Autism and Probable Prerequisites: Severe and Scheduled Prenatal Stresses at Spotligh

Background: Due to the importance of prenatal maternal stress as environmental factor on autism, the influ-ence of prenatal maternal psychological agitations was assessed in relation with the risk of autism. Methods: In this case-control study, some mothers of autistic children in Isfahan, central Iran, in 2014, were retrospectively compared with control mothers in terms of quantity, quality, andschedule of exposure to 45 stressful events in a 15-month period. In addition, dividing the stressors into two groups of genome-dependent/independent events, their prevalence was separately scrutinized and compared among patient and control families. Results: Although the child’s risk of autism increases significantly with the increase of maternal stress during months 4-7 of pregnancy, the increased stress during months 2-3 of pregnancy can lead to a significant increase in the severity of autism affliction as well as a slight but significant increase in the possibility of LFA in afflicted children (P<0.05). The overall prevalence of genome-dependent stressful events among two patient and control groups was significantly higher than that of genome-independent events (P=0.000), but genome-dependent events led to more stress inpatient families. Conclusion: Although the present study consistent with recent findings in the fields of epigenetics and gene-environment interactions can confirm the role of severe and scheduled prenatal stresses in causing autism, it does not deny the necessity of a perspective and wider study in Isfahan and Iran

Clinical Trial: CYP2D6 Related Dose Escalation of Tamoxifen in Breast Cancer Patients With Iranian Ethnic Background Resulted in Increased Concentrations of Tamoxifen and Its Metabolites

Introduction: The polymorphic enzyme cytochrome P450 2D6 (CYP2D6) catalyzes a major step in the bioactivation of tamoxifen. Genotyping of clinically relevant CYP2D6 alleles and subsequent dose adjustment is a promising approach to individualize breast cancer therapy. The aim of this study was to investigate the relationship between the plasma levels of tamoxifen and its metabolites and different CYP2D6 genotypes under standard (20 mg/day) and dose-adjusted therapy (Registration ID in Iranian Registry of Clinical Trials: IRCT2015082323734N1).Materials and Methods: Using TaqMan® assays common alleles of CYP2D6 (∗1, ∗2, ∗4, ∗5, ∗6, ∗10, ∗17, and ∗41) and gene duplication were identified in 134 breast cancer patients. Based on CYP2D6 genotypes patients with an activity score 1 (n = 15) and 0–0.5 (n = 2) were treated with tamoxifen adjusted dosage of 30 and 40 mg/day, respectively. The concentration of tamoxifen and its metabolites before and after 4 and 8 months of dose adjustment were measured using LC-MS/MS technology.Results: At baseline, (Z)-endoxifen plasma concentrations (33 ± 15.5, 28.1 ± 14, 26.6 ± 23.4, 14.3 ± 8.6, and 10.7 ± 5.5 nmol/l for EM/EM, EM/IM, EM/PM, IM/IM and PM/PM, respectively) and the metabolic ratio (Z)-Endoxifen/N-desmethyltamoxifen (0.0558 ± 0.02, 0.0396 ± 0.0111, 0.0332 ± 0.0222, 0.0149 ± 0.0026, and 0.0169 ± 0.0177 for EM/EM, EM/IM, EM/PM, IM/IM, and PM/PM, respectively) correlated with CYP2D6 genotype (Kruskal–Wallis p = 0.013 and p &lt; 0.0001, respectively). Dose escalation to 30 and 40 mg/day in patients with a CYP2D6 activity score of 1 (n = 15) and 0–0.5 (n = 2) resulted in a significant increase in (Z)-endoxifen plasma levels (22.17 ± 24.42, 34.43 ± 26.54, and 35.77 ± 28.89 nmol/l at baseline, after 4 and 8 months, respectively, Friedman p = 0.0388) along with the plasma concentrations of tamoxifen and its other metabolites. No severe side effects were recorded during dose escalation.Conclusion: For the first time, we show the feasibility of dose escalation of tamoxifen in breast cancer patients with compromised CYP2D6 activity and Iranian ethnic background to increase the plasma concentrations of (Z)-endoxifen

Novel mutations of PCCA and PCCB genes found by whole-exome sequencing related to propionic acidemia patients

Propionic acidemia (PROP) is an autosomal recessive inherited metabolic deficiency caused by multimeric mitochondrial enzyme propionyl‐coenzyme A (CoA) carboxylase (PCC). PCC enzyme contains a and b subunits, encoded by the PCCA and PCCB genes that mutations in both subunits are related to propionic acidemia. About 50% of disease-causing variants have been found in PCCA and most mutations related to propionic acidemia are missense mutations. The present study involves three families that are suspicious to hereditary propionic acidemia syndrome. The first family has four, the second family has one, and the third family has two passed-away children. All these families were diagnosed with the same clinical conditions such as poor feeding, vomiting, hypotonia, and lethargy. In the process of finding and confirming the mutation, pathological tests and whole-exome sequencing and sanger sequencing were done. In order to pathological tests and whole-exome sequencing, this is the first report of three novel variants related to propionic acidemia: 1. Novel pathogenic homozygous NM_000532.5: c.503_505del: p.Glu168del mutation of the PCCB exon5 gene, 2. Novel pathogenic homozygous splicing NM_000282:c.1900- 1G&gt;A mutation of PCCA exon22 and exon21, 3. Novel compound heterozygous pathogenic NM_000532.5: c.503_505del: p.Glu168del and likely pathogenic NM_000532.5:c.539T&gt;C: P.F180S mutation of the PCCB exon5 gene. The study shows that PCCA and PCCB have a great role in hereditary propionic acidemia and the results of the present study may be of importance in genetic counseling and finding the best treatment of this syndrome. DOI: http://dx.doi.org/10.5281/zenodo.737427

Apoptosis inhibition or inflammation: the role of NAIP protein expression in Hodgkin and non-Hodgkin lymphomas compared to non-neoplastic lymph node

<p>Abstract</p> <p>Background</p> <p>Inhibitors of Apoptosis (IAP) family play a critical role in apoptosis and inflammatory response. Neuronal Apoptosis Inhibitory Protein (NAIP), as a member of both IAPs and NLR families (NOD-Like Receptor), is a unique IAP harboring NOD (Nucleotide Oligomerization Domain) and LLR (Leucine Rich Repeat) motifs. Considering these motifs in NAIP, it has been suggested that the main function of NAIP is distinct from other members of IAPs. As a member of NLR, NAIP mediates the assembly of 'Inflammasome' for inflammatory caspase activation. Pathologic expression of NAIP has been reported not only in some infectious and inflammatory diseases but also in some malignancies. However, there is no report to elucidate NAIP expression in lymphomatic malignancies.</p> <p>Methods</p> <p>In this study, we examined <it>NAIP </it>protein expression in 101 Formalin-Fixed Paraffin-Embedded blocks including samples from 39 Hodgkin Lymphoma and 23 Non Hodgkin Lymphoma cases in comparison with 39 control samples (30 normal and 9 Reactive Lymphoid Hyperplasia (RLH) lymph nodes) using semi-quantitative immuno-flourecent Staining.</p> <p>Results</p> <p>NAIP expression was not statistically different in lymphoma samples neither in HL nor in NHL cases comparing to normal samples. However, we evaluated NAIP expression in normal and RLH lymph nodes. Surprisingly, we have found a statistically significant-difference between the NAIP expression in RLH (M.R of NAIP/GAPDH expression = 0.6365 ± 0.017) and normal lymph node samples (M.R of NAIP/GAPDH expression = 0.5882 ± 0.047) (<it>P </it>< 0.01).</p> <p>Conclusions</p> <p>These findings show that the regulation of apoptosis could not be the main function of NAIP in the cell, so the pathologic expression of NAIP is not involved in lymphoma. But, we concluded that the over expression of NAIP has more effective role in the inflammatory response. Also, this study clarifies the NAIP expression level in lymphoma which is required for IAPs profiling in order to be used in potential translational applications of IAPs.</p

Estimating the Risk for Chromosomal Abnormalities and Heteromorphic Variants in Azoospermic and Severe Oligozoospermic Men

Objectives: A reasonable number of male infertility cases are related to genetic factors. Considering the high prevalence of chromosomal abnormalities related to male infertility, this study investigated the association of the chromosomal aberrations and chromosome variants with hormonal levels, a positive family history, parental consanguinity and a specific lifestyle. We also aimed to find a predictive factor to estimate the risk of the presence of an abnormal karyotype in the azoospermic and especially sever oligozoospermic men. Materials and Methods: A total of 230 infertile men and 50 healthy controls enrolled in the study for cytogenetic evaluation. Data on patients" characteristics were gathered, accurately. Results: Among aforementioned factors, only luteinizing hormone (LH) >12 IU/l raised the chance of detecting a chromosomal abnormality (P < 0.05). The results also showed a higher level of follicle stimulating hormone (FSH) and parental consanguinity and a positive family history of infertility in infertile men compared with the control group (P < 0.05). The incidence of chromosome abnormalities and chromosomal variants were 15.2% and 10.9%, respectively. The investigated variables revealed no association with the prevalence of chromosome heteromorphic variants. Conclusiond: This study suggests a positive family history of infertility, parental consanguineous marriages and high levels of FSH as strong determinants or risk factors for male infertility. Nonetheless, the presence of these patient characteristics did not prove to have a direct correlation with chromosomal abnormalities in male infertility. Among the various possible risk factors studied, an elevated gonadotropin level provides a better risk assessment for the incidence of chromosomal abnormality in infertile men

Identification of Proximal and Distal 22q11.2 Microduplications among Patients with Cleft Lip and/or Palate: A Novel Inherited Atypical 0.6 Mb Duplication

Misalignments of low-copy repeats (LCRs) located in chromosome 22, particularly band 22q11.2, predispose to rearrangements. A variety of phenotypic features are associated with 22q11.2 microduplication syndrome which makes it challenging for the genetic counselors to recommend appropriate genetic assessment and counseling for the patients. In this study, multiplex ligation probe dependent amplification (MLPA) analysis was performed on 378 patients with cleft lip and/or palate to characterize rearrangements in patients suspected of 22q11.2 microduplication and microdeletion syndromes. Of 378 cases, 15 were diagnosed with a microdeletion with various sizes and 3 with duplications. For the first time in this study an atypical 0.6 Mb duplication is reported. Illustration of the phenotypes associated with the microduplications increases the knowledge of phenotypes reported in the literature

Genetic Analysis of MECP2 Gene in Iranian Patients with Rett Syndrome

AbstractObjectivesRett syndrome is an X linked dominant neurodevelopmental disorder which almost exclusively affects females. The syndrome is usually caused by mutations in MECP2 gene, which is a nuclear protein that selectively binds CpG dinucleotides in the genome.Materials &amp; MethodsTo provide further insights into the distribution of mutations in MECP2 gene, we investigated 24 females with clinical characters of Rett syndrome referred to Alzahra University Hospital in Isfahan, Iran during 2015-2017. We sequenced the entire MECP2 coding region and splice sites for detection of point mutations in this gene. Freely available programs including JALVIEW, SIFT, and PolyPhen were used to find out the damaging effects of unknown mutations.ResultsDirect sequencing revealed MECP2 mutations in 13 of the 24 patients. We identified in 13 patients, 10 different mutations in MECP2 gene. Three of these mutations have not been reported elsewhere and are most likely pathogenic.ConclusionDefects in MECP2 gene play an important role in pathogenesis of Rett syndrome. Mutations in MECP2 gene can be found in the majority of Iranian RTT patients. We failed to identify mutations in MECP2 gene in 46% of our patients. For these patients, further molecular analysis might be necessary

Study of type and frequency of Alfa-thalassemia mutations in a cohort of 3,823 patients from Isfahan Province, Iran

Introduction: Alpha-thalassemia (α-thalassemia) is caused by a range of mutations in the α-globin gene resulting in the complete reduction or absence of α-globin chain production. Material and methods: This study assessed the presence of α-thalassemia in 3,823 patients referred to Al-Zahra Hospital, Isfahan, Iran during a 10-year period (from 2012 to 2022). These patients experienced anaemia for more than ten years but had not the full indication for β-thalassemia or iron deficiency. Results: Based on the present assessment, 3,483 cases out of 3,823 suspicious cases had an α-Thalassemia-involved mutation (91.1%). According to the results, the most common detected mutation in the α-thalassemia carriers of Isfahan province was –α3.7 with a frequency of 81.58% (3,119 individuals), followed by α5nt (–TGAGG) (3.71% in total or 39.01% between 364 patients), polyadenylation signal mutations (polyA2) (14.28% between 364 patients), αcodon 19 (GCG4GC–, a2) (11.53%), –α3.7/–α3.7 (11.53%), –α20.5 (7.69%), Hb Constant Spring [Hb CS, a142, Stop →Gln; HBA2: c.427T4C] (5.7%), α4.2 (5.49) and – –MED (4.67%). Conclusion: The results of this investigation may be valuable for designing a program for carrier screening, premarital genetic counselling, and prenatal diagnosis in the Isfahan province

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

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

Identification of disease-causing genes using microarray data mining and gene ontology

Background: One of the best and most accurate methods for identifying disease-causing genes is monitoring gene expression values in different samples using microarray technology. One of the shortcomings of microarray data is that they provide a small quantity of samples with respect to the number of genes. This problem reduces the classification accuracy of the methods, so gene selection is essential to improve the predictive accuracy and to identify potential marker genes for a disease. Among numerous existing methods for gene selection, support vector machine-based recursive feature elimination (SVMRFE) has become one of the leading methods, but its performance can be reduced because of the small sample size, noisy data and the fact that the method does not remove redundant genes. Methods: We propose a novel framework for gene selection which uses the advantageous features of conventional methods and addresses their weaknesses. In fact, we have combined the Fisher method and SVMRFE to utilize the advantages of a filtering method as well as an embedded method. Furthermore, we have added a redundancy reduction stage to address the weakness of the Fisher method and SVMRFE. In addition to gene expression values, the proposed method uses Gene Ontology which is a reliable source of information on genes. The use of Gene Ontology can compensate, in part, for the limitations of microarrays, such as having a small number of samples and erroneous measurement results. Results: The proposed method has been applied to colon, Diffuse Large B-Cell Lymphoma (DLBCL) and prostate cancer datasets. The empirical results show that our method has improved classification performance in terms of accuracy, sensitivity and specificity. In addition, the study of the molecular function of selected genes strengthened the hypothesis that these genes are involved in the process of cancer growth. Conclusions: The proposed method addresses the weakness of conventional methods by adding a redundancy reduction stage and utilizing Gene Ontology information. It predicts marker genes for colon, DLBCL and prostate cancer with a high accuracy. The predictions made in this study can serve as a list of candidates for subsequent wet-lab verification and might help in the search for a cure for cancers