Publications by authors named "Morteza Hashemzadeh Chaleshtori"

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

Novel MYO15A variants are associated with hearing loss in the two Iranian pedigrees.

BMC Med Genet 2020 11 18;21(1):226. Epub 2020 Nov 18.

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

Background: Clinical genetic diagnosis of non-syndromic hearing loss (NSHL) is quite challenging. With regard to its high heterogeneity as well as large size of some genes, it is also really difficult to detect causative mutations using traditional approaches. One of the recent technologies called whole-exome sequencing (WES) has been thus developed in this domain to remove the limitations of conventional methods.

Methods: This study was a report on a research study of two unrelated pedigrees with multiple affected cases of hearing loss (HL). Accordingly, clinical evaluations and genetic analysis were performed in both families.

Results: The results of WES data analysis to uncover autosomal recessive non-syndromic hearing loss (ARNSHL) disease-causing variants was reported in the present study. Initial analysis identified two novel variants of MYO15A i.e. c.T6442A:p.W2148R and c.10504dupT:p.C3502Lfs*15 correspondingly which were later confirmed by Sanger validations and segregation analyses. According to online prediction tools, both identified variants seemed to have damaging effects.

Conclusion: In this study, whole exome sequencing were used as a first approach strategy to identify the two novel variants in MYO15A in two Iranian families with ARNSHL.
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http://dx.doi.org/10.1186/s12881-020-01168-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672957PMC
November 2020

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

Upregulation of Neuroprogenitor and Neural Markers via Enforced miR-124 and Growth Factor Treatment.

Int J Mol Cell Med 2020 ;9(1):62-70

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

Previous studies have shown that miR-124 plays an important role in the development of auditory neurons, which are degenerated in the sensorineural hearing loss. However, whether the combined use of miR-124 and growth factors can increase the expression of neural related markers in human dental pulp stem cells has been remained unknown so far. In this study, human dental pulp stem cells were transfected with miR-124 following treatment with brain-derived neurotrophic factor or epidermal growth factor/basic fibroblast growth factor. The expression of some neural related markers (nestin, , β-tubulin III, , and peripherin) was analyzed in two groups by qRT-PCR or immunofluorescence. Cellular treatment resulted in morphological changes including neurosphere-like colonies formation. Nestin and were up-regulated, and and peripherin were down-regulated in dental pulp stem cells transfected by miR-124 following treatment with brain-derived neurotrophic factor. Replacement of brain-derived neurotrophic factor with epidermal growth factor/ basic fibroblast growth factor resulted in the up-regulation of , , peripherin, and β-tubulin III and down-regulation of . The expression of SOX2 and nestin was also confirmed by immunofluorescence. The combination of miR-124 and growth factors would provide a promising starting point for upregulating the neural progenitor markers in human dental pulp stem cells.
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http://dx.doi.org/10.22088/IJMCM.BUMS.9.1.62DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7422846PMC
January 2020

Increased levels of miR-124 in human dental pulp stem cells alter the expression of neural markers.

J Otol 2019 Dec 16;14(4):121-127. Epub 2019 Apr 16.

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

Auditory neuropathy is the particular form of deafness in humans which cannot be treated by replacement therapy. Human dental pulp stem cells (hDPSCs) are derived from an ectomesenchymal neural crest cell population. Therefore, they possess a promising capacity for neuronal differentiation and repair. miR-124, a key regulator of neuronal development in the inner ear, is expressed at high levels in auditory and vestibular neurons. Here, we evaluated the possible effect of miR-124 in alteration of neural protein markers expression. Using quantitative reverse transcription-PCR (qRT-PCR) analyses and immunofluorescence staining, we studied the expression patterns of neural progenitor markers (Nestin, NOTCH1, and SOX2) and neural markers (β-tubulin III, GATA-3, and peripherin) upon transfection of hDPSCs with miR-124. The qRT-PCR results showed that Nestin was upregulated 6 h post-transfection. In contrast, Nestin expression exhibited a decreasing trend 24 h and 48 h post-transfection. Higher levels of β-tubulin III, 6 h and 16 h post transfection in RNA level as compared with control cells, were determined in transfected DPSCs. However, β-tubulin-III expression decreased 48 h post-transfection. The immunoflourescence results indicated that transfection of hDPSCs with miR-124, only affected Nestin among the studied neural progenitor and neural marker expression in protein level.
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http://dx.doi.org/10.1016/j.joto.2019.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387844PMC
December 2019

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

In silico and in vitro effects of the I30T mutation on myelin protein zero instability in the cell membrane.

Cell Biol Int 2020 Feb 4;44(2):671-683. Epub 2019 Dec 4.

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

Charcot-Marie-Tooth (CMT) diseases are a heterogeneous group of genetic peripheral neuropathies caused by mutations in a variety of genes, which are involved in the development and maintenance of peripheral nerves. Myelin protein zero (MPZ) is expressed by Schwann cells, and MPZ mutations can lead to primarily demyelinating polyneuropathies including CMT type 1B. Different mutations demonstrate various forms of disease pathomechanisms, which may be beneficial in understanding the disease cellular pathology. Our molecular dynamics simulation study on the possible impacts of I30T mutation on the MPZ protein structure suggested a higher hydrophobicity and thus lower stability in the membranous structures. A study was also conducted to predict native/mutant MPZ interactions. To validate the results of the simulation study, the native and mutant forms of the MPZ protein were separately expressed in a cellular model, and the protein trafficking was chased down in a time course pattern. In vitro studies provided more evidence on the instability of the MPZ protein due to the mutation. In this study, qualitative and quantitative approaches were adopted to confirm the instability of mutant MPZ in cellular membranes.
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http://dx.doi.org/10.1002/cbin.11268DOI Listing
February 2020

Plasma Level Of miR-21 And miR-451 In Primary And Recurrent Breast Cancer Patients.

Breast Cancer (Dove Med Press) 2019 25;11:293-301. Epub 2019 Oct 25.

Department of Hematology and Oncology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.

Purpose: MiR-21 and miR-451 are closely associated with tumor initiation, drug resistance, and recurrence of breast cancer (BC). This study was conducted to evaluate the possible value of the plasma level of miR-21 and miR-451 as potential biomarkers for the detection of primary and recurrent BC.

Patients And Methods: In this descriptive-analytical study, the plasma level of miR-21 and miR-451 was measured in 23 primary BC patients, 24 recurrent (local/distant metastasis) BC patients, and 24 aged-match women as healthy controls using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Finally, data were analyzed using SPSS software, and the area under the receiver operating characteristic (ROC) curve of miRNAs was measured.

Results: The plasma level of miR-21 was significantly increased in both groups of primary (P<0.001) and recurrent (P<0.001) BC patients in comparison with healthy women. However, the plasma level of miR-451 was not significantly changed in primary (P=0.065) and recurrent (P=0.06) BC patients than healthy controls. The elevation of both miR-21 and miR-451 plasma level was not significantly changed in recurrent patients compared with non-recurrent (primary) patients (P=0.481, and P=1, respectively). Based on the ROC analyses, the areas under the curves (AUC) for miR-21 in discriminating primary BC and recurrent BC patients from healthy controls were 0.828 (95% CI: 0.712 to 0.944) and 0.865 (95% CI: 0.756 to 0.974), respectively.

Conclusion: These data indicating that plasma miR-21 may be useful as a biomarker for the detection of both primary and recurrent BC. However, plasma miR-451 lacks enough sensitivity in the detection of primary and recurrent BC, and more studies are needed in this area.
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http://dx.doi.org/10.2147/BCTT.S224333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6818541PMC
October 2019

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 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

Differentiation of dental pulp stem cells into neuron-like cells.

Int J Neurosci 2020 Feb 10;130(2):107-116. Epub 2019 Oct 10.

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

With regard to their ease of harvest and common developmental origin, dental pulp stem cells (DPSCs) may act as a favorable source of stem cells in generation of nerves. Moreover; cellular migration and differentiation as well as survival, self-renewal, and proliferation of neuroprogenitor species require the presence of the central nervous system (CNS) mitogens including EGF and bFGF. Accordingly, the possibility of the induction of neuronal differentiation of DPSCs by EGF and bFGF was evaluated in the present study. DPSCs were treated with 20 ng/ml EGF, 20 ng/ml bFGF, and 10 µg/ml heparin. In order to further induce the neuroprogenitor differentiation, DPSC-derived spheres were also incubated in serum-free media for three days. The resulting spheres were then cultured in high-glucose Dulbecco's Modified Eagle Medium (DMEM) with 10% FBS. The morphology of the cells and the expression of the differentiation markers were correspondingly analyzed by quantitative polymerase chain reaction (qPCR), western blotting, and immunofluorescence (IF). The EGF/bFGF-treated DPSCs showed significant increase in the expression of the neuroprogenitor markers of Nestin and SRY (sex determining region Y)-box 2 (SOX2), 72 h after treatment. The up-regulation of Nestin and SOX2 induced by growth factors was confirmed using western blotting and IF. The cultures also yielded some neuron-like cells with a significant rise in Nestin, microtubule-associated protein 2 (MAP2), and Neurogenin 1 (Ngn1) transcript levels; compared with cells maintained in the control media ( < 0.05). DPSCs seemed to potentially differentiate into neuron-like cells under the herein-mentioned treatment conditions.
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http://dx.doi.org/10.1080/00207454.2019.1664518DOI Listing
February 2020

Genetics of Hearing Loss in North Iran Population: An Update of Spectrum and Frequency of GJB2 Mutations.

J Audiol Otol 2019 Oct 27;23(4):175-180. Epub 2019 Jun 27.

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

Diagnosis of pre-lingual hearing loss (HL) is difficult owing to the high number of genes responsible. The most frequent cause of HL is DFNB1 due to mutations in the GJB2 gene. It represents up to 40% of HL cases in some populations. In Iran, it has previously been shown that DFNB1 accounts for 16-18% of cases but varies among different ethnic groups. Here, we reviewed results from our three previous publications and data from other published mutation reports to provide a comprehensive collection of data for GJB2 mutations and HL in northern Iran. In total, 903 unrelated families from six different provinces, viz., Gilan, Mazandaran, Golestan, Ghazvin, Semnan, and Tehran, were included and analyzed for the type and prevalence of GJB2 mutations. A total of 23 different genetic variants were detected from which 18 GJB2 mutations were identified. GJB2 mutations were 20.7% in the studied northern provinces, which was significantly higher than that reported in southern populations of Iran. Moreover, a gradient in the frequency of GJB2 mutations from north to south Iran was observed. c.35delG was the most common mutation, accounting for 58.4% of the cases studied. This study suggests that c.35delG mutation in GJB2 is the most important cause of HL in northern Iran.
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http://dx.doi.org/10.7874/jao.2019.00059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6773957PMC
October 2019

Genetics of hereditary hearing loss in east Iran population: A systematic review of mutations.

Intractable Rare Dis Res 2019 Aug;8(3):172-178

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

Mutations in the gene are the most common cause of pre-lingual hearing loss (HL) worldwide. Previous studies have shown the frequency of mutations to be 16% in Iran, but varies among different ethnic groups. Here, we have reviewed results from previous published mutation reports to provide a comprehensive collection of data for mutations and HL in eastern Iran. We conducted a systematic literature review of PubMed, Google Scholar, Web of Science, and Science Direct databases for articles published before March, 2019. The literature search was performed by 2 independent researchers. The primary data of these studies including the number of samples, allelic frequency, and so on were extracted. Six studies involving 812 unrelated families from four different eastern provinces were included and analyzed for the type and prevalence of mutations. A total of 19 different genetic variants were detected. mutations were 8.8% in the studied eastern provinces, which was lower than that reported in northern populations of Iran. Moreover, a gradient in the frequency of GJB2 mutations from north to south Iran was observed. c.35delG was the most frequent mutation, accounting for 48.5% % of the populations studied. However, this mutation was absent in the Baluchi population. This review shows that particular rare mutations are frequent in some Iranian ethnic groups, and should be considered for genetic counselling.
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http://dx.doi.org/10.5582/irdr.2019.01070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6743427PMC
August 2019

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

An update of spectrum and frequency of GJB2 mutations causing hearing loss in the south of Iran: A literature review.

Int J Pediatr Otorhinolaryngol 2019 Apr 25;119:136-140. Epub 2019 Jan 25.

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

Objective: Mutations in the GJB2 gene are a major cause of autosomal recessive non-syndromic HL (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. Here, we have taken together and reviewed results from our three previous publications and data from search other published mutation reports to provide a comprehensive collection of data for GJB2 mutations and HL in the south of Iran.

Methods: In all, 447 unrelated families were included and analyzed for the prevalence and type of the GJB2 gene mutations.

Results: Totally, the frequency of GJB2 mutations was found to be 11.5% in the southern provinces studied which is significantly lower than that identified in Northern populations of Iran, and also a southwest to southeast Iranian gradient in the frequency of GJB2 mutations is suggested.

Conclusions: This study highlights the importance of establishing prevalence, based on the local population for screening and diagnostic programs of live births in Iran.
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http://dx.doi.org/10.1016/j.ijporl.2019.01.036DOI Listing
April 2019

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

Update of spectrum c.35delG and c.-23+1G>A mutations on the GJB2 gene in individuals with autosomal recessive nonsyndromic hearing loss.

Ann Hum Genet 2019 01 3;83(1):1-10. Epub 2018 Sep 3.

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

Hearing loss (HL) is the most common birth defect and the most prevalent sensorineural condition worldwide. It is associated with more than 1,000 mutations in at least 90 genes. Mutations of the gap junction beta-2 protein (GJB2) gene located in the nonsyndromic hearing loss and deafness (DFNB1) locus (chromosome 13q11-12) are the main causes of autosomal recessive nonsyndromic hearing loss worldwide, but important differences exist between various populations. In the present article, two common mutations of the GJB2 gene are compared for ethnic-specific allele frequency, their function, and their contribution to genetic HL in different populations. The results indicated that mutations of the GJB2 gene could have arisen during human migration. Updates on the spectrum of mutations clearly show that frequent mutations in the GJB2 gene are consistent with the founder mutation hypothesis.
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http://dx.doi.org/10.1111/ahg.12284DOI Listing
January 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

rs12480307 and rs6050307 Polymorphisms of VSX1 Gene in Patient with Keratoconusin Southwest Iran Using PCR-RFLP.

Iran J Public Health 2018 Mar;47(3):455-457

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

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5971187PMC
March 2018

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

Clinical Aspects of Microsatellite Instability Testing in Colorectal Cancer.

Adv Biomed Res 2018 16;7:28. Epub 2018 Feb 16.

Department of Internal Medicine, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.

Microsatellite instability (MSI) is a molecular hallmark for some colorectal cancers (CRCs) in which short tandem repeats are prone to mutations along with DNA sequences. It is due to DNA-mismatch-repair system deficiency because of a germline/somatic mutation in mismatch-repair (MMR) genes. The germline mutations lead to Lynch syndrome (LS) while epigenetic gene silencing results in sporadic CRC tumors. We discuss in our paper the most important clinical aspects of MSI testing in CRCs. We reviewed the most reliable relevant studies and clinical trials according to their high-quality methods, particularly within two recent decades. MSI testing is used to classify CRC tumors as MSI-high (MSI-H), MSI-low, and microsatellite stable tumors. MSI-H or MMR deficient tumors have shown the best prognosis among all CRCs, so MSI testing is considered as a good prognostic marker. Moreover, it is used to identify LS among familial CRC patients. There is a diagnostic mutation in gene (V600E) by which sporadic CRCs could be distinguished from LS associated CRCs, due to its concordance with sporadic CRCs not LS. Although, some previous studies had demonstrated a predictive role for MSI testing in chemotherapy process, emerging some controversial findings in recent studies has not convinced many authors to recommend it as a routine examination to evaluate therapeutic response. Though emerging new molecular findings have opened novel windows to develop clinical management of CRC, MSI testing has remained as an excellent prognostic and diagnostic tool for CRC tumors.
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http://dx.doi.org/10.4103/abr.abr_185_16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5841008PMC
February 2018

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

Differentiation of Human Bone Marrow Mesenchymal Stem Cells to Hair Cells Using Growth Factors.

Int Tinnitus J 2017 Dec 1;21(2):179-184. Epub 2017 Dec 1.

Department of Genetic & Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran.

Objective: In this study, we attempted to differentiated human bone marrow-derived mesenchymal stem cells (hBMSCs) to auditory hair cells using growth factors.

Methods: Retinoic acid (RA), basic fibroblast growth factor (bFGF), and epidermal growth factor (EGF) were added to hBMSCs cell culture medium. The cells were evaluated morphologically and the expression of SOX2, POU4F3, MYO7A, and Calretinin at mRNA level and ATOH1 mRNA and protein expression.

Results: After treatment with the growth factors, the morphology of the cells did not change, but evaluation of gene expression at the mRNA level increased the expression of the ATOH1, SOX2, and POU4F3 markers. Growth factors increased the expression of ATOH1 at the protein level. The expression of calretinin showed decreased and MYO7A no significant change in expression.

Conclusion: hBMSCs have the potential to differentiate to hair cell-like using the RA, bFGF, and EGF.
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http://dx.doi.org/10.5935/0946-5448.20170030DOI Listing
December 2017

Comparison of Three Types of Mesenchymal Stem Cells (Bone Marrow, Adipose Tissue, and Umbilical Cord-Derived) as Potential Sources for Inner Ear Regeneration.

Int Tinnitus J 2017 Dec 1;21(2):122-127. Epub 2017 Dec 1.

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

In this review, we compared the potential of mesenchymal stem cells derived from bone marrow, adipose tissue and umbilical cord as suitable sources for regeneration of inner ear hair cells and auditory neurons. Our intensive literature search indicates that stem cells in some of adult mammalian tissues, such as bone marrow, can generate new cells under physiological and pathological conditions. Among various types of stem cells, bone marrow-derived mesenchymal stem cells are one of the most promising candidates for cell replacement therapy. Mesenchymal stem cells have been reported to invade the damaged area, contribute to the structural reorganization of the damaged cochlea and improve incomplete hearing recovery. We suggest that bone marrow-derived mesenchymal stem cells would be more beneficial than other mesenchymal stem cells.
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http://dx.doi.org/10.5935/0946-5448.20170023DOI Listing
December 2017

Evaluation of response to hepatitis B vaccine in Iranian 6-18-year-old students.

J Res Med Sci 2017 31;22:116. Epub 2017 Oct 31.

Chaharmahal Va Bakhtiari Province Health Center, Shahrekord University of Medical Sciences, Shahrekord, Iran.

Background: Hepatitis B is a dangerous disease with high morbidity and mortality rates all around the world. Vaccination is the most important way to its prevention and control. This cross-sectional study was carried out to study the levels of immunogenicity to hepatitis B vaccine in students.

Materials And Methods: Six hundred and forty-four students aged 6-18 years including 316 girls and 328 boys were selected from the Chaharmahal Va Bakhtiari province. Selected students had been received three doses of recombinant vaccine (0, 1, and 6 months). Blood samples were taken and the titers of hepatitis B surface antigen were studied.

Results: From a total of 644 students, 396 (61.5%) had a titer lesser than 10 mIu/ml and 248 (38.5%) had a titer higher than 10 mIu/ml. Therefore, the level of respond to vaccine with 95% confidence was 38.5% (34.7%-42.4%). Levels of respond to vaccine were related to age, body mass index (BMI), and educational level and were not related to sex and habit of students.

Conclusion: Reverse significant relation was seen between the respond to vaccine and age and BMI in a way which the titers of antibody were lower in students with higher age and BMI.
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http://dx.doi.org/10.4103/jrms.JRMS_204_17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5680656PMC
October 2017

Familial Colorectal Cancer Type X in Central Iran: A New Clinicopathologic Description.

Int J Hematol Oncol Stem Cell Res 2017 Jul;11(3):240-245

Poursina Hakim Research Institute, Isfahan, Iran.

Familial colorectal cancer type X (FCCX) is a subtype of mismatch repair (MMR)-proficient colorectal cancerin which the patients are clinically at risk for Lynch syndrome (LS), a common hereditary cancer predisposing syndrome. In this study, we described a new clinicopathological feature of the condition in central Iran. We designed a descriptive, retrospective study to screenat-risk colorectal cancer (CRC) patients, using Amsterdam II criteria and Molecular analysis in Isfahan (central Iran) throughout 2000-2013 period. 219 early-onset (≤ 50 years) CRC patients of 1659 were selected for the evaluation. Amsterdam II criteria were positive in 45 families; of whom 31 were finally analyzed by molecular testing. MMR deficiency was detected in 7/31 probands (22.6%) as affected to LS, so 24 families (77.4%) were identified as FCCX. The mean age of the probands at diagnosis among FCCX families was 45.3 years (range 24-69) versus 38.0 years (range 31-50) in LS families. The frequency of CRC among FCCX and LS families was calculated 27.9% and 67.5%, respectively. Also, the most frequent extracolonic cancer among both FCCX and LS families was stomach by 25.5% and 30.8%, respectively. Tumor site was proximal to the splenic flexure in 20.8% and 57.1% of index CRC patients in FCCX and LS families, respectively. Given the relative high frequency of FCCX and its different phenotype among Iranian populations, we need to set up more advanced molecular studies for exploration of unknown molecular pathways leading to tumorigenesis in this class of CRC patients.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5625475PMC
July 2017