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Salman Sadeghzadeh,1 Mahmood Dehghani Ashkezari,1 Seyed Morteza Seifati,1 Mohammad Yahya Vahidi Mehrjardi,2,3 Masoud Dehghan Tezerjani,4 Sara Sadeghzadeh,5 Seyed Amir Behtash Ladan1 1Medical Biotechnology Research Center, Ashkezar Branch, Islamic Azad University, Ashkezar, Yazd, Iran; 2Diabetes Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran; 3Department of Genetics, Medical School, Shahid Sadoughi University of Medical Sciences, Yazd, Iran; 4Abortion Research Center, Yazd Institute of Reproductive Sciences, Shahid Sadoughi University of Medical Sciences, Yazd, Iran; 5Department of Physiology, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, IranCorrespondence: Mahmood Dehghani AshkezariMedical Biotechnology Research Center, Ashkezar Branch, Islamic Azad University, Ashkezar, Yazd, IranEmail mdashkezary@gmail.comBackground: In recent years, considerable attention has been paid to the role of microRNAs (miRs) as biomarkers in type 2 diabetes (T2D). The aim of the study was to evaluate the expression levels of miR-15a and miR-222 in diabetic, pre-diabetic, and healthy individuals.Materials and Methods: Ninety individuals, who were referred to the Yazd diabetic center, were enrolled in this study and then classified into three groups as healthy, pre-T2D, and diabetic based on the clinical manifestations. Real-time PCR was performed to explore miRs expression in the plasma samples of the studied population. The correlation between the biochemical characteristic and the expression of these miRs as well as specificity and sensitivity of different clinical markers in healthy and pre-diabetic groups was evaluated.Results: miR-222 expression was significantly upregulated in the pre-T2D cases compared to the control subjects (P< 0.001), while no significant difference was found between the pre-T2D and T2D groups (P< 0.05). The expression of miR-15a was statistically downregulated in the pre-T2D and T2D subjects (P< 0.05). The receiver operating characteristic (ROC) curve analysis of miR-15a expression with a cutoff point of 1.12 resulted in the area under the curve (AUC) of 85% (95% CI 0.865– 0.912; P< 0.001) with 84% and 85% sensitivity and specificity, respectively. Similarly, for miR-222, the cutoff point of 4.03 and AUC of 86% (95% CI 0.875– 0.943; P< 0.001) discriminated against the pre-T2D and control subjects via the sensitivity and specificity of 86% and 87%, respectively. Moreover, miR-15a values showed a negative correlation with FG (R=− 0.32, P=0.005); however, miR-222 values were positively correlated with FG (R=0.25, P=0.03) in the pre-T2D group. Furthermore, miR-222 values were correlated with OGTT in the pre-T2D group (R=0.27, P=0.001). In addition, LDL-C had a negative correlation with miR-222 values in the pre-T2D group (R=− 0.23, P=0.02).Conclusion: This study indicated that the plasma expression levels of miR-222 and miR-15a can be considered as non-invasive, fast tools to separate the pre-T2D individuals from their healthy counterparts. Accordingly, this information could be used to predict the development of the disease as well as a direction for optimal therapy, thus refining outcomes in patients with diabetes.Keywords: type 2 diabetes, miR-15a, miR-222, biomarker, gene expression

The aim of this work was to identify the underlying genetic cause in a four-generation family segregating an unusual phenotype comprising a severe form of skeletal Class II malocclusion with gingival hyperplasia. SNP array identified a copy number gain on chromosome 1 (chr1); however, this chromosomal region did not segregate correctly in the extended family. Exome sequencing also failed to identify a candidate causative variant but highlighted co-segregating genetic markers on chr17 and chr19. Short- and long-read genome sequencing allowed us to pinpoint and characterize at nucleotide-level resolution a chromothripsis-like complex rearrangement (CR) inserted into the chr17 co-segregating region at the KCNJ2-SOX9 locus. The CR involved the gain of five different regions from chr1 that are shuffled, chained, and inserted as a single block (∼828 kb) at chr17q24.3. The inserted sequences contain craniofacial enhancers that are predicted to interact with KCNJ2/KCNJ16 through neo-topologically associating domain (TAD) formation to induce ectopic activation. Our findings suggest that the CR inserted at chr17q24.3 is the cause of the severe skeletal Class II malocclusion with gingival hyperplasia in this family and expands the panoply of phenotypes linked to variation at the KCNJ2-SOX9 locus. In addition, we highlight a previously overlooked potential role for misregulation of the KCNJ2/KCNJ16 genes in the pathomechanism of gingival hyperplasia associated with deletions and other rearrangements of the 17q24.2-q24.3 region (MIM 135400)., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Variants in the Aristaless-related homeobox (ARX) gene lead to a variety of phenotypes, with intellectual disability being a steady feature. Other features can include severe epilepsy, spasticity, movement disorders, hydranencephaly, and ambiguous genitalia in males. X-linked Ohtahara syndrome or Type 1 early infantile epileptic encephalopathy (EIEE1) is a severe early-onset epileptic encephalopathy with arrested psychomotor development caused by hemizygous mutations in the ARX gene, which encodes a transcription factor in fundamental brain developmental processes., Methods: We presented a case report of a 2-year-old boy who exhibited symptoms such as microcephaly, seizures, and severe multifocal epileptic abnormalities, and genetic techniques such as autozygosity mapping, Sanger sequencing, and whole-exome sequencing., Results: We confirmed that the patient had the NM&#95;139058.3:c.84C>A; p.(Cys28Ter) mutation in the ARX gene., Conclusion: The patient with EIEE1 had physical symptoms and hypsarrhythmia on electroencephalogram. Genetic testing identified a causative mutation in the ARX gene, emphasizing the role of genetic testing in EIEE diagnosis., (© 2024 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Coronary artery disease (CAD) is one of the most important cardiovascular diseases. Lifestyle and genetic factors play important roles in the development of CAD. The aim of the study is to examine the interaction of dietary patterns and genes on the likelihood of abnormal lipid profile and coronary artery stenosis in Iranians undergoing coronary angiography. This cross-sectional study was performed on 440 patients who underwent coronary angiography. The factor analysis method was used to extract dietary patterns. Commercial kits have been used to assess biochemical parameters. The detection of the rs28362491 genotype was carried out by the method of restriction fragment length polymorphism. Traditional (TDP) and western dietary pattern (WDP) were extracted. We observed an interaction of adherence to TDP and rs28362491 on the odds of having a high Gensini score. These interactions indicated that higher adherence to TDP was associated with higher odds of having a high Gensini score for patients with DD genotype than for those with II genotype. (OR 2.33, 95%CI 1.00-5.44; P = 0.05). These interactions remained statistically significant even after confounder variables. We observed an interaction between higher adherence to TDP and rs28362491 variants on the odds of high low-density lipoprotein cholesterol levels (P = 0.04) in the unadjusted model. We found a significant interaction of this polymorphism and higher adherence to WDP on the odds of having a high Gensini score in the unadjusted model (P = 0.04). This study provides a basis for future research on NF-KB1 gene and diet interaction. More large-scale longitudinal studies are needed to validate these findings., (© 2023. Springer Nature Limited.)

Background: Endometriosis is a female reproductive system disease in which the endometrial tissue is found in other women's organs. Various factors are effective in the development of endometriosis, and because of the interaction of genetics and environmental factors, this disease is a multi-factorial disease. MAPK/ERK and PI3K/Akt/mTOR pathways are activated by growth factors and steroid hormones and are known as two important pathways involved in the processes of growth, proliferation, and survival of endometriosis cells. Raps, monomeric GTPase of the Ras family, are able to activate these pathways independent of Ras. The goal of our study was to evaluate the expression level of Rap1GAP and EPAC1 genes as two important RapGAPs (GTPase-activating proteins) and RapGEFs (guanine nucleotide exchange factors), respectively, in endometriosis tissues and normal endometrium tissues., Materials and Methods: In this study, 15 samples of women without signs of endometriosis were taken as control samples. Fifteen ectopic and 15 eutopic samples were taken from women with endometriosis using laparoscopic surgery. The expression of EPAC1 and Rap1GAP genes was investigated by the real-time polymerase chain reaction technique, and the results were analyzed by one-way ANOVA test., Results: EPAC1 upregulated significantly in ectopic tissues compared to eutopic and control tissues. Rap1GAP expression was lower in ectopic tissues compared to control and eutopic tissues., Conclusions: Based on these results, it may be concluded that changes in the expression of the Rap1GAP and Epca1 genes may play a role in the pathways involved in the pathogenesis, displacement, and migration of endometriosis cells., Competing Interests: There are no conflicts of interest., (Copyright: © 2023 Advanced Biomedical Research.)

Introduction: Considering the emergence of the concept of personalized nutrition in recent years and its importance in the treatment of diseases, the purpose of this study was to investigate the interaction of paraoxonase (PON)1 rs662 polymorphism and vitamin C/E intake on coronary artery disease (CAD) severity and lipid profile in patients undergoing diagnostic angiography., Methods: This cross-sectional study was carried out on 428 patients undergoing angiography. The PON-1 genotypes were detected by the polymerase chain reaction-restriction fragment length polymorphism technique. Dietary intake was obtained using a valid questionnaire., Results: After adjustment for potential confounders, R allele carriers (RR + RQ) have lower HDL-C levels than non-carriers (QQ) ( P ≤ 0.05). On the other hand, higher consumption of vitamin C was associated with a reduced risk of high total cholesterol (OR: 0.42, 95% CI 0.23-0.75, P = 0.003) and low-density lipoprotein cholesterol (OR: 0.49, 95% CI 0.25-0.96, P = 0.038) and an increased risk of low high-density lipoprotein cholesterol (OR: 1.88, 95% CI 1.03-3.42, P = 0.037). Furthermore, a significant interaction was observed between vitamin C intake and genotypes of rs66 polymorphism on LDL-C ( P = 0.050). In detail, the R-allele carriers with lower vitamin C intake had higher LDL-C levels than QQ genotype carriers. No significant interaction was found between vitamin E intake and rs662 polymorphism genotypes on the Gensini and SYNTAX scores and lipid profile ( P > 0.05)., Conclusion: The novel finding of the present study was the existence of a significant interaction between rs662 polymorphism and vitamin C intake on LDL-C. More specifically, R allele carriers with lower vitamin C intake were susceptible to higher LDL-C., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Darand, Salehi-Abargouei, Vahidi Mehrjardi, Feizi, Seyedhossaini and Askari.)

Introduction: The present study aimed to investigate the association of the paraoxonase 1 (PON1) Q192R polymorphism with coronary artery disease (CAD) and cardiometabolic risk factors in Iranian patients suspected of CAD., Methods: This cross-sectional study was conducted on 428 patients undergoing angiography. The data related to demographic information and physical activity were collected by valid and reliable questionnaires. The PON-1 genotypes were detected by the polymerase chain reaction-restriction fragment length polymorphism (RFLP-PCR) technique. The Gensini and SYNTAX score, anthropometric measurements, and biochemical and clinical parameters were measured by standard protocols., Results and Discussion: Findings indicated that the odds of obesity was significantly higher in people with the RR genotype compared to the QQ genotype carriers (OR: 2.95 CI: 1.25-6.93, P = 0.014) and also odds of low high-density lipoprotein cholesterol (HDL-C) was marginally higher (OR: 2.31 CI: 0.97-5.49, P = 0.056). There was no significant association between other CAD risk factors with PON1 Q192R polymorphism ( P > 0.05). Further analysis showed a significant interaction between sex and 192QR ( P = 0.019) and 192 RR ( P = 0.007) genotypes on body mass index (BMI). More specifically, the risk of obesity in men carrying the RR genotype was 3.38 times (OR: 3.38 CI: 1.08-10.58, P = 0.036). Also, a significant joint effect of the RR genotype and sex on HDL-C was seen ( P = 0.003). The stratification based on sex showed that the risk of low HDL-C is significantly higher in women carrying the RR genotype (OR: 6.18 CI: 1.21-31.46, P = 0.028). A marginal sex-genotype interaction was also found in the risk of elevated alanine aminotransferase (ALT) ( P = 0.057). In summary, the findings showed that the risk of obesity and low HDL-C was higher in people carrying the RR genotype. On the other hand, a Q192R polymorphism-sex interaction was observed on the risk of obesity, elevated ALT, and low HDL-C., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Darand, Salehi-Abargouei, Vahidi Mehrjardi, Feizi, Seyedhossaini and Askari.)

Introduction: Genetic and environmental factors are involved in the pathogenesis of cardiovascular diseases (CVDs). The aim of the study was to investigate between the genotype of the NFKB1 gene and the cardiometabolic risk factor in patients undergoing coronary angiography., Methods: This cross-sectional study was conducted on 462 adults (male and women) aged between 35 and 75 years who referred to Afshar Hospital for coronary angiography in 2021- 2022. The polymerase chain reaction restriction fragment length polymorphism method was used to detect the genotype of rs28362491. Biochemical parameters were measured using commercial kits. Gensini and Syntax scores were calculated using the angiography result to assess the extent of coronary artery stenosis. We used multivariate logistic regression analysis to examine the relationship between genotype variants and cardiometabolic risk factors., Results: There was no association between variant genotypes and abnormally levels of serum alanine aminotransferase (ALT) ( P value=0.51), aspartate aminotransferase (AST) ( P value=0.99), triglyceride (TG) ( P value=0.48), total cholesterol ( P value=0.79), low density lipoprotein-cholestero (LDL-C) ( P value=0.31), high-density lipoprotein-cholesterol (HDL-C) ( P value=0.53), fast blood sugar (FBS) ( P value=0.39), systolic blood pressure ( P value=0.14), diastolic blood pressure ( P value=0.64), Gensini score ( P value=0.48) and syntax score ( P value=0.74) in the crude model even after adjustment for confounding factors., Conclusion: We found no association between the ATTG polymorphism and cardiometabolic risk factors in patients who had coronary angiography. Further investigations are needed to assess the association between variants of 28362491 and cardiometabolic markers., Competing Interests: There is no conflict of interest., (© 2023 The Author(s).)

Biallelic variants of the gene encoding for the zinc-finger protein 142 (ZNF142) have recently been associated with intellectual disability (ID), speech impairment, seizures, and movement disorders in nine individuals from five families. In this study, we obtained phenotype and genotype information of 26 further individuals from 16 families. Among the 27 different ZNF142 variants identified in the total of 35 individuals only four were missense. Missense variants may give a milder phenotype by changing the local structure of ZF motifs as suggested by protein modeling; but this correlation should be validated in larger cohorts and pathogenicity of the missense variants should be investigated with functional studies. Clinical features of the 35 individuals suggest that biallelic ZNF142 variants lead to a syndromic neurodevelopmental disorder with mild to moderate ID, varying degrees of delay in language and gross motor development, early onset seizures, hypotonia, behavioral features, movement disorders, and facial dysmorphism. The differences in symptom frequencies observed in the unpublished individuals compared to those of published, and recognition of previously underemphasized facial features are likely to be due to the small sizes of the previous cohorts, which underlines the importance of larger cohorts for the phenotype descriptions of rare genetic disorders., (© 2022 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.)

Background: Endometrios affecting 6-10% of women of reproductive ages around the globe. Important pathways, including the MAPK and PI3K / Akt pathways, have been identified in the disease. The NF1 and RASA1 genes inactivate Ras by their own GTPase activity and controlled the high activity of these pathways., Objective: In this study, we measured NF1 and RASA1 gene expression in the endometrial tissues of patients (eutopic and ectopic tissues) compared to the control samples., Materials and Methods: In our study, tissue samples were collected from 15 patients with endometriosis and 15 healthy women. We used quantitative polymerase chain reaction (qRT-PCR) to measure the NF1 and RASA1 gene expression levels in these samples., Results: We observed a significant decrease in the expression level of the NF1 gene in both eutopic and ectopic samples of endometriosis patients compared to control samples, while the expression of the RASA1 gene was significantly reduced only in ectopic tissues., (© 2022 The Authors.)

Background: Intellectual disability (ID) is a heterogeneous group of neurodevelopmental disorders that is characterized by significant impairment in intellectual and adaptive functioning with onset during the developmental period. Whole-exome sequencing (WES)-based studies in the consanguineous families with individuals affected with ID have shown a high burden of relevant variants. So far, over 700 genes have been reported in syndromic and non-syndromic ID. However, genetic causes in more than 50% of ID patients still remain unclear., Methods: Whole-exome sequencing was applied for investigation of various variants of ID, then Sanger sequencing and in silico analysis in ten patients from five Iranian consanguineous families diagnosed with autosomal recessive neurodevelopmental disorders, intellectual disability, performed for confirming the causative mutation within the probands. The most patients presented moderate-to-severe intellectual disability, developmental delay, seizure, speech problem, high level of lactate, and onset before 10 years., Results: Filtering the data identified by WES, two novel homozygous missense variants in FBXO31 and TIMM50 genes and one previously reported mutation in the CEP290 gene in the probands were found. Sanger sequencing confirmed the homozygote variant's presence of TIMM50 and FBXO31 genes in six patients and two affected siblings in their respective families. Our computational results predicted that the variants are located in the conserved regions across different species and have the impacts on the protein stability., Conclusion: Hence, we provide evidence for the pathogenicity of two novel variants in the patients which will expand our knowledge about potential mutation involved in the heterogeneous disease., (© 2022 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.)

Type 2 diabetes mellitus (T2DM) is a heritable metabolic perturbation, rapidly growing across the world. Primary recognition of susceptible individuals with a family history of type 2 diabetes (FHD) in the prediabetes stage could delay the onset of T2DM or reduce complications induced by diabetes. This study aims to evaluate the expression levels of miR-21, miR-126 as noninvasive predictive biomarkers in individuals with genetic predisposition and investigate the correlation of miRNAs and cardiometabolic risk factors. Our study demonstrated that miR-21 expression has a notable elevate in both groups of T2DM and pre-T2DM. miR-21 expression was distinguished in the pre-T2DM and T2DM from the nondiabetic individuals by ROC curve analysis with AUC of 0.77 (95% CI 0.65-0.90; p = 0.0004) and AUC of 0.78 (95% CI 0.64-0.92; p = 0.0042), respectively. The relative gene expression of miR-126 was nearly equal among groups. miR-21 expression was positively associated with glycosylated hemoglobin (HbA1c), fasting blood sugar (FBS), and triglyceride (TG) and might have diagnostic value for T2DM and pre-T2DM. This study has revealed that the expression level of miR-21 can be considered as a non-invasive and rapid tool for distinguishing pre-T2DM and T2DM counterparts from healthy individuals., (© 2022 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

The prevalence of type 2 diabetes mellitus (T2DM) is increasing dramatically worldwide. Dysregulation of microRNA (miRNA) as key regulators of gene expression, has been reported in numerous diseases including diabetes. The aim of this study was to investigate the expression levels of miRNA-122, miRNA-126-3p and miRNA-146a in diabetic and pre-diabetic patients and in healthy individuals, and to determine whether the changes in the level of these miRNAs are reliable biomarkers in diagnosis, prognosis, and pathogenesis of T2DM. Additionally, we examined the relationship between miRNA levels and plasma concentrations of inflammatory factors including tumor necrosis factor alpha (TNF-α) and interleukin 6 (Il-6) as well as insulin resistance. In this case-control study, participants (n = 90) were allocated to three groups (n = 30/group): T2DM, pre-diabetes and healthy individuals as control (males and females, age: 25-65, body mass index: 25-35). Expression of miRNA was determined by real-time polymerase chain reaction (RT-PCR). Furthermore, plasma concentrations of TNF-α, IL-6 and fasting insulin were measured by enzyme-linked immunosorbent assay. Homeostatic model assessment for insulin resistance (HOMA-IR) was calculated as an indicator of insulin resistance. MiRNA-122 levels were higher while miRNA-126-3p and miRNA-146a levels were lower in T2DM and pre-diabetic patients compared to control (p<0.05). Furthermore, a positive correlation was found between miRNA-122 expression and TNF-α (r = 0.82), IL-6 (r = 0.83) and insulin resistance (r = 0.8). Conversely, negative correlations were observed between miRNA-126-3p and miRNA-146a levels and TNF-α (r = -0.7 and r = -0.82 respectively), IL-6 (r = -0.65 and r = -0.78 respectively) as well as insulin resistance (r = -0.67 and r = -0.78 respectively) (all p<0.05). Findings of this study suggest the miRNAs can potentially contribute to the pathogenesis of T2DM. Further studies are required to examine the reproducibility of these findings., Competing Interests: The authors have declared that no competing interests exist.

Background: Type 2 diabetes mellitus (T2DM) is a progressive metabolic disorder whose prevalence is rising very fast across the world. Diagnosis of this disease in early stages (pre-diabetic stage) plays an important role in reducing mortality associated with this disorder. miRNAs, as key players in the pathogenesis of T2DM, have been investigated in several studies. Furthermore, their expression profile changes in the early stages of diabetes mellitus in body fluids such as serum, peripheral blood, and peripheral blood mononuclear cell (PBMC) have been studied. Due to their high stability and the presence of non-invasive sensitive methods for their measurement, such as real-time PCR, they can be used for early diagnosis of T2DM as a biomarker. In this experimental study, the expression levels of miR-181b, miR-126-5p, and NF-κB were measured in patients with T2DM, pre-diabetic subjects, and healthy controls in a Yazd population., Material and Method: Ninety asymptomatic subjects including 30 T2DM, 30 pre-diabetic, and 30 healthy subjects (diagnosis based on WHO criteria) were included in this study. Real-time PCR was used to measure the expression levels of miR-181b and miR-126-5p. Moreover, the NF-κB expression level was also measured to determine its relationship with these two microRNAs., Result: In this study, the expression level of miR-181b and miR-126-p decreased gradually in pre-diabetic as well as T2DM subjects compared to healthy controls. Furthermore, our study showed a significant negative correlation between these two miRNAs and NF-κB for the first time., Conclusion: These results introduce these anti-inflammatory miRNAs as powerful tools for early diagnosis of T2DM., (Copyright © 2019 SEEN y SED. Publicado por Elsevier España, S.L.U. All rights reserved.)

Background: The dramatic increase in the prevalence of type 2 diabetes mellitus (T2DM) is a global major challenge to health. Circulating microRNAs have been suggested as promising biomarkers for different disorders such as diabetes. Imbalances in the gut microbiome have been revealed to contribute to the progression of multiple diseases including T2DM. Recently, the consumption of probiotics and synbiotics in the treatment of various diseases has shown a substantial growth. The anti-diabetes and anti-inflammatory effects of synbiotics have been indicated, which may be due to their beneficial effects on the gut microbiome. However, further research is needed to assess the effects of synbiotics on the microbiota and their impacts on expression of microRNAs relating to T2DM. Thus, we will aim to assess the effects of synbiotics on microbiota, serum level of tumor necrosis factor-α (TNF-α), and expression of microRNA-126 and microRNA-146a in patients with T2DM., Methods: Seventy-two patients with T2DM will be recruited in this double-blind randomized parallel placebo-controlled clinical trial. After block matching based on age and sex, participants will be randomly assigned to receive 1000 mg/day synbiotic (Familact) or placebo for 12 weeks. The microRNA-126 and microRNA-146a expression levels will be measured by real-time polymerase chain reaction and serum TNF-α level will be assessed by enzyme-linked immunosorbent assay kit at the beginning and at the end of the study. Determination of the gut microbiota will be done by quantitative polymerase chain reaction methods at baseline and at the end of the trial. Biochemical assessments (glycemic and lipid profiles) will also be conducted at onset and end of the study., Discussion: This is the first randomized controlled trial that will determine the effect of synbiotic supplementation on the gut microbiota and its probable impacts on serum levels of TNF-α and expression of related microRNAs in patients with T2DM., Trial Registration: Iranian Registry of Clinical Trials: IRCT20180624040228N2. Registered on 27 March 2019. http://www.irct.ir/trial/38371.

Background: Diabetes mellitus (DM) is a growing epidemic metabolic syndrome, which affects near 5.6% of the world's population. Almost 12% of health expenditure is dedicated to this disorder. Discovering and developing biomarkers as a practical guideline with high specificity and sensitivity for the diagnosis, prognosis, and clinical management of DM is one of the subjects of great interest among DM researchers due to the long-lasting asymptomatic clinical manifestation of DM. In this study, we described a recently identified molecular biomarker involved in DM. Methods: This review study was done at the Diabetes Research Center affiliated to Shahid Sadoughi University of Medical Sciences. PubMed, Scopus, Google Scholar, and Web of Science were searched using the following keywords: "diabetes mellitus", "biomarker", "microRNA", "diagnostic tool" and "clinical manifestation." Results: A total of 107 studies were finally included in this review. After evaluating numerous articles, including original, metaanalysis, and review studies, we focused on molecular biomarkers involved in DM diagnosis and management. Conclusion: Increasing interest in biomarkers associated with DM goes back to its role in decreasing diabetes-related morbidity and mortality. This review focused on major molecular biomarkers such as proteomic and microRNA (miRNAs) as novel and interesting DM biomarkers that can help achieve timely diagnosis of DM., (© 2020 Iran University of Medical Sciences.)

NTNG2 encodes netrin-G2, a membrane-anchored protein implicated in the molecular organization of neuronal circuitry and synaptic organization and diversification in vertebrates. In this study, through a combination of exome sequencing and autozygosity mapping, we have identified 16 individuals (from seven unrelated families) with ultra-rare homozygous missense variants in NTNG2; these individuals present with shared features of a neurodevelopmental disorder consisting of global developmental delay, severe to profound intellectual disability, muscle weakness and abnormal tone, autistic features, behavioral abnormalities, and variable dysmorphisms. The variants disrupt highly conserved residues across the protein. Functional experiments, including in silico analysis of the protein structure, in vitro assessment of cell surface expression, and in vitro knockdown, revealed potential mechanisms of pathogenicity of the variants, including loss of protein function and decreased neurite outgrowth. Our data indicate that appropriate expression of NTNG2 plays an important role in neurotypical development., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Pathogenic variants in COL9A1 are primarily associated with autosomal recessive Stickler syndrome. Patients with COL9A1-associated Stickler syndrome (STL) present hearing loss (HL), ophthalmic manifestations and skeletal abnormalities. However, the clinical spectrum of patients with COL9A1 variants can also include multiple epiphyseal dysplasia, as well as non-syndromic HL that was observed in one previously reported proband. Exome sequencing was performed on the genomic DNA of an Iranian patient and his affected brother who both report non-syndromic HL. A 44.6 kb homozygous in-frame deletion spanning exons 6 to 33 of COL9A1 was detected via exome-based copy number variation analysis. The deleted exons were confirmed by PCR in the patient and his affected brother, who both have non-syndromic HL. Segregation analysis via qPCR confirmed the parents as heterozygous deletion carriers. Breakpoint analysis mapped the homozygous deletion spanning introns 5 to 33 (g.70,948,188&#95;70,997,277del, NM&#95;001851.4(COL9A1):c.697-3754&#95;2112+769del, p.(Phe233&#95;Ser704del), with an additional 67 bp of inserted intronic sequence that may have originated due to a fork stalling and template switching/microhomology-mediated break-induced replication (FoSTeS/MMBIR) mechanism. This mechanism has not been previously implicated in HL or STL. This is also the first reported copy number variation in COL9A1 that was identified through an exome data set in an Iranian family with apparent non-syndromic HL. The present study emphasizes the importance of exome-wide copy number variation analysis in molecular diagnosis and provides supporting evidence to associate COL9A1 with autosomal recessive non-syndromic HL., (Copyright © 2019 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Objective: To characterize clinically and molecularly an early-onset, variably progressive neurodegenerative disorder characterized by a cerebellar syndrome with severe ataxia, gaze palsy, dyskinesia, dystonia, and cognitive decline affecting 11 individuals from 3 consanguineous families., Methods: We used whole-exome sequencing (WES) (families 1 and 2) and a combined approach based on homozygosity mapping and WES (family 3). We performed in vitro studies to explore the effect of the nontruncating SQSTM1 mutation on protein function and the effect of impaired SQSTM1 function on autophagy. We analyzed the consequences of sqstm1 down-modulation on the structural integrity of the cerebellum in vivo using zebrafish as a model., Results: We identified 3 homozygous inactivating variants, including a splice site substitution (c.301+2T>A) causing aberrant transcript processing and accelerated degradation of a resulting protein lacking exon 2, as well as 2 truncating changes (c.875&#95;876insT and c.934&#95;936delinsTGA). We show that loss of SQSTM1 causes impaired production of ubiquitin-positive protein aggregates in response to misfolded protein stress and decelerated autophagic flux. The consequences of sqstm1 down-modulation on the structural integrity of the cerebellum in zebrafish documented a variable but reproducible phenotype characterized by cerebellum anomalies ranging from depletion of axonal connections to complete atrophy. We provide a detailed clinical characterization of the disorder; the natural history is reported for 2 siblings who have been followed up for >20 years., Conclusions: This study offers an accurate clinical characterization of this recently recognized neurodegenerative disorder caused by biallelic inactivating mutations in SQSTM1 and links this phenotype to defective selective autophagy., (© 2018 American Academy of Neurology.)

Background: ATP8A2 mutations have recently been described in several patients with severe, early-onset hypotonia and cognitive impairment. The aim of our study was to characterize the clinical phenotype of patients with ATP8A2 mutations., Methods: An observational study was conducted at multiple diagnostic centres. Clinical data is presented from 9 unreported and 2 previously reported patients with ATP8A2 mutations. We compare their features with 3 additional patients that have been previously reported in the medical literature., Results: Eleven patients with biallelic ATP8A2 mutations were identified, with a mean age of 9.4 years (range 2.5-28 years). All patients with ATP8A2 mutations (100%) demonstrated developmental delay, severe hypotonia and movement disorders, specifically chorea or choreoathetosis (100%), dystonia (27%) and facial dyskinesia (18%). Optic atrophy was observed in 78% of patients for whom funduscopic examination was performed. Symptom onset in all (100%) was noted before 6 months of age, with 70% having symptoms noted at birth. Feeding difficulties were common (91%) although most patients were able to tolerate pureed or thickened feeds, and 3 patients required gastrostomy tube insertion. MRI of the brain was normal in 50% of the patients. A smaller proportion was noted to have mild cortical atrophy (30%), delayed myelination (20%) and/or hypoplastic optic nerves (20%). Functional studies were performed on differentiated induced pluripotent cells from one child, which confirmed a decrease in ATP8A2 expression compared to control cells., Conclusions: ATP8A2 gene mutations have emerged as the cause of a novel neurological phenotype characterized by global developmental delays, severe hypotonia and hyperkinetic movement disorders, the latter being an important distinguishing feature. Optic atrophy is common and may only become apparent in the first few years of life, necessitating repeat ophthalmologic evaluation in older children. Early recognition of the cardinal features of this condition will facilitate diagnosis of this complex neurologic disorder.

Hereditary congenital facial palsy (HCFP) is a rare congenital cranial dysinnervation disorder, recognisable by non-progressive isolated facial nerve palsy (cranial nerve VII). It is caused by developmental abnormalities of the facial nerve nucleus and its nerve. So far, 4 homozygous mutations have been identified in 5 unrelated families (12 patients) with HCFP worldwide. In this study, a large Iranian consanguineous kindred with 5 members affected by HCFP underwent thorough clinical and genetic evaluation. The candidate gene HOXB1 was screened and analysed by Sanger sequencing. As in previous cases, the most remarkable findings in the affected members of the family were mask-like faces, bilateral facial palsy with variable sensorineural hearing loss, and some dysmorphic features. Direct sequencing of the candidate gene HOXB1 identified a novel homozygous frameshift mutation (c.296&#95;302del; p.Y99Wfs*20) which co-segregated with the disease phenotype within the extended family. Our findings expand the mutational spectrum of HOXB1 involved in HCFP and consolidate the role of the gene in the development of autosomal recessive HCFP. Moreover, the truncating mutation identified in this family leads to a broadly similar presentation and severity observed in previous patients with nonsense and missense mutations. This study characterises and defines the phenotypic features of this rare syndrome in a larger family than has previously been reported.

Background: Joubert syndrome (JS) is a clinically and genetically heterogeneous group of rare neurodevelopmental disorder characterised by peculiar midbrain-hindbrain malformation, known as the "molar tooth" sign. JS can manifest a broad range of signs and symptoms. The most common features of JS are hypotonia, ataxia, developmental delay/intellectual disability, abnormal eye movements, and neonatal breathing abnormalities. To date, 29 genes have been shown to cause JS., Methods: We employed whole-genome single nucleotide polymorphism genotyping in a group of Iranian families with JS and Sanger sequencing of a known mutation associated with JS located in a single homozygous regions shared by affected members of the families., Results: Homozygosity mapping uncovered a shared ∼2.2-Mb run of homozygosity on chromosome 8q21.3-q22.1 encompassing the known JS-causing TMEM67 gene. Sanger sequencing of a known mutation (NM&#95;153704.5: c.725A>G; p.Asn242Ser) in TMEM67 identified from studying another Iranian family using whole-exome sequencing confirmed the presence of the homozygous mutation in 22 affected members of 12 nuclear families. "Molar tooth" sign of brain magnetic resonance imaging, moderate-to-severe neurodevelopmental delay, and abnormal eye movements were the most common features of affected individuals. In addition, liver disease, seizure, behavioural abnormalities, failure to thrive, and kidney disease were observed variably in some of the patients., Conclusion: We propose that Asn242Ser is a founder mutation in the Iranian population, which might explain a significant proportion of JS cases from eastern Iran. Therefore, screening for this variant should be considered for genetic testing in Iranian patients with JS. In addition, this finding is important for developing population-specific genetic testing in Iran., (© 2017 S. Karger AG, Basel.)

Oral-facial-digital syndrome as heterogeneous developmental conditions is characterized by abnormalities in the oral cavity, facial features and digits. Furthermore, central nervous system (CNS) abnormalities can also be part of this developmental disorder. At least 13 forms of OFDS based on their pattern of signs and symptoms have been identified so far. Type 1 which is now considered to be a ciliopathy accounts for the majority of cases. It is transmitted in an X-linked dominant pattern and caused by mutations in OFD1 gene, which can result in embryonic male lethality. In this study, we present a family suffering from orofaciodigital syndrome type I who referred to Medical Genetics Research Center, Shahid Sadoughi University of Medical Sciences in 2015. Two female siblings and their mother shared a novel 2-base pair deletion (c.1964-1965delGA) in exon 16 of OFD1 gene. Clinically, the sibling had oral, facial and brain abnormalities, whereas their mother is very mildly affected. She also had history of recurrent miscarriage of male fetus.

The interpretation of supernumerary chromosome is important for genetic counseling and prognosis. Here, we used SNP array and conventional karyotyping method to identify a denovo marker chromosome originated from chromosome 22 and 11 in a newborn transferred to the Neonatal Intensive Care Unit of Shahid Sadoughi Hospital in 2015. Clinical abnormalities identified in the newborn were dysmorphic face, intrauterine growth retardation, atrial septal defect (ASD), the hypoplasia of corpus callosum and septum pellucidum. These clinical abnormalities can be related to this marker, and it may help genetic counselor for predicting abnormality risk in susceptible individuals as well as prenatal diagnosis.