A de novo TINF2, R282C Mutation in a Case of Dyskeratosis Congenital Founded by Next-Generation Sequencing.

Background: Dyskeratosis congenita (DC), an inherited and rare disease prevalent in males, is clinically manifested by reticulate hyperpigmentation, nail dystrophy, and leukoplakia. DC is associated with the increased risk of malignancy and other potentially lethal complications such as bone marrow failure, as well as lung and liver diseases. Mutations in 19 genes were found to be correlated with DC. Herein, we report a 12-year-old boy carrying a de novo mutation in TINF2 gene. Methods: Whole exome sequencing (WES) was performed on DNA sample of the proband, and the variant was investigated in the family by Sanger sequencing. Population and bioinformatics analysis were performed. Results: The NM_ 001099274.3(TINF2): c.844C>T (p.Arg282Cys) mutation was found by WES. Conclusion: There was no history of the disease in the family, and the variant was classified as a de novo mutation.

Homozygosity for Robertsonian Translocation (14q;15q) in a Newborn with a Familial History of Recurrent Abortion and Newborns Affected by Hepatosplenomegaly: A Case Report.

Background: Robertsonian translocations (RobTs) are one of the major chromosomal abnormalities which lead to spontaneous abortion. They occur in the human population at the rate of 1 in 1000 live infants. In this paper, a family carrying one of the rare RobTs was presented and some features of all kinds of RobTs were reviewed. Case Presentation: A couple with a history of three miscarriages was referred to Omid Health Clinic of Hamadan, Iran. The karyotype of the woman was 45,XX, rob(14;15)(q10;q10) and she exhibited phenotypically good health. Karyotype analysis of proband's uncle and his wife with a consanguineous marriage revealed that they were both carriers of rob(14;15). This couple had six offspring, three of which were dead, and the other three were alive with a normal phenotype. Besides, this couple had an unborn child, with a karyotype of 44,XX,rob(14;15)(q10;q10). Conclusion: These observations showed that genetic counseling, pedigree, and chromosomal analysis are needed to discover the cause of spontaneous abortion, stillbirth, congenital anomalies, sudden infant death syndrome (SIDS), etc. Moreover, families carrying RobTs would be offered prenatal diagnosis screening tests and, if necessary, assisted reproductive technology methods to assist with preimplantation genetic test for structural rearrangement (PGT-SR) reproduction.

Hb Narges Lab, a Novel Hemoglobin Variant of the ß-Globin Gene.

In this study, we describe a new missense variant on the ß-globin gene in a heterozygous form in a female individual. Standard methods were used to determine red blood cell indices and perform hemoglobin analyses. Molecular studies were performed on the genomic DNA isolated from peripheral blood cells. Beta-globin genes were amplified and sequenced. We report a novel mutation on the ß-globin gene (HBB), c.134 C>T; p.S44F variant, in the heterozygote state which was detected in a female of Persian ethnic origin in the Khuzestan province, southern Iran, that we named Hb Narges Lab (HbNL) variant. This mutation was predicted to be disease-causing in all except one in silico prediction tools. This variant was reported for the first time worldwide, had no shown hematological abnormalities but should be considered when inherited in the compound heterozygous form with ß- thalassemia (ß0-thal) carrier, which might result in the phenotype of thalassemia intermedia.

Myocardial Function Prediction After Coronary Artery Bypass Grafting Using MRI Radiomic Features and Machine Learning Algorithms.

The main aim of the present study was to predict myocardial function improvement in cardiac MR (LGE-CMR) images in patients after coronary artery bypass grafting (CABG) using radiomics and machine learning algorithms. Altogether, 43 patients who had visible scars on short-axis LGE-CMR images and were candidates for CABG surgery were selected and enrolled in this study. MR imaging was performed preoperatively using a 1.5-T MRI scanner. All images were segmented by two expert radiologists (in consensus). Prior to extraction of radiomics features, all MR images were resampled to an isotropic voxel size of 1.8 × 1.8 × 1.8 mm3. Subsequently, intensities were quantized to 64 discretized gray levels and a total of 93 features were extracted. The applied algorithms included a smoothly clipped absolute deviation (SCAD)-penalized support vector machine (SVM) and the recursive partitioning (RP) algorithm as a robust classifier for binary classification in this high-dimensional and non-sparse data. All models were validated with repeated fivefold cross-validation and 10,000 bootstrapping resamples. Ten and seven features were selected with SCAD-penalized SVM and RP algorithm, respectively, for CABG responder/non-responder classification. Considering univariate analysis, the GLSZM gray-level non-uniformity-normalized feature achieved the best performance (AUC: 0.62, 95% CI: 0.53-0.76) with SCAD-penalized SVM. Regarding multivariable modeling, SCAD-penalized SVM obtained an AUC of 0.784 (95% CI: 0.64-0.92), whereas the RP algorithm achieved an AUC of 0.654 (95% CI: 0.50-0.82). In conclusion, different radiomics texture features alone or combined in multivariate analysis using machine learning algorithms provide prognostic information regarding myocardial function in patients after CABG.

Genetic mutations and immunological features of severe combined immunodeficiency patients in Iran.

BACKGROUND: Severe combined immunodeficiency (SCID) is the most severe form of primary immunodeficiency disorders that is characterized by impaired early T lymphocyte differentiation and is variably associated with abnormal development of other lymphocyte lineages. SCID can be caused by mutations in more than 20 different genes. Molecular diagnosis in SCID patients contributes to genetic counseling, prenatal diagnosis, treatment modalities, and overall prognosis. In this cohort, the clinical, laboratory and genetic data related to Iranian SCID patients were comprehensively evaluated and efficiency of stepwise sequencing methods approach based on immunophenotype grouping was investigated METHODS: Clinical and laboratory data from 242 patients with SCID phenotype were evaluated. Molecular genetic analysis methods including Sanger sequencing, targeted gene panel and whole exome sequencing were performed on 62 patients. RESULTS: Mortality rate was 78.9% in the cohort with a median follow-up of four months. The majority of the patients had a phenotype of T-NK-B+ (34.3%) and the most severe clinical manifestation and highest mortality rate were observed in T-NK-B- SCID cases. Genetic mutations were confirmed in 50 patients (80.6%), of which defects in recombination-activating genes (RAG1 and RAG2) were found in 16 patients (32.0%). The lowest level of CD4+ and CD8+ cells were observed in patients with ADA deficiency (p = 0.026) and IL2RG deficiency (p = 0.019), respectively. CONCLUSION: Current findings suggest that candidate gene approach based on patient's immunophenotype might accelerate molecular diagnosis of SCID patients. Candidate gene selection should be done according to the frequency of disease-causing genes in different populations. Targeted gene panel, WES and WGS methods can be used for the cases which are not diagnosed using this method.

Graft versus host disease and microchimerism in a JAK3 deficient patient.

BACKGROUND: The lymphohematopoietic cells originating from feto-maternal trafficking during pregnancy may cause microchimerism and lead to materno-fetal graft versus host disease (GVHD) in severe combined immunodeficiency (SCID) patients. However, definitive diagnosis between GVHD and Omenn's syndrome is often difficult based on clinical and immunological phenotypes particularly in the patients with hypomorphic mutations. CASE PRESENTATION: A 3-year-old girl with a history of erythroderma and immunodeficiency was studied. The whole exome sequencing method was used to find the disease-causing variants, and T-A cloning and Quantitative Florescence Polymerase Chain Reaction (QF-PCR) methods were utilized to detect the presence of mosaicism or microchimerism. We identified a homozygous missense Janus Kinase 3 mutation (JAK3, c.2324G>A, p.R775H) as a new disease-causing variant in the patient, and the presence of microchimerism with maternal origin was proven as an underlying cause of her clinical presentation. CONCLUSION: The findings highlighted the importance of appropriate diagnostic approach in GVHD cases with hypomorphic JAK3 mutations. When analyzing the results of the next generation sequencing, the possibility of microchimerism should be considered based on the context of the disease.

Association Study of rs1333040 and rs1004638 Polymorphisms in the 9p21 Locus with Coronary Artery Disease in Southwest of Iran.

BACKGROUND: Coronary artery disease (CAD) is a multifactorial and heterogenic disease. Recently, genome-wide association studies have reported that rs1333040 (C/T) and rs1004638 (A/T) single nucleotide polymorphisms (SNPs) in the 9p21 locus have very strong association with CAD. This study aimed to examine these associations in Southwest of Iran. METHODS: Blood samples were collected from 200 CAD patients and 110 healthy individuals with no CAD. The association of two SNPs with CAD was evaluated by PCR and restriction fragment length polymorphism. RESULTS: Chi-square test showed no association between rs1333040 SNP and CAD (X2: 4.66, df: 2, P=0.09). Also, there was no association between rs1004638 SNP and CAD (X2: 0.27, df: 2, P=0.88). CONCLUSION: No association was observed between rs1333040 and rs1004638 SNPs in the 9P21 region and CAD in Southwest of Iran.

Relationship between progesterone level on the day of human chorionic gonadotropin administration with outcomes of intra-cytoplasmic sperm injection in infertile couples.

BACKGROUND: Gonadotropin-releasing hormone agonists or antagonists are used in assisted reproductive technique cycles as premature luteinizing hormone secretion inhibition. Studies have been reported different and contradictory results on the serum progesterone effect on intra-cytoplasmic sperm injection. OBJECTIVE: The purpose of this study was to evaluate the effect of serum progesterone level on the day of Human chorionic gonadotropin (HCG) administration on the intra-cytoplasmic sperm injection (ICSI) outcome in infertile women. MATERIALS AND METHODS: 249 infertile couples candidated for ICSI were enrolled in the study. Their serum progesterone level on the day of HCG administration was measured and according to serum level, patients were divided into four groups of less than 0.9, 0.9-1.4, 1.5-1.9, and ≥2 ng/mL. The four groups were compared with each other regarding fertility outcomes. RESULTS: Pregnancy rate was not significantly different among the four groups (p>0.05). Also, there was no significant difference among the groups regarding frequency of abortion and ectopic pregnancy. CONCLUSION: Serum progesterone level on the day of HCG administration does not have any significant effect on pregnancy outcomes, including abortion, ectopic pregnancy, and pregnancy rate in patients undergoing ICSI treatment.

SULF 1 gene polymorphism, rs6990375 is in significant association with fetus failure in IVF technique.

BACKGROUND: Sulfatase 1 (SULF1) function is to remove the 6-O-sulphate group from heparan sulfate. This action changes the binding sites of extracellular growth factors. SULF1 expression has been reported to be changed in angiogenesis. We hypothesized that single nucleotide polymorphisms (SNPs) of SULF1 would impact clinicopathologic characteristics. OBJECTIVE: Study of SULF1 gene polymorphism with fetus failure in in vitro fertilization (IVF) technique. MATERIALS AND METHODS: We studied one common (minor allele frequency >0.05) regulatory SNP, rs6990375, with polymerase chain reaction and restriction fragment length polymorphism method, in 53 infertile women with fetus failure in IVF technique and 53 women with at least one healthy child as controls. RESULTS: We found that rs6990375 is significantly associated with an early failure in IVF and frequency of G allele is high in women with fetus failure in IVF technique (p<0.001). CONCLUSION: These findings suggest that SULF1genetic variations may play a role in IVF technique fetus failure. Further studies with large sample sizes on SULF1 SNPs may be useful in support of this claim.

Association of MEF2A gene polymorphisms with coronary artery disease.

BACKGROUND: Coronary Artery Disease (CAD) is the most common cause of death worldwide. MEF2A directly regulates target genes in the process of muscle development. This gene product is a transcription factor. MEF2A protein in homodimer or heterodimer forms binds to A/T-rich cis elements with conserved sequence in promoter, regulator, and enhancer of many genes, which are determining in evolution and development of skeletal, heart, and smooth muscle cells, especially endothelial cells. In fact, this protein maximizes the activity of these elements. OBJECTIVES: The two MEF2A gene polymorphisms that were proposed to have an association with CAD are rs34851361 (A/G) and rs325400 (T/G) SNPs. This study aimed to examine these associations. PATIENTS AND METHODS: This study was a molecular case-control study. Blood samples were collected from 300 patients with CAD and 150 healthy people from Golestan and Imam Khomeini Hospitals, Ahvaz, Iran. In both groups, angiography had confirmed the presence or lack of stenosis. Association of rs34851361 and rs325400 with CAD was evaluated by PCR and then restriction fragment length polymorphism (RFLP) analysis was performed. RESULTS: Chi square test showed no association between rs34851361 SNP and CAD (χ(2) = 3.59, df = 2, and P = 0.16); however, there was an association between rs325400 SNP and CAD (χ(2) = 24.77, df = 2, and P < 0.001). A/T haplotype showed association with CAD and G/G and G/T showed protective effect against CAD. CONCLUSIONS: The results of this study show that rs325400 polymorphism is in association with CAD; meanwhile, none of the rs34851361 genotypes was associated with CAD.

Spasmolytic effect of stachys lavandulifolia vahl. Crude methanolic extract and fractions on rat ileum.

The aim of this study was to investigate the effect of aerial parts of Stachys lavandulifolia Vahl. Extract on the rat ileum contractions. The crude extract was prepared by maceration method (90% methanol) followed by fractionating into chloroform, ethyl acetate, petroleum ether and water. In adult male Wistar rats, ileum was sectioned and mounted in tissue bath and their contractility was recorded is otonically. KCl (60 mM)- induced ileum contractions were attenuated by crude extract and its fractions. The most potent fraction was chloroformic fraction (CF) with IC50 0.018 ± 0.126 = mg/mL. In calcium-free Tyrode solution with high K(+,) the CF (0.01 - 0.04 mg/ml) attenuated CaCl2-induced contractions (p< 0.001). The CF (0.05-0.8 mg/mL) attenuated the carbachol-induced contraction (p<0.001). The CF antispasmodic effect was reduced by naloxone (as a non-selective opioid antagonist), not by propranolol and L-NAME as ß-adrenoceptors antagonist and nitric oxide synthase inhibitor respectively. It was concluded that S . . lavandulifolia can inhibit ileum contractility mainly via disturbing the calcium mobilization and partly by opioid receptors' activation. Our results may support the traditional usage of this herb for treating diarrhea.