Molecular and phenotypical findings of a novel de novo SYNGAP1 gene variant in an 11-year-old Iranian boy with intellectual disability.

OBJECTIVE: Intellectual developmental disorder (IDD) type 5 is an autosomal dominant (AD) disorder and is characterized by intellectual disability (ID), psychomotor developmental delay, variable autism phenotypes, microcephaly, and seizure. IDD can be caused by mutations in the SYNGAP1 gene, which encodes a Ras GTPase-activating protein. This study revealed a novel de novo nonsense variant in SYNGAP1. The identification of such variants is essential for genetic counseling in patients and their families. METHODS: Exome sequencing implicated the causative variant. Sanger sequencing and cosegregation analyses were used to confirm the variant. Multiple in silico analysis tools were applied to interpret the variant using the American College of Medical Genetics and Genomics and the Association for Molecular Pathology guidelines. RESULTS: The de novo NM_006772.3(SYNGAP1):c.3685C>T variant was identified in an 11-year-old boy with severe intellectual disability, neurodevelopmental delay, speech disorder, ataxia, specific dysmorphic facial features, and aggressive behavior. CONCLUSION: The current study findings expand the existing knowledge of variants in SYNGAP1 that have been previously associated with nonsyndromic intellectual disability and autism, extending the spectrum of phenotypes associated with this gene. The data have implications for genetic diagnosis and counseling in similar phenotypic presentations.

A novel de novo frameshift variant in the CHD2 gene related to intellectual and developmental disability, seizures and speech problems.

BACKGROUND: The chromodomain helicase DNA-binding protein 2 (CHD2) is a member of the ATP-dependent chromatin remodelling family of proteins, which are critical for the assembly and regulation of chromatin. De novo variants and deletions in the CHD2 gene have been associated with childhood-onset developmental and epileptic encephalopathies type 94 (DEE 94). This study reports a novel deleterious de novo heterozygous frameshift insertion variant in the CHD2 gene. METHODS: The causative variant was diagnosed using whole-exome sequencing. Sanger sequencing and cosegregation analysis were applied to confirm the candidate variant. Multiple in silico analysis tools were employed to interpret the variant using the American College of Medical Genetics and Genomics and the Association for Molecular Pathology guidelines. RESULTS: A de novo deleterious variant, NM_001271.4:c.1570dup (NP_001262.3:p.Ser524PhefsTer30), in the CHD2 gene, was identified in a 16-year-old boy with an intellectual and developmental disability, seizures and speech problems. The de novo occurrence of the variant was confirmed by segregation analysis in the family. CONCLUSION: The findings of this study expand the existing knowledge of variants of the CHD2 gene and provide a detailed phenotype associated with this gene. These data could have implications for genetic diagnosis and counselling in similar conditions. Moreover, this information could be useful for therapeutic purposes, including the proper administration of medication to control epilepsy.

Possible role of pannexin 1 channels and purinergic receptors in the pathogenesis and mechanism of action of SARS-CoV-2 and therapeutic potential of targeting them in COVID-19.

Identifying signaling pathways and molecules involved in SARS-CoV-2 pathogenesis is pivotal for developing new effective therapeutic or preventive strategies for COVID-19. Pannexins (PANX) are ATP-release channels in the plasma membrane essential in many physiological and immune responses. Activation of pannexin channels and downstream purinergic receptors play dual roles in viral infection, either by facilitating viral replication and infection or inducing host antiviral defense. The current review provides a hypothesis demonstrating the possible contribution of the PANX1 channel and purinergic receptors in SARS-CoV-2 pathogenesis and mechanism of action. Moreover, we discuss whether targeting these signaling pathways may provide promising preventative therapies and treatments for patients with progressive COVID-19 resulting from excessive pro-inflammatory cytokines and chemokines production. Several inhibitors of this pathway have been developed for the treatment of other viral infections and pathological consequences. Specific PANX1 inhibitors could be potentially included as part of the COVID-19 treatment regimen if, in future, studies demonstrate the role of PANX1 in COVID-19 pathogenesis. Of note, any ATP therapeutic modulation for COVID-19 should be carefully designed and monitored because of the complex role of extracellular ATP in cellular physiology.

Association Study between Functional Polymorphisms of MMP9 Gene Promoter and Multiple Sclerosis Susceptibility in an Iranian Population.

BACKGROUND: Matrix metalloproteinase-9 (MMP-9) polymorphisms, C-1562 T and -90 (CA) n repeats, which influence transcriptional activity of this gene, are proposed to play a role in MS susceptibility and its development. In the present study, the possible association of MMP-9 polymorphisms in Iranian MS patients is studied. METHODS: Association of MMP-9 mentioned gene polymorphisms with MS susceptibility was evaluated in unrelated Iranian subjects referred to Al-Zahra Hospital, Isfahan, Iran during 2014 to 2017. RESULTS: -1562 T allele of MMP-9 was associated with increased MS risk. However, we found no overall significant effect of -90 (CA)n repeat on MS susceptibility. CONCLUSION: For as much as MMP-9 molecule is a potential target for MS therapy, to determine whether any of MMP-9 polymorphisms influence MS susceptibility in Iranian MS patients or not, concerning the significant influence of T allele on MS susceptibility and the non-significant association regarding CA repeats, further research is needed before proposing any definite conclusion.

UGT1A1 gene linkage analysis: application of polymorphic markers rs4148326/rs4124874 in the Iranian population.

OBJECTIVES: Mutations in the UGT1A1 gene are responsible for hyperbilirubinemia syndromes including Crigler-Najjar type 1 and 2 and Gilbert syndrome. In view of the genetic heterogeneity and involvement of large numbers of the disease causing mutations, the application of polymorphic markers in the UGTA1 gene could be useful in molecular diagnosis of the disease. MATERIALS AND METHODS: In the present study, two polymorphic markers including rs4148326 and rs4124874 in the UGT1A1 gene region were characterized. The markers were selected using bioinformatics analysis of the UGT1A1 gene region and genotyped in 212 unrelated healthy individuals and 13 family trios in the Iranian population using Tetra-Primer ARMS PCR technique. The allele frequency and population status of the alleles were estimated using GENEPOP, FBAT, PowerMarker and Arlequin software. RESULTS: The results indicated that in the case of rs4148326 marker, allele frequency for T and C allele was 66.04% and 33.96%, respectively. For rs4124874 marker, allele frequency for G and T alleles was 39.4% and 60.6%, respectively. The values of heterozygosity index for the markers examined were 64.1 for rs4148326 and 72.1 for rs4124874, respectively. The haplotype estimation analysis of the markers resulted in three informative haplotypes with frequencies ≥0.05. Moreover, the results suggested the presence of linkage disequilibrium between two markers. CONCLUSION: Altogether, the data suggested that rs4148326 and rs4124874 could be introduced as informative markers for molecular diagnosis of Crigler-Najjar type 1 and 2 and Gilbert syndrome in the Iranian population.

Factors influencing sperm retrieval following testicular sperm extraction in nonobstructive azoospermia patients.

OBJECTIVE: Azoospermia owing to testicular disorders is the most severe manifestation of male infertility. The main concern for patients with nonobstructive azoospermia (NOA) is the probability of successful sperm retrieval following testicular sperm extraction (TESE). Therefore, the goal of this study was to determine predictive factors correlated with sperm retrieval. METHODS: We assessed the testicular histopathological patterns, the choice of TESE surgical procedure, hormone levels, and chromosomal abnormalities in patients with NOA (n=170). The histopathology specimens were analyzed based on the histopathological patterns of hypospermatogenesis, maturation arrest, and Sertoli cell-only syndrome. RESULTS: The mean rate of sperm retrieval was 48.8%. The rate of sperm retrieval was significantly higher in the hypospermatogenesis group than in the other groups (p<0.001). There was a positive correlation between micro-TESE (vs. conventional TESE) and the sperm retrieval rate (odds ratio, 8.077; p<0.01). A logistic regression model demonstrated that high levels of follicle-stimulating hormone (FSH) and small testicular volume were significantly associated with lower chances of successful sperm retrieval. CONCLUSION: Some parameters, including testicular histopathology patterns, FSH levels, testicular volume, and method of TESE surgery, may be able to predict the chances of obtaining spermatozoa in patients with NOA. However, despite the efficiency of some predictive models, the hope of retrieving any functioning spermatozoa may be sufficient to disregard predictive factors of the success of intracytoplasmic sperm injection in these patients.

Mutation spectrum of autosomal recessive non-syndromic hearing loss in central Iran.

OBJECTIVE: To identify the spectrum of mutations in connexin 26 gene and frequency of two deletions in connexin 30 gene in central Iran. METHODS: After extraction of DNA from 300 blood samples, connexin 26 gene coding region was amplified using specific primers. PCR products were used for bidirectional sequencing. Multiplex PCR was used for detection of del(GJB6-D13S1830) and del(GJB6-D13S1854) in the GJB6 gene. RESULTS: Eighteen different mutations including two novel variants in GJB2 gene were detected. The GJB2 mutations were observed in 23.3% of all the subjects. In addition, none of the deaf patients carried the del(GJB6-D13S1830) and del(GJB6-D13S1854) in the GJB6 gene. The 35delG mutation was the most common mutation, accounting for 32.65% of the mutant alleles. CONCLUSION: The present study indicates that mutations in the GJB2 gene particularly 35delG are important causes for ARNSHL. 60% of the patients were heterozygous carriers. Thus, further investigation is needed to detect the genetic cause of hearing loss in patients with mono allelic mutations in the coding region of GJB2.

Parental age-related risk of retinoblastoma in Iranian children.

BACKGROUND: Retinoblastoma is a rare malignant intraocular neoplasm. About 90% of cases feature a germline mutation in the RB1 gene and these will develop retinoblastoma during their early childhood. An association between mutations in germline cells and aging has been demonstrated. This suggests a higher incidence of childhood cancer including retinoblastoma among children of older parents. MATERIALS AND METHODS: In the present study we aimed to determine the association of paternal and maternal age with an increased risk of retinoblastoma in a case-control study in Iranian population. The study was carried out on 240 persons who were born during 1984-2012 in Mahak and Mofid hospitals in Tehran, Iran. The statistical analysis included studying the mean age of parents and in order to know whether parental age of patients is different from parental age of control group, (t-test) compare averages test is used perfectly. By binary logistic regression, odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. RESULTS: The results of statistical analysis including the study of mean parental age by the use of (t-test) compare averages test showed a significant difference between parental ages of patients and controls. Logistic regression showed that coefficients were significant for maternal but not paternal age. CONCLUSIONS: Our findings indicate that advanced maternal age can increase the risk of retinoblastoma in offspring, but the paternal age has no significant effect.