalies.

Objective: A large multiplex family with NDNC was referred for genetic counselling. Thorough genetic evaluation was performed.

Methods: PCR-Sanger sequencing was carried out for the coding exons and exon-intron boundaries of the FZD6 gene. Co-segregation analysis, in silico evaluation and computational protein modeling was accomplished.

Results: A homozygous 1bp deletion variant, c.1859delC (p.Ser620Cysfs*75), leading to a truncating protein was found in the patient. Parents were heterozygous for the variant. The variant was found to be co-segreagting with the phenotype in the family. Computational analysis and protein modeling revealed its pathogenic consequence by disturbing the cytoplasmic domain structure and signaling through loss of phosphorylation residues. The variant met the criteria of being pathogenic according to the ACMG guideline.

Conclusions: This is the first report of the genetic diagnosis of NDNC in Iran. We also report a novel pathogenic variant. The study of the FZD6 gene is recommended as the first step in the diagnostic routing of the autosomal recessive NDNC patients with enlarged nails.
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http://dx.doi.org/10.1016/j.jdermsci.2017.04.017DOI Listing
October 2017