Hossein Najmabadi

Kariminejad & Najmabadi Pathology and Genetics Center, Teheran, Tehrān, Iran

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Publications (240)717.1 Total impact

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    ABSTRACT: Hemoglobin (Hb) variants are abnormalities resulting from point mutations in either of the two α-globin genes (HBA2 or HBA1) or the β-globin gene (HBB). Various reports of Hb variants have been described in Iran and other countries around the world. Hb Setif (or HBA2: c.283G>T) is one of these variants with a mutation at codon 94 of of the α2-globin gene that is characterized in clinically normal heterozygous individuals. We here report clinical and hematological findings in two homozygous cases of Iranian origin for this unstable Hb variant.
    No preview · Article · Nov 2015 · Hemoglobin
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    ABSTRACT: α-Thalassemia (α-thal) is a common genetic disorder in Iran and many parts of the world. Genetic defects on the α-globin gene cluster can result in α-thal that may develop a clinical phenotype varying from almost asymptomatic to a lethal hemolytic anemia. In the present study, four Iranian individuals with hypochromic microcytic anemia, who revealed none of the known mutations responsible for α-thal, were subjected for further investigations. The thalassemic phenotype of these patients resulted from abnormal RNA splicing sites owing to a missense at the splice donor site, a truncated protein or hemoglobin (Hb) variants as a result of two different substitutions on the α1-globin gene. The clinical presentation of mild anemia in these individuals showed the contribution of these novel mutations in α-thal in spite of the dominantly expressed α2-globin gene. This study describes hematological manifestations of subjects carrying some novel mutations comparable to the reported phenotype of α(+)-thal trait.
    Full-text · Article · Nov 2015 · Hemoglobin
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    ABSTRACT: Background: Hb H disease is an alpha-thalassemia (α-thal) syndrome characterized by chronic hemolytic anemia that occurs when three of total four α-globin genes lost their function due to completely deletions or different kind of mutations. Objective: We here described 66 patients who have been diagnosed for Hb H disease during the last five years in our center. The genotypes involving point mutations present more severe phenotype than deletional forms that make them of primary important to health management. Study design: Hb H subjects carry different α-globin genotypes including deletional and non-deletional mutations showing heterogenous clinical manifestations. Results: The Hb H patients presenting a wide range of phenotype carried different deletional, non-deletional mutations or compound heterozygosity of them. Conclusion: We emphasize the importance of some point mutations responsible for more severe form of Hb H disease in Iranian population and the necessity for consideration of prenatal diagnosis (PND) in high-risk couples.
    Full-text · Article · Nov 2015 · Expert Review of Hematology
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    ABSTRACT: Background: Non-syndromic autosomal recessive Retinitis Pigmentosa (arRP) is a highly heterogeneous genetic visual disorder with a large number of causative genes. We aimed to determine the power of Whole Exome Sequencing (WES) in the identification of the genes responsible for non-syndromic arRP among Iranian patients. Methods: We used WES, followed by the Sanger sequencing to identify the underlying gene mutations causing non-syndromic arRP. Results: Our study revealed disease-causing mutations in known arRP genes for 10 of the 13 families studied (76.9%). These mutations included two-frameshift insertion/deletion in CRB1 and ABCA4, one splicing mutation in PDE6B, four missense mutations in RP1, CRB1, PANK2 and IFT140, as well as three stop codon mutations in RDH12, PRCD, and C2orf71. Three remaining families harbored no mutation in previously known RP genes. Of the 10 diseases causing mutations identified among the investigated Iranian patients with non-syndromic arRP, eight variants had not been reported previously. We confirmed segregation of all 10 mutations with disease phenotypes in our studied population. Conclusion: This study supports the genetic heterogeneity of non-syndromic arRP in Iranian patients, and provides an opportunity to show the effectiveness of WES in the identification of pathogenic mutations among patients with non-syndromic arRP born to consanguineous parents.
    No preview · Article · Oct 2015
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    ABSTRACT: Background: Countries with culturally accepted consanguinity provide a unique resource for the study of rare recessively inherited genetic diseases. Although hereditary hearing loss (HHL) is not uncommon, it is genetically heterogeneous, with over 85 genes causally implicated in non-syndromic hearing loss (NSHL). This heterogeneity makes many gene-specific types of NSHL exceedingly rare. We sought to define the spectrum of autosomal recessive HHL in Iran by investigating both common and rarely diagnosed deafness-causing genes. Design: Using a custom targeted genomic enrichment (TGE) panel, we simultaneously interrogated all known genetic causes of NSHL in a cohort of 302 GJB2-negative Iranian families. Results: We established a genetic diagnosis for 67% of probands and their families, with over half of all diagnoses attributable to variants in five genes: SLC26A4, MYO15A, MYO7A, CDH23 and PCDH15. As a reflection of the power of consanguinity mapping, 26 genes were identified as causative for NSHL in the Iranian population for the first time. In total, 179 deafness-causing variants were identified in 40 genes in 201 probands, including 110 novel single nucleotide or small insertion-deletion variants and three novel CNV. Several variants represent founder mutations. Conclusion: This study attests to the power of TGE and massively parallel sequencing as a diagnostic tool for the evaluation of hearing loss in Iran, and expands on our understanding of the genetics of HHL in this country. Families negative for variants in the genes represented on this panel represent an excellent cohort for novel gene discovery.
    No preview · Article · Oct 2015 · Journal of Medical Genetics
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    ABSTRACT: Background: Intellectual Disability (ID) is one of the most common disabling impairments worldwide. Autosomal recessive ID (ARID), a genetically heterogeneous disorder, is more common in countries such as Iran where the rate of consanguineous marriages is high. Considering the social-economic burden of ARID in our country, it is crucial to find out whether couples who are cousins are carriers for disease causing mutations, in order to prevent the birth of an affected child. Methods: Using exome sequencing, we screened known ARID genes in a normal individual to identify possible mutations in heterozygous form. Results: We identified fourprotein coding heterozygous alleles which possibly affect protein function, in different ID genes PMM2, RBM28, SLC19A3, and VPS13B. Conclusion: These findings can be used to prevent the birth of children with ARID by checking the other partner for possible disease causing variants. © 2015 Academy of Medical Sciences of I.R. Iran. All rights reserved.
    No preview · Article · Oct 2015 · Archives of Iranian medicine
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    ABSTRACT: Background: Intellectual disability (ID) is a neuro-developmental disorder which causes considerable socio-economic problems. Some ID individuals are also affected by ataxia, and the condition includes different mutations affecting several genes. Methods: We used whole exome sequencing (WES) in combination with homozygosity mapping (HM) to identify the genetic defects in five consanguineous families among our cohort study, with two affected children with ID and ataxia as major clinical symptoms. Results: We identified three novel candidate genes, RIPPLY1, MRPL10, SNX14, and a new mutation in known gene SURF1. All are autosomal genes, except RIPPLY1, which is located on the X chromosome. Two are housekeeping genes, implicated in transcription and translation regulation and intracellular trafficking, and two encode mitochondrial proteins. The pathogenesis of these variants was evaluated by mutation classification, bioinformatic methods, review of medical and biological relevance, co-segregation studies in the particular family, and a normal population study. Conclusions: Linkage analysis and exome sequencing of a small number of affected family members is a powerful new technique which can be used to decrease the number of candidate genes in heterogenic disorders such as ID, and may even identify the responsible gene(s). © 2015 Academy of Medical Sciences of I.R. Iran. All rights reserved.
    Full-text · Article · Oct 2015 · Archives of Iranian medicine
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    ABSTRACT: Background: The genetic basis of longevity is an important field of study because the majority of supercentenarian cases experience healthy aging and may only show age-related diseases in their last few years of life. It is clear that genetic factors play an important role in survival beyond 90 years ofage, but the exact relationship of geneticvariantsto this phenomenon remains unknown. Objective: The aim of this project was to investigate different hypotheses that describe the relationship between genetic variants and human longevity in a living Iranian man by Whole Exome Sequencing (WES). Methods: Initially, we conducted high quality DNA extraction on a peripheral blood sample. Then, WES was performed on the DNA and different bioinformatic software packages and databases were used to analyze the data. Tertiary analysis was performed on four genetic hypotheses for longevity. Results: Analysis showed that among 27 metabolic variants which are related to longevity, 18 variants encompassed the exceptional longevity allele. In comparison with the NHGRI GWAS catalog, the case had 58 trait-associated variants of which 11 were homozygous for the risk allele. We also discovered 25 novel variants within candidate genes for aging and longevity and we detected seven longevity-associated variants in the sample. Conclusion: This study was performed on just one sample and so the results cannot be interpreted as a generalized principle for other elderly societies, but this is the first step towards investigation of the genetic basis of longevity in Iran and provides an insight for further studies in the field of longevity. © 2015 Academy of Medical Sciences of I.R. Iran. All rights reserved.
    No preview · Article · Oct 2015 · Archives of Iranian medicine
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    ABSTRACT: Deafness is the most frequent sensory disorder. With over 90 genes and 110 loci causally implicated in non-syndromic hearing loss, it is phenotypically and genetically heterogeneous. Here, we investigate the genetic etiology of deafness in four families of Iranian origin segregating autosomal recessive non-syndromic hearing loss (ARNSHL). We used a combination of linkage analysis, homozygosity mapping, and a targeted genomic enrichment platform to simultaneously screen 90 known deafness-causing genes for pathogenic variants. Variant segregation was confirmed by Sanger sequencing. Linkage analysis and homozygosity mapping showed segregation with the DFNB57 locus on chromosome 10 in two families. Targeted genomic enrichment with massively parallel sequencing identified causal variants in PDZD7: a homozygous missense variant (p.Gly103Arg) in one family and compound heterozygosity for missense (p.Met285Arg) and nonsense (p.Tyr500Ter) variants in the second family. Screening of two additional families identified two more variants: (p.Gly228Arg) and (p.Gln526Ter). Variant segregation with the hearing loss phenotype was confirmed in all families by Sanger sequencing. The missense variants are predicted to be deleterious, and the two nonsense mutations produce null alleles. This report is the first to show that mutations in PDZD7 cause ARNSHL, a finding that offers addition insight into the USH2 interactome. We also describe a novel likely disease-causing mutation in CIB2 and illustrate the complexity associated with gene identification in diseases that exhibit large genetic and phenotypic heterogeneity. © 2015 Wiley Periodicals, Inc.
    No preview · Article · Sep 2015 · American Journal of Medical Genetics Part A
  • ZOHREH MEHRJOO · MOJGAN BABANEJAD · KIMIA KAHRIZI · HOSSEIN NAJMABADI

    No preview · Article · Sep 2015 · Journal of Genetics
  • L. Jamali · M.R. Akbari · M. Mohseni · K. Kahrizi · H. Najmabadi
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    ABSTRACT: Cancer, with a high rate of mortalities worldwide, pose a major threat to human health. Although family history accounts for at least 5-10% of all cancers, it is conferred to be as a significant risk of developing cancer. Recently, application of high speed and low cost high-throughput nucleotide sequencing technologies has provided an opportunity to assess cancer risk in at risk healthy individuals. The present study has aimed to detect susceptible variants relevant to 69 known cancer genes on a 42-year-old Iranian healthy volunteer with familial history of cancer syndromes using Whole Exome Sequencing (WES). Exome enrichment and sequencing were applied using SureSelect V4 kit and Illumina Hiseq2000, respectively. Analysis of data was carried out by Insilico thoroughly methods. Some filtering criteria were considered to exclude the common (MAF>1%) and nonfunctional variants as well as any variants out of +- 2 bp exons boundaries according to RefSeq database. We focused on deleterious rare alternations. To further validation, data was compared to 300 Iranian normal controls and confirmed by Sanger sequencing method. As a result, 89 variants were identified totally which passed filtering process and eventually, the data emerging from Insilico analysis revealed a novel variant of WRN gene (c.953_954delTTA). Given the fact that cancer potentially could be predictable, genetic screening of hereditable deleterious variants in at risk individuals is crucial stage stag in terms of improving the quality of life allowing prevention and control. In this regards, WES, as cost-benefit diagnostic tool, effectively is capable of determining all susceptibility cancer genes variations predisposing to disease. The project as a first carrier detection is being emerged as a new insight to take a step to establish new genetic molecular approach in our country, as well as supporting the potential utilization of powerful WES in the field of early detection.
    No preview · Article · Sep 2015
  • S.S. Abedini · M. Azad · M. Hassanzad · K. Kahrizi · H. Najmabadi
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    ABSTRACT: Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by homozygous deletion of the survival motor neuron gene 1 (SMN1) in more than 90% of patients. According to the age of onset and severity of the disease, SMA is classified into three groups: type I (severe), type II (intermediate) and type III (mild). As reported, the SMN2 gene, centromeric copy gene, showed correlation with severity of the disease. To determine genotype-phenotype correlation, we studied 45 Iranian patients (15 SMA I, 10 SMA II, and 20 SMA III) using multiplex ligation-dependent probe amplification (MLPA) assay.14 out of 15 SMA I patients (93.3%) carried two copies of SMN2, while the remaining 6.7% carried three copies. Among the type II and type III, 30% of the type II and 10% of the type III SMA patients carried two copies of the gene, while 70% of the type II and 90% of the type III carried three or four copies of SMN2, respectively. This study showed that SMN2 copy number can effect on survival duration in SMA type I and ambulation conservation or loss in type III. Thus, investigation of SMN2 copy number could be an appropriate predictor for SMA disease types.
    No preview · Article · Sep 2015
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    ABSTRACT: Our previous studies on thalassemia patients, homozygous or compound heterozygous for severe beta thalassemia mutations, has suggested that 5’HS4-LCR and/or Xmn1-HBG2 backgrounds, which were linked in our thalassemia patients, are important in determining the blood transfusion dependency of these individuals. While the majority of patients with AA/-- 5’HS4/Xmn1 background, were severely dependent on blood transfusion, a considerable variation in blood transfusion requirement was observed among patients with GG/++background. To investigate other factors that could explain this diversity among GG/++ patients, 2 BCL11A together with 2 HBS1L-MYB SNPs, associated with HbF levels in GWAS, were genotyped. Five groups of patients with specific genotypic patterns for these SNPs were identified. However, a similar distribution pattern of phenotypes was observed in all groups, ranging from extremely mild to severe. These preliminary results indicate that the heterogeneity observed in the phenotype of patients with the same background for 5’HS4-Xmn1, could not be explained by the difference in BCL11A and/or HBS1L-MYB SNPs in this study. Therefore these SNPs alone, could have limited value in terms of clinical decision making.
    Full-text · Article · Sep 2015
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    ABSTRACT: In the present study, a total of 11 individuals with hypochromic microcytic anemia who did not reveal the most common α-thalassemia (α-thal) deletions or mutations, were subjected to more investigations by DNA sequencing of the α-globin genes. Seven novel nondeletional α-thal mutations localized on the α2-globin gene in the heterozygous state were identified. These mutations either corrupted regulatory splice sites and consequently affected RNA processing or created unstable hemoglobin (Hb) variants. The mutations described here produced globin gene variants that lead to amino acid changes in critical regions of the globin chain. The clinical presentation of most patients was a persistent mild microcytic anemia similar to an α(+)-thal. In the last decade, numerous α-globin mutations have been observed leading to an α-thal phenotype and these studies have been considered to be important as discussed here.
    No preview · Article · Sep 2015 · Hemoglobin
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    ABSTRACT: Cognitive impairment or intellectual disability (ID) is a widespread neurodevelopmental disorder characterized by low IQ (below 70). ID is genetically heterogeneous and is estimated to affect 1-3% of the world's population. In affected children from consanguineous families, autosomal recessive inheritance is common, and identifying the underlying genetic cause is an important issue in clinical genetics. In the framework of a larger project, aimed at identifying candidate genes for autosomal recessive intellectual disorder (ARID), we recently carried out single nucleotide polymorphism-based genome-wide linkage analysis in several families from Ardabil province in Iran. The identification of homozygosity-by-descent loci in these families, in combination with whole exome sequencing, led us to identify possible causative homozygous changes in two families. In the first family, a missense variant was found in GRM1 gene, while in the second family, a frameshift alteration was identified in TRMT1, both of which were found to co-segregate with the disease. GRM1, a known causal gene for autosomal recessive spinocerebellar ataxia (SCAR13, MIM#614831), encodes the metabotropic glutamate receptor1 (mGluR1). This gene plays an important role in synaptic plasticity and cerebellar development. Conversely, the TRMT1 gene encodes a tRNA methyltransferase that dimethylates a single guanine residue at position 26 of most tRNAs using S-adenosyl methionine as the methyl group donor. We recently presented TRMT1 as a candidate gene for ARID in a consanguineous Iranian family (Najmabadi et al., 2011). We believe that this second Iranian family with a biallelic loss-of-function mutation in TRMT1 gene supports the idea that this gene likely has function in development of the disorder.
    Full-text · Article · Aug 2015 · PLoS ONE
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    ABSTRACT: Copy number variations in α-globin genes are results of unequal crossover between homologous segments in the α-globin gene cluster that misalign during the meiosis phase of the gametogenesis process. Reduction or augmentation of α-globin genes leads to imbalance of α/β chains in hemoglobin tetramer and consequently attenuate or worsen the β-thal clinical symptoms, respectively. Multiplications in α-globin genes have been found in some populations, justifying unexpected severe phenotype of β-thal carriers. Unexpected severe phenotype in the family members may result from coexistence of extra α-globin genes, which is an important factor in the causation of thalassemia intermedia and major in heterozygous β-thalassemia. We described different multiplications in α-globin locus in an Iranian family with one, two or three extra α-globin genes (ααα/αα, αααα/αα and αααα/ααα). The excess α-globin gene/genes cause increment in β/α chain imbalance and leads to worsening pathophysiology and clinical severity of β-thalassemia carriers.
    No preview · Article · Aug 2015 · Expert Review of Hematology
  • Samaneh Farashi · Hossein Najmabadi
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    ABSTRACT: HbH disease had been introduced as a mild anemia disease. It recently has become the most challenging hemoglobinopathy due to the increasingly described genotype patterns and very variable phenotypic presentations in different ethnics. Phenotypic severity of HbH syndrome is not simply related to the degree of α-globin deficiency and being influenced by several environmental and/or genetic factors. Hence, more investigation needs to identify factors like other genetic loci linked and/or unlinked to the α-globin genes affecting molecular mechanisms that influence clinical expression of HbH disease. Altogether, the complicated pathophysiology of HbH disease makes it to be known as a poorly understood syndrome. It may offer the hypothesis that it is a multifactorial disease, which needs to be investigated by more comprehensive genetic approach like genome wide association studies (GWAS) looking for genetic variants. Moreover, extended haplotype analysis to find out probable specific association between haplotypes of modifier genes and disease severity in patients with a specific HbH genotype may be a key point. In this review, we aim to provide important information regarding phenotypic presentation of different genotypes that have been described worldwide. It may help geneticists regarding challenging health care aspects of HbH disease in a specific ethnic.
    No preview · Article · Aug 2015 · Blood Cells Molecules and Diseases
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    ABSTRACT: We describe a case of Hb H disease associated with homozygosity for a two nucleotide deletion in the polyadenylation signal of the α2-globin gene (HBA2: c.*93_*94delAA). The patient, a 27-year-old son of a consanguineous couple, needs regular blood transfusions every 6 months.
    Full-text · Article · Jul 2015 · Hemoglobin
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    ABSTRACT: AIMP1/p43 is a multifunctional non-catalytic component of the multisynthetase complex. The complex consists of nine catalytic and three non-catalytic proteins, which catalyze the ligation of amino acids to their cognate tRNA isoacceptors for use in protein translation. To date, two allelic variants in the AIMP1 gene have been reported as the underlying cause of autosomal recessive primary neurodegenerative disorder. Here, we present two consanguineous families from Pakistan and Iran, presenting with moderate to severe intellectual disability, global developmental delay, and speech impairment without neurodegeneration. By the combination of homozygosity mapping and next generation sequencing, we identified two homozygous missense variants, p.(Gly299Arg) and p.(Val176Gly), in the gene AIMP1 that co-segregated with the phenotype in the respective families. Molecular modeling of the variants revealed deleterious effects on the protein structure that are predicted to result in reduced AIMP1 function. Our findings indicate that the clinical spectrum for AIMP1 defects is broader than witnessed so far.European Journal of Human Genetics advance online publication, 15 July 2015; doi:10.1038/ejhg.2015.148.
    Full-text · Article · Jul 2015 · European Journal of HumanGenetics
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    ABSTRACT: Histamine acts as a neurotransmitter in the brain which participates in the regulation of many biological processes including inflammation, gastric acid secretion, and neuromodulation. The enzyme histamine N-methyltransferase (HNMT) inactivates histamine by transferring a methyl group from S-adenosyl-L-methionine to histamine, and is the only well-known pathway for termination of neurotransmission actions of histamine in mammalian CNS. We performed autozygosity mapping followed by targeted exome sequencing and identified two homozygous HNMT alterations, p.Gly60Asp and p.Leu208Pro in patients affected with nonsyndromic autosomal recessive intellectual disability (NS-ARID) from two unrelated consanguineous families of Turkish and Kurdish ancestry, respectively. We verified the complete absence of a functional HNMT in patients using in vitro toxicology assay. Using mutant and wild type (WT) DNA constructs as well as in silico protein modelling, we confirmed that p.Gly60Asp disrupts the enzymatic activity of the protein, and that p.Leu208Pro results in reduced protein stability, resulting in decreased histamine inactivation. Our results highlight the importance of inclusion of HNMT for genetic testing of individuals presenting with ID. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
    Full-text · Article · Jul 2015 · Human Molecular Genetics

Publication Stats

4k Citations
717.10 Total Impact Points

Institutions

  • 2003-2015
    • Kariminejad & Najmabadi Pathology and Genetics Center
      Teheran, Tehrān, Iran
  • 2001-2015
    • University of Social Welfare and Rehabilitation Sciences
      • Genetics Research Center
      Teheran, Tehrān, Iran
  • 2011
    • Quaid-i-Azam University
      • Department of Biochemistry
      Islāmābād, Islāmābād, Pakistan
  • 2007
    • Max Planck Institute for Molecular Genetics
      • Department of Human Molecular Genetics
      Berlin, Land Berlin, Germany
  • 2004
    • Tehran University of Medical Sciences
      • School of Medicine
      Tehrān, Ostan-e Tehran, Iran
  • 2000
    • Cyprus Institute of Neurology and Genetics
      Lefkoşa, Lefkosia, Cyprus