Bi-allelic variants in OGDHL cause a neurodevelopmental spectrum disease featuring epilepsy, hearing loss, visual impairment, and ataxia.

The 2-oxoglutarate dehydrogenase-like (OGDHL) protein is a rate-limiting enzyme in the Krebs cycle that plays a pivotal role in mitochondrial metabolism. OGDHL expression is restricted mainly to the brain in humans. Here, we report nine individuals from eight unrelated families carrying bi-allelic variants in OGDHL with a range of neurological and neurodevelopmental phenotypes including epilepsy, hearing loss, visual impairment, gait ataxia, microcephaly, and hypoplastic corpus callosum. The variants include three homozygous missense variants (p.Pro852Ala, p.Arg244Trp, and p.Arg299Gly), three compound heterozygous single-nucleotide variants (p.Arg673Gln/p.Val488Val, p.Phe734Ser/p.Ala327Val, and p.Trp220Cys/p.Asp491Val), one homozygous frameshift variant (p.Cys553Leufs∗16), and one homozygous stop-gain variant (p.Arg440Ter). To support the pathogenicity of the variants, we developed a novel CRISPR-Cas9-mediated tissue-specific knockout with cDNA rescue system for dOgdh, the Drosophila ortholog of human OGDHL. Pan-neuronal knockout of dOgdh led to developmental lethality as well as defects in Krebs cycle metabolism, which was fully rescued by expression of wild-type dOgdh. Studies using the Drosophila system indicate that p.Arg673Gln, p.Phe734Ser, and p.Arg299Gly are severe loss-of-function alleles, leading to developmental lethality, whereas p.Pro852Ala, p.Ala327Val, p.Trp220Cys, p.Asp491Val, and p.Arg244Trp are hypomorphic alleles, causing behavioral defects. Transcript analysis from fibroblasts obtained from the individual carrying the synonymous variant (c.1464T>C [p.Val488Val]) in family 2 showed that the synonymous variant affects splicing of exon 11 in OGDHL. Human neuronal cells with OGDHL knockout exhibited defects in mitochondrial respiration, indicating the essential role of OGDHL in mitochondrial metabolism in humans. Together, our data establish that the bi-allelic variants in OGDHL are pathogenic, leading to a Mendelian neurodevelopmental disease in humans.

ACER3-related leukoencephalopathy: expanding the clinical and imaging findings spectrum due to novel variants.

BACKGROUND: Leukodystrophies are the main subgroup of inherited CNS white matter disorders which cause significant mortality and morbidity in early years of life. Diagnosis is mostly based on clinical context and neuroimaging findings; however, genetic tools, particularly whole-exome sequencing (WES), have led to comprehending the causative gene and molecular events contributing to these disorders. Mutation in Alkaline Ceramidase 3 (ACER3) gene which encodes alkaline ceramidase enzyme that plays a crucial role in cellular growth and viability has been stated as an uncommon reason for inherited leukoencephalopathies. Merely only two ACER3 mutations in cases of progressive leukodystrophies have been reported thus far. RESULTS: In the current study, we have identified three novel variants in ACER3 gene in cases with new neurological manifestations including developmental regression, dystonia, and spasticity. The detected variants were segregated into family members. CONCLUSION: Our study expands the clinical, neuroimaging, electroencephalographic, and genetic spectrum of ACER3 mutations. Furthermore, we reviewed and compared the findings of all the previously reported cases and the cases identified here in order to facilitate their diagnosis and management.

Biallelic variants in TMEM222 cause a new autosomal recessive neurodevelopmental disorder.

PURPOSE: To elucidate the novel molecular cause in families with a new autosomal recessive neurodevelopmental disorder. METHODS: A combination of exome sequencing and gene matching tools was used to identify pathogenic variants in 17 individuals. Quantitative reverse transcription polymerase chain reaction (RT-qPCR) and subcellular localization studies were used to characterize gene expression profile and localization. RESULTS: Biallelic variants in the TMEM222 gene were identified in 17 individuals from nine unrelated families, presenting with intellectual disability and variable other features, such as aggressive behavior, shy character, body tremors, decreased muscle mass in the lower extremities, and mild hypotonia. We found relatively high TMEM222 expression levels in the human brain, especially in the parietal and occipital cortex. Additionally, subcellular localization analysis in human neurons derived from induced pluripotent stem cells (iPSCs) revealed that TMEM222 localizes to early endosomes in the synapses of mature iPSC-derived neurons. CONCLUSION: Our findings support a role for TMEM222 in brain development and function and adds variants in the gene TMEM222 as a novel underlying cause of an autosomal recessive neurodevelopmental disorder.

Lack of association between FTO gene variations and metabolic healthy obese (MHO) phenotype: Tehran Cardio-metabolic Genetic Study (TCGS).

BACKGROUND: Obesity is currently an international epidemic and metabolic derangements pose these individuals at greater risk for future morbidity and mortality. Genetics and environmental factors have undeniable effects and among genetic risk factors, FTO/CETP genes are important. The current study examines the interaction between obesity phenotypes and FTO/CETP SNPs and their effects on lipid profile changes. MATERIALS AND METHODS: We selected 954 adult subjects from TCGS (47.9% male). Participants were stratified according to their BMI and presence of metabolic syndrome according to the Joint Interim Statement (JIS) definition. Nine selected polymorphisms from FTO/CETP genes were genotyped using Tetra ARMS-PCR method. After age and sex adjustment the interaction of 9 markers with lipid profiles among phenotypes were tested by PASW. RESULTS: In three main groups, HDL_C level had a strong significant association with CETP markers: (rs3764261, ß(95% CI) - 0.48(- 0.61 to - 0.35), P = 1.0 × 10-11), (rs1800775, ß(95% CI) 0.5(0.36;0.65), P = 1.0 × 10-6) and (rs1864163, ß(95% CI) 0.3(0.16;0.43), P = 9.1 × 10-5). This association was also seen in rs7202116 within the total population. In only unhealthy metabolic obese (MUHO) subgroups four new FTO markers (rs1421085, rs1121980, rs1558902 and rs8050136) (P value < 0.01) demonstrated significant association, even after lipid profile adjustment. CONCLUSION: In the present study, we investigated the association between obesity phenotypes and some variations in FTO/CETP genes for the first time. Our study showed that four markers in the first intron of the FTO gene should be the risk marker in MUHO participants. LEVEL OF EVIDENCE: Level III, case-control study.

Molecular genetics of a cohort of 635 cases of phenylketonuria in a consanguineous population.

Phenylketonuria (PKU) is an inborn error of amino acid metabolism caused by mutations in the phenylalanine hydroxylase (PAH) gene, characterized by intellectual deficit and neuropsychiatric complications in untreated patients with estimated frequency of about one in 10,000 to 15,000 live births. PAH deficiency can be detected by neonatal screening in nearly all cases with hyperphenylalaninemia on a heel prick blood spot. Molecular testing of the PAH gene can then be performed in affected family members. Herein, we report molecular study of 635 patients genetically diagnosed with PKU from all ethnicities in Iran. The disease-causing mutations were found in 611 (96.22%) of cases. To the best of our knowledge, this is the most comprehensive molecular genetics study of PKU in Iran, identifying 100 distinct mutations in the PAH gene, including 15 previously unreported mutations. Interestingly, we found unique cases of PKU with uniparental disomy, germline mosaicism, and coinheritance with another Mendelian single-gene disorder that provides new insights for improving the genetic counseling, prenatal diagnosis (PND), and/or pre-implantation genetic diagnosis (PGD) for the inborn error of metabolism group of disorders.

Reporting the presence of three different diseases causing GJB2 mutations in a consanguineous deaf family.

OBJECTIVE: This paper reports a consanguineous deaf family with three different mutations in the GJB2 gene. DESIGN: Four members of an Iranian deaf family were recruited in this study. The GJB2 coding region and exon-intron boundaries were investigated using direct sequencing. STUDY SAMPLE: The proposita was a 12-year-old girl with congenital non-syndromic hearing loss. She was born to consanguineous parents. The proposita, her parents and deaf maternal uncle were screened for GJB2 mutations. RESULTS: Sequencing demonstrated the presence of the c.176_191del and c.327_328delGGinsA mutations in the proposita, the c.176_191del mutation in her father, and the c.35delG and c.327_328delGGinsA mutations in trans in her apparently unaffected mother as well as in her congenitally deaf uncle. Follow-up pure-tone audiometry revealed moderate to severe mid- and high-frequency hearing loss in the mother. CONCLUSIONS: This study shows the complexity of genetic testing and counseling for hearing loss.

Heritability of the metabolic syndrome and its components in the Tehran Lipid and Glucose Study (TLGS).

Growing evidence suggests that metabolic syndrome (MetS) has both genetic and environmental bases. We estimated the heritability of the MetS and its components in the families from the Tehran Lipid and Glucose Study (TLGS). We investigated 904 nuclear families in TLGS with two biological parents and at least one offspring (1565 parents and 2448 children), aged 3-90 years, for whom MetS information was available and had at least two members of family with MetS. Variance component methods were used to estimate age and sex adjusted heritability of metabolic syndrome score (MSS) and MetS components using SOLAR software. The heritability of waist circumference (WC), HDL-cholesterol (HDL-C), triglycerides (TGs), fasting blood sugar (FBS), systolic blood pressure (SBP) and diastolic blood pressure (DBP) as continuous traits after adjusting for age and gender were 27, 46, 36, 29, 25, 26 and 15%, respectively, and MSS had a heritability of 15%. When MetS components were analysed as discrete traits, the estimates of age and gender adjusted heritability for MetS, abdominal obesity, low HDL-C, high TG, high FBS and high blood pressure (BP) were 22, 40, 34, 38 and 23%, respectively (P < 0·05). Three factors were extracted from the six continuous traits of the MetS including factor I (BP), factor II (lipids) and factor III (obesity and FBS). Heritability estimation for these three factors were 7, 13 (P < 0·05) and 2%, respectively. The highest heritability was for HDL-C and TG. The results strongly encourage efforts to identify the underlying susceptibility genes.

Neonatal Onset of Hemophagocytic Lymphohistiocytosis Due to Prenatal Varicella-Zoster Infection in a Neonate with Griscelli Syndrome Type 2.

Type 2 Griscelli syndrome (Type2 GS) is a primary inborn error of the immune system, classified in the immune dysregulation group.1,2 There are three different types of the disease, with different genetic causes responsible for the autosomal recessive inheritance pattern. Although hypopigmentation is common in all variants, neurological involvement or immunodeficiency with varying severity is seen in different types. Molecular motor protein myosin 5 an (MYo5A) [Type1GS], guanosine Triphosphate (GTP) binding protein (RAB27A) [Type2GS], and mutation in human melanophilin (MLPH) [Type 3GS] which is limited to hypopigmentation are reported as the known genetic defects in GS.3 Severe, ineffective, and uncontrolled inflammatory reactions are referred to as the pathogenesis of Hemophagocytic lymphohistiocytosis (HLH). HLH is a life-threatening condition that can be defined as either primary or secondary. Secondary causes happen in the context of autoimmunity, malignancy, spontaneous, or infections.4 Prenatal infections play an important role in causing long-term complications in the fetus. Some of them include toxoplasmosis, rubella, cytomegalovirus, herpes simplex, and other organisms including syphilis, parvovirus, and Varicella zoster, known as TORCH syndrome (5).TORCH has been well described for a long time but there are limited reports of developing HLH in the context of prenatal infections. We described a type 2GS syndrome with neonatal-onset HLH triggered by a prenatal infection.

Low HDL concentration in rs2048327-G carriers can predispose men to develop coronary heart disease: Tehran Cardiometabolic genetic study (TCGS).

Recent genome-wide association studies (GWAS) highlighted the importance of genetic variations on SLC22A3 and MIA3 genes in developing coronary heart disease (CHD) among different ethnicities. However, the influence of these variations is not recognized within the Iranian population. Hence, in the present study, we aim to investigate two key single nucleotide polymorphisms (SNPs) on CHD incidence in this population. For this purpose, from Tehran Cardiometabolic Genetic Study (TCGS), 453 individuals with CHD were selected as a case and 453 individuals as a control that matched their age and gender. After quality control of two selected SNPs, rs2048327 (SLC22A3) and rs17465637 (MIA3), we used genotyps resulted from chip-typing technology and conducted the logistic regression analysis adjusted for non-genetic risk factors to detect the possible association of these SNPs with the CHD development. Our findings demonstrated the rs2048327-G and rs17465637-C can significantly increase the risk of CHD development about two times in only males and females, respectively. Interestingly, in the male carriers of the risk allele (G) of rs2048327, the low high-density lipoprotein (HDL) level can significantly predispose them to develop coronary heart disease in the future. According to our results, paying more attention to gender and genetic markers can help more efficient coronary heart disease screening and diagnosis.

Comprehensive Mutation Analysis and Report of 12 Novel Mutations in a Cohort of Patients with Spinal Muscular Atrophy in Iran.

Spinal muscular atrophies (SMAs) are a heterogeneous group of neuromuscular diseases characterized by loss of motor neurons, muscle weakness, hypotonia and muscle atrophy, with different modes of inheritance; however, the survival motor neuron 1 (SMN1) gene is predominantly involved. The aims of the current study were to clarify the genetic basis of SMA and determine the mutation spectrum of SMN1 and other associated genes, in order to provide molecular information for more accurate diagnosis and future prospects for treatment. We performed a comprehensive analysis of 5q SMA in 1765 individuals including 528 patients from 432 unrelated families with at least one child with suspected clinical presentation of SMA. Copy number variations of the SMN1 and SMN2 genes and linkage analysis were performed using multiplex ligation-dependent probe amplification (MLPA) and short tandem repeat (STR) markers linked to the SMN1 gene. Cases without mutation in the SMA locus on 5q were analyzed for the DNAJB2, IGHMBP2, SIGMAR1 and PLEKHG5 genes using linked STR markers. Sanger sequencing of whole genes was performed for cases with homozygous haplotypes. Whole-genome sequencing (WGS) and whole-exome analysis was conducted for some of the remaining cases. Mutations in the SMN1 gene were identified in 287 (66.43%) families including 269 patients (62.26%) with homozygous deletion of the entire SMN1 gene. Only one of the patients had a homozygous point mutation in the SMN1 gene. Among the remaining families, three families showed mutations in either the DNAJB2, SIGMAR1 or PLEKHG5 genes, which were linked using STR analysis and Sanger sequencing. From 10 families who underwent WGS, we found six homozygous point mutations in six families for either the TNNT1, TPM3, TTN, SACS or COL6A2 genes. Two mutations in the PLA2G6 gene were also found in another patient as compound heterozygous. This rather large cohort allowed us to identify genotype patterns in Iranian 5q SMA patients. The process of identifying 11 mutations (9 novel) in 9 different genes among non-5q SMA patients shows the diversity of genes involved in non-5q SMA in Iranians. Genotyping of patients with SMA is essential for prenatal and preimplantation genetic diagnosis (PGD), and may be very helpful for guiding treatment, with the advent of new, more effective, albeit very expensive, therapies. Also, combining linkage analysis was shown to be beneficial in many ways, including sample authenticity and segregation analysis, and for ruling out maternal cell contamination during prenatal diagnosis (PND).

Biallelic variants in MESD, which encodes a WNT-signaling-related protein, in four new families with recessively inherited osteogenesis imperfecta.

The bone disorder osteogenesis imperfecta (OI) is genetically heterogeneous. Most affected individuals have an autosomal dominant disorder caused by heterozygous variants in either of the type I collagen genes (COL1A1 or COL1A2). To date, two reports have linked Mesoderm Development LRP Chaperone (MESD) to autosomal recessive OI type XX. Four different biallelic pathogenic variants in MESD were shown to cause a progressively deforming phenotype, associated with recurrent fractures and oligodontia in five individuals in five families. Recently, compound heterozygosity for a frameshift predicted to lead to a premature termination codon in exon 2 of the 3-exon gene and a second frameshift in the terminal exon in MESD were detected in three stillbirths in one family with severe OI consistent with the neonatal lethal phenotype. We have identified four additional individuals from four independent families with biallelic variants in MESD: the earlier reported c.632dupA (p.Lys212Glufs∗19) and c.676C>T (p.Arg226∗)-which are associated with a severe form of OI-and one new pathogenic variant, c.603-606delTAAA (p.Asn201Lysfs∗15), which causes a neonatal lethal form of OI. MESD acts in the WNT signaling pathway, where it is thought to play a role in the folding of the WNT co-receptors low-density lipoprotein receptor-related proteins 5 and 6 (LRP5/LRP6) and in chaperoning their transit to the cell surface. Our report broadens the phenotypic and genetic spectrum of MESD-related OI, provides additional insight into the pathogenic pathways, and underscores the necessity of MESD for normal WNT signaling in bone formation.

Development of a quantitative real-time PCR assay for detection of unknown alpha-globin gene deletions.

BACKGROUND: Alpha-Thalassemia is the most common inherited disorder of hemoglobin (Hb) synthesis in the world. Unlike beta-thalassemia, in which non-deletional mutations predominate, most of recognized alpha-thalassemia mutations include deletion of one or both alpha-globin genes. The importance of alpha-thalassemia detection is mainly due to its shared blood parameters with beta-thalassemia and its impact on discrimination between unknown alpha-thalassemia and normal HbA2 beta-thalassemia during thalassemia prevention program. MATERIALS AND METHODS: Cases with hematologic profile of low MCV, MCH, and normal HbA2 were enrolled in this study. Common alpha-globin deletional mutations including alpha(3.7)kb, alpha(4.2)kb, alpha(20.5)kb, and alpha(MED) and point mutation including 5 nt, Constant Spring (CS), and C19 were checked using either GAP-PCR or ARMS-PCR. Cases with unknown molecular defects were investigated further by direct gene sequencing. Finally, further study was done for probable unknown deletions by gene dosage analysis using real-time PCR. For this, five pairs of primers were used spanning from theta-globin gene up to the 3' upstream of alpha(2) gene. RESULTS: After validation of primers specificity and performing serial dilution analysis in order to calculate PCR efficiency, the assay was performed on normal samples and cases with known alpha-globin gene deletions as positive and negative controls, respectively. The assay was able to diagnose the control groups successfully. In 21 out of 29 unknown cases (72.4%), the assay showed various patterns of deletions in at 2 to 5 screened regions (theta gene up to the upstream of alpha2 gene). In 8 (27.6%) cases, deletions were seen in all regions. CONCLUSION: Gene dosage study by quantitative real-time PCR can be suggested as a rapid and reliable assay to screen probable carrier of alpha-thalassemia for unknown alpha-globin gene deletions.

Anti­inflammatory effect of Migri­Heal® in an in vitro inflammatory model of primary mixed glial cells.

Migri­Heal®, is a novel herbal remedy that was introduced for the treatment of migraine headaches. Previous studies revealed that this drug may reduce nitric oxide (NO) in an in vitro inflammatory model. The aim of the present study was to investigate the anti­inflammatory effect of Migri­Heal® on primary mix glial cells stimulated with LPS. In the current study, neonatal rat primary mix glial cells were isolated from the mixed glial cultures via shaking, and cultured in Dulbecco's' modified Eagle's medium supplemented with 10% fetal bovine serum. Following pretreatment with Migri­Heal® (25, 75, 100, 150, 200 and 300 µg/ml) and cells were treated with LPS (10 µg/ml) for 1 h, and incubated for 48 h. The present study determined that 150 µg/ml Migri­Heal® significantly reduced the production of NO in rat mix glial cells stimulated with 10 µg/ml LPS. Migri­Heal® also suppressed mRNA expression level of LPS­induced inducible nitric oxide synthase and tumor necrosis factor α, which was accompanied by inhibition of the transcription factor nuclear factor­κB. Additionally, MTT assay determined that Migri­Heal® was not cytotoxic, suggesting that the anti­inflammatory effects of Migri­Heal® observed were not due to cell death. In conclusion, the findings of the present study demonstrated that Migri­Heal® may be useful as a potential anti­inflammatory agent in inflammatory diseases. However, additional studies are required to confirm these findings.

Increased Risk of CHD in the Presence of rs7865618 (A allele): Tehran Lipid and Glucose Study.

BACKGROUND: Recent genome-wide association studies (GWAS) in European populations have indicated that the rs12526453 polymorphism located in phosphatase and actin regulator 1 gene (PHACTR1), mapping to chromosome 6p24 and rs7865618 polymorphism in the cyclin-dependent kinase inhibitor B antisense RNA 1 gene (CDKN2B-AS1) on 9p21.3 are associated with coronary heart disease (CHD). This study was carried out to investigate the association of these polymorphisms and CHD in an Iranian population. METHODS: In the present case-control study, 420 patients with CHD events were recruited from the population of the Tehran lipid and glucose study (TLGS); 407 healthy controls matched for age and sex were selected from the same population. The SNPs rs12526453 and rs7865618 were genotyped using amplification refractory mutation system-polymerase chain reaction (ARMS-PCR). RESULTS: The allele frequency of both SNPs deviated from Hardy-Weinberg equilibrium. The C allele frequency of the rs12526453 (68.5%, P = 0.11) and A allele of the rs7865618 (68.8%, P = 0.09) were the most prevalent alleles in both the case and control groups. The results indicated a significant association between the presence of risk alleles of rs7865618 and CHD in the TLGS population (P = 0.03; OR: 1.73; CI95%: 1.04 - 2.88). CONCLUSION: Due to the importance of chromosome 9p21 region and its relation with cardiovascular disease, the allelic pattern of its variation should be studied in different populations. The relation between this polymorphism and cardiovascular disease in the studied population confirms the importance of this region.

Rationale and Design of a Genetic Study on Cardiometabolic Risk Factors: Protocol for the Tehran Cardiometabolic Genetic Study (TCGS).

BACKGROUND: Cardiometabolic risk factors comprise cardiovascular diseases and/or diabetes, and need to be evaluated in different fields. OBJECTIVE: The primary aim of the Tehran Cardiometabolic Genetic Study (TCGS) is to create a comprehensive genome-wide database of at least 16,000 Tehranians, who are participants of the ongoing Tehran Lipid and Glucose Study (TLGS) cohort. METHODS: TCGS was designed in collaboration with the Research Institute for Endocrine Sciences and the genetic company deCODE. Participants had already been followed for over a 20-year period for major cardiometabolic-related health events including myocardial infarction, stroke, diabetes mellitus, hypertension, obesity, hyperlipidemia, and familial hypercholesterolemia. RESULTS: The TCGS cohort described here comprises 17,186 (86.3%) of the 19,905 TLGS participants who provided a baseline blood sample that was adequate for plasma and deoxyribonucleic acid analysis. This study is comprised of 849 individuals and 3109 families with at least one member having genotype information. Finally, 5977 males and 7422 females with the total genotyping rate of 0.9854 were genotyped with HumanOmniExpress-24-v1-0 bead chips (containing 649,932 single-nucleotide polymorphism loci with an average mean distance of 4 kilobases). CONCLUSIONS: Investigations conducted within the TCGS will seek to identify relevant patterns of genetic polymorphisms that could be related to cardiometabolic risk factors in participants from Tehran. By linking genome-wide data to the existing databank of TLGS participants, which includes comprehensive behavioral, biochemical, and clinical data on each participant since cohort inception in 1999, the TCGS will also allow exploration of gene-gene and gene-environment interactions as they relate to disease status.

The Relation between Metabolic Syndrome Risk Factors and Genetic Variations of Apolipoprotein V in Relation with Serum Triglyceride and HDL-C Level.

INTRODUCTION: Metabolic syndrome (MetS) is a multi-factorial disorder with five important components. A high triglyceride level combined with low HDL cholesterol has been reported to be associated with Apolipoprotein A5 (APOA5) gene variations. In this study, we aimed to determine the association of single nucleotide polymorphisms including: rs662799, rs3135506 and rs2075291 in the apolipoprotein A-V (APOA5) gene in relation to MetS component like triglyceride and HDL-C level in Tehran Lipid and Glucose Study (TLGS). MATERIALS AND METHODS: Metabolic syndrome was defined according to ATPIII and phenotypes were defined by the National Cholesterol Education Program (NCEP) criteria for MetS. Demographic, biochemical parameters and anthropometric variables were measured. Selected APOA5 gene polymorphisms were genotyped using PCR-RFLP method. RESULTS: From TLGS population, 947 adults, aged 19 - 70 years, were randomly selected and recruited into the study. Mean age, triglyceride and WC were higher and mean HDL was lower in MetS vs. non-MetS group. C allele in rs2075291 showed a significant association with MetS (OR: 2.38, 95% CI; 1.11 - 5.08, P = 1.5 ×10(-2)). The association was shown between higher serum triglyceride and the presence of T allele (P = 4.5 × 10(-4)) and also lower serum HDL-C and the presence of T allele (P = 1.6 × 10(-3)) in rs2075291. Also this association showed between raised waist circumference and C allele in rs3135506 (P = 3.5 × 10(-2) ) and raised systolic and diastolic blood pressure level and C allele of rs662799 (P = 4.5 × 10(-2)). CONCLUSION: According to the results, there is a relationship between lipid profile and studied polymorphism in the presence of metabolic syndrome. It seems that APOA5 rs2075291 could play an important role in triglyceride and HDL-C level in metabolic syndrome affected, while the association of APOA5 rs662799 polymorphism is still under debate.

Low gradient ascites: a seven-year course review.

AIM: To study the patients with low gradient ascites in hospitals of Guilan Province (northern Iran). METHODS: Patients admitted in hospitals of Guilan Province with low gradient ascites from 1993 to 2000 were enrolled in the study. Serum and ascitic fluid albumin levels were determined by biochemical reactions. The serum-ascitic albumin gradient (SAAG) less than 1.1 g/dL was considered low. Statistical analysis was performed with SPSS 9.0 software and P<0.05 was considered statistically significant. RESULTS: Of the 148 patients enrolled in the study, 72 (48.6%) were males and 76 (51.4%) were females with a mean age of 59.03+/-13.54 years. Tuberculous peritonitis was the most frequent cause of low gradient ascites in 68 (45.9%). Other most frequent causes were cancer in 62 (41.9%), nephrotic syndrome in 9 (6%), pancreatitis in 6 (4%). Peritoneal cancer was found in 22 (35%), ovarian and gastric cancers were found in 14 (22.5%) and 12 (19.3%), respectively. All of which were the causes of ascites. The mean SAAG was 0.68+/-0.19 g/dL. The mean serum and ascitic fluid albumin concentrations were higher in tuberculous patients (P<0.006), but lactate dehydrogenase (LDH) level was higher in cancer patients (P<0.0001). In peritoneal tuberculosis, mean ascitic glucose concentration was significantly lower than other patients (P<0.0001). CONCLUSION: Tuberculosis should be considered in all patients with low gradient ascites especially in developing countries (like Iran), as the first cause of ascites. In the approach to patients with low gradient ascites, ascitic fluid glucose, and LDH level are useful indicators for decision making.

A Large Cohort Study of Genotype and Phenotype Correlations of Beta- Thalassemia in Iranian Population.

BACKGROUND: Thalassemia syndromes are the most prevalent single gene disorders in Iran. This study aimed to evaluate the effect of different types of beta-globin gene mutations, co-inheritance of alpha-globin gene mutations and/or Xmn1 SNP on disease phenotype in a large cohort of Iranian patients. SUBJECTS AND METHODS: In total, 433 patients were clinically classified into ß-thalassemia major (TM) or intermedia (TI). Multiplex PCR, ARMS-PCR, RFLP-PCR and DNA sequencing were performed to identify both α- and ß-globin gene mutations and Xmn1 polymorphism as well. All data were compared and analyzed by SPSS software in TM and TI groups, consequently. RESULTS: A total of 39 different ß-globin mutations were identified. Among them, the most common were IVS IInt1 (40.33%) followed by IVS Int5 (9.56%), C30 (7.22%) and Fr8-9(7%). All patients were subjected to evaluate common α-globin gene deletions. The patients inherited concomitant mutations of α- and ß-globin, showed no clinical modifications compared with those who had only ß-globin mutation. The TI patients showed a significant increase in frequency of both heterozygous and homozygous form of the Xmn1 polymorphism. It was also found that ß(0)/ß(0) genotype patients, inherited the Xmn1 polymorphism required lesser blood transfusion. CONCLUSION: No significant differences were observed, on the severity of disease, between patient's inherited defective α- and ß-globin genes and ones with just ß-globin gene mutation. Taking the results of this research into account, Xmn1 polymorphism can be considered as an important genetic factor modulating the severity of disease.

Allelic heterogeneity among Iranian DFNB7/11 families: report of a new Iranian deaf family with TMC1 mutation identified by next-generation sequencing.

CONCLUSION: Co-segregation of c.2030T>C mutation with hearing loss in an Iranian family and absence of this mutation in 100 Iranian controls confirms the pathogenicity of this mutation. Allelic heterogeneity among Iranian DFNB7/11 families has been shown by the identification of six different mutations in eight families. OBJECTIVES: Transmembrane channel-like 1 (TMC1) gene encodes an integral membrane protein such that its mutations can cause DFNB7/11 hearing loss. To date, several TMC1 mutations have been reported from Iran. Here we report a new DFNB7/11 Iranian family with an unreported TMC1 mutation in Iran. METHODS: A total of 66 genes related to hearing loss were analyzed using the OtoSCOPE platform in an affected member of an Iranian deaf family (Irn-Deaf-6866). Sanger sequencing was performed to confirm next-generation sequencing findings. RESULTS: A mutation, c.2030T>C, was identified in exon 21 of the TMC1 gene in the investigated member of the family. Sequencing results in all members of the family confirmed association of this mutation with hearing loss. None of 100 ethnically matched healthy controls had this mutation.