Putative founder effect of Arg338* AP4M1 (SPG50) variant causing severe intellectual disability, epilepsy and spastic paraplegia: Report of three families.

Bi-allelic variants affecting one of the four genes encoding the AP4 subunits are responsible for the "AP4 deficiency syndrome." Core features include hypotonia that progresses to hypertonia and spastic paraplegia, intellectual disability, postnatal microcephaly, epilepsy, and neuroimaging features. Namely, AP4M1 (SPG50) is involved in autosomal recessive spastic paraplegia 50 (MIM#612936). We report on three patients with core features from three unrelated consanguineous families originating from the Middle East. Exome sequencing identified the same homozygous nonsense variant: NM_004722.4(AP4M1):c.1012C>T p.Arg338* (rs146262009). So far, four patients from three other families carrying this homozygous variant have been reported worldwide. We describe their phenotype and compare it to the phenotype of patients with other variants in AP4M1. We construct a shared single-nucleotide polymorphism (SNP) haplotype around AP4M1 in four families and suggest a probable founder effect of Arg338* AP4M1 variant with a common ancestor most likely of Turkish origin.

Phenotypic continuum of NFU1-related disorders.

Bi-allelic variants in Iron-Sulfur Cluster Scaffold (NFU1) have previously been associated with multiple mitochondrial dysfunctions syndrome 1 (MMDS1) characterized by early-onset rapidly fatal leukoencephalopathy. We report 19 affected individuals from 10 independent families with ultra-rare bi-allelic NFU1 missense variants associated with a spectrum of early-onset pure to complex hereditary spastic paraplegia (HSP) phenotype with a longer survival (16/19) on one end and neurodevelopmental delay with severe hypotonia (3/19) on the other. Reversible or irreversible neurological decompensation after a febrile illness was common in the cohort, and there were invariable white matter abnormalities on neuroimaging. The study suggests that MMDS1 and HSP could be the two ends of the NFU1-related phenotypic continuum.

Whole-exome sequencing deciphers the genetic profile of visual impairments in patients from Southwest Iran.

Genetic ocular diseases are heterogeneous disorders. Recent advances have led to a paradigm shift in the discovery of eye disease-associated genetic variants from linkage and genome-wide association studies to next-generation sequencing-based genome studies. The aim of the current study was to investigate the spectrum of possible vision impairment-related variants in 66 Iranian patients. Whole-exome sequencing (WES) technology followed by bioinformatics analysis, Sanger validation, and co-segregation study were done to find eye disease-causing variants in the patients with vision impairments from Southwest Iran. WES revealed disease-causing variants in 82% of the enrolled cases. WES of understudied cohorts presented an effective strategy for determining pathogenic variants in heterogeneous eye diseases and demonstrated the distribution of causative genetic mutations in Iranian patients. The present data could provide the potential to accelerate genetic screening and a reference for treatment modalities for patients with different types of eye disorders from Southwest Iran.

Association of HLA-DR2-Related Haplotype (HLA-DRB5*01-DRB1*1501-DQB1*0602) in Patients with Multiple Sclerosis in Khuzestan Province.

OBJECTIVE: Multiple sclerosis (MS) is a partially heritable autoimmune disease. HLA-DR2 is the largest identified genetic risk factor for MS. The largest identified genetic risk factor is haplotype from the MHC class II HLA-DR2, which increases the disease risk. The HLA-DR2 distribution in MS patients has been confirmed, but contradictory outcomes have been found. Moreover, the HLA-DR2 effect on ethnicity and gender is unclear. There are no data regarding the HLA-DR2 (HLA-DRB1*1501-DRB5*01-DQB1*0602) association with MS in Khuzestan Province, Iran. This study aimed to investigate the association of HLA-DR2 with MS regarding both sex and ethnicity in this province. MATERIALS & METHODS: A total of 399 individuals were recruited. HLA typing was conducted using the polymerase chain reaction amplification with sequence-specific primers technology. The HLA-DR2 association with MS was analyzed, and also its probable association with gender, ethnicity, the expanded disability status scale (EDSS), and MS clinical course was examined using the Chi-square test. RESULTS: HLA-DRB5*01 - -DQB1*0602 - as the most common HLA haplotype was found in both patient and control groups. In contrast, the DRB5*01 + -DRB1*1501 + -DQB1*0602 - frequency was very low in the groups. It was observed that haplotypes had no association with MS susceptibility. Most of the haplotypes showed no association with ethnicity, sex, EDSS, and MS course except for the HLA-DRB5*01 + -DRB1*1501 + -DQB1*0602 - haplotype that was positively associated with EDSS steps 5 to 10 (p=0.014) and non-RRMS (p=0.023). CONCLUSION: There was no association between HLA-DR2 and MS susceptibility. However, the higher HLA-DRB5*01 + -DRB1*1501 + -DQB1*0602 - frequency may play a role in MS development. Also, HLA-DR2 did not increase significantly concerning clinical course, ethnicity, sex, and EDSS. This study further supports the importance of replication studies as susceptible loci that might differ in various ethnicities. Therefore, it is concluded that the association between HLA-DR2 and MS is more allelic than haplotypic in Khuzestan.

Antiviral performance of graphene-based materials with emphasis on COVID-19: A review.

Coronavirus disease-2019 has been one of the most challenging global epidemics of modern times with a large number of casualties combined with economic hardships across the world. Considering that there is still no definitive cure for the recent viral crisis, this article provides a review of nanomaterials with antiviral activity, with an emphasis on graphene and its derivatives, including graphene oxide, reduced graphene oxide and graphene quantum dots. The possible interactions between surfaces of such nanostructured materials with coronaviruses are discussed. The antiviral mechanisms of graphene materials can be related to events such as the inactivation of virus and/or the host cell receptor, electrostatic trapping and physico-chemical destruction of viral species. These effects can be enhanced by functionalization and/or decoration of carbons with species that enhances graphene-virus interactions. The low-cost and large-scale preparation of graphene materials with enhanced antiviral performances is an interesting research direction to be explored.

Anti-pathogenic activity of graphene nanomaterials: A review.

Graphene and its derivatives are promising candidates for a variety of biological applications, among which, their anti-pathogenic properties are highly attractive due to the outstanding physicochemical characteristics of these novel nanomaterials. The antibacterial, antiviral and antifungal performances of graphene are increasingly becoming more important due to the pathogen's resistance to existing drugs. Despite this, the factors influencing the antibacterial activity of graphene nanomaterials, and consequently, the mechanisms involved are still controversial. This review aims to systematically summarize the literature, discussing various factors that affect the antibacterial performance of graphene materials, including the shape, size, functional group and the electrical conductivity of graphene flakes, as well as the concentration, contact time and the pH value of the graphene suspensions used in related microbial tests. We discuss the possible surface and edge interactions between bacterial cells and graphene nanomaterials, which cause antibacterial effects such as membrane/oxidative/photothermal stresses, charge transfer, entrapment and self-killing phenomena. This article reviews the anti-pathogenic activity of graphene nanomaterials, comprising their antibacterial, antiviral, antifungal and biofilm-forming performance, with an emphasis on the antibacterial mechanisms involved.

Identification of Three Novel Mutations in the FANCA, FANCC, and ITGA2B Genes by Whole Exome Sequencing.

BACKGROUND: Various blood diseases are caused by mutations in the FANCA, FANCC, and ITGA2B genes. Exome sequencing is a suitable method for identifying single-gene disease and genetic heterogeneity complaints. METHODS: Among families who were referred to Narges Genetic and PND Laboratory in 2015-2017, five families with a history of blood diseases were analyzed using the whole exome sequencing (WES) method. RESULTS: We detected two novel mutations (c.190-2A>G and c.2840C>G) in the FANCA gene, c. 1429dupA mutation in the FANCC gene, and c.1392A>G mutation in the ITGA2B gene. The prediction of variant pathogenicity has been done using bioinformatics tools such as Mutation taster PhD-SNP and polyphen2 and were confirmed by Sanger sequencing. CONCLUSIONS: WES could be as a precise tool for identifying the pathologic variants in affected patient and heterozygous carriers among families. This highly successful technique will remain at the forefront of platelet and blood genomic research.

Characterization of a novel pathogenic variation c.1237T>G in the FZD4 gene presenting new inheritance from an Iranian individual suffering vitreoretinopathy.

Whole Exome Sequencing (WES) has been used increasingly in genetic determination of various known and unknown genetic disorders. Various genes are involved in the development of the vascular network of retina. Assessment of a collection of these genes could be provided by WES. Here we used WES for a patient suffering vitreoretinopathy to detect the disease causing variant. Sanger sequencing has been applied for variant verification and allelic segregation. After analysis of WES data we found a new variant c.1237T>G in the FZD4 locus which causes retinopathy of prematurity and exudative vitreoretinopathy (MIM number: 133780). Sanger sequencing showed this single nucleotide variation inherited as homozygous in the patient and heterozygous in her unaffected parents. Notably, bioinformatics analysis predicted the variant as disease causing and it has not been described yet in home datasets and public SNP databases. FZD4 mutations are mostly inherited as autosomal dominant traits. Our findings showed the first autosomal recessive inheritance of the FZD4 gene related retinopathy. On the other hand, our data shed light on the significance of an Exome sequencing application as a genetic test to identify and characterize the comprehensive spectrum of genetic variation and classification for patients with retinopathies.

Identification of the rs797045105 in the SERAC1 Gene by Whole-exome Sequencing in a Patient Suspicious of MEGDEL Syndrome.

INTRODUCTION: Whole Exome Sequencing (WES) has been increasingly utilized in genetic determinants of various inherited diseases. METHODS: We applied WES for a patient presenting 3-Methylglutaconic Aciduria (MEG), Deafness (D), Encephalopathy (E), and Leigh-like (L) syndrome. Then Sanger sequencing was used for the detected variant validation. RESULTS: We found an insertion, rs797045105 (chr6, 158571484, C>CCATG), in the SERAC1 gene with homozygous genotype in the patient and heterozygous genotype in her unaffected parents. Notably, bioinformatics analysis using mutation taster (prob>0.99) and DDIGin (prob=86.51) predicted this mutation as disease-causing. Also, the variant was not present in our database, including 700 exome files. CONCLUSION: These findings emphasize the pathogenicity of rs797045105 for MEGDEL syndrome. On the other hand, our data shed light on the significance of WES application as a genetic test to identify and characterize the comprehensive spectrum of genetic variation and classification for patients with neurometabolic disorders.

Analysis of enriched rare variants in JPH2-encoded junctophilin-2 among Greater Middle Eastern individuals reveals a novel homozygous variant associated with neonatal dilated cardiomyopathy.

Junctophilin-2 (JPH2) is a part of the junctional membrane complex that facilitates calcium-handling in the cardiomyocyte. Previously, missense variants in JPH2 have been linked to hypertrophic cardiomyopathy; however, pathogenic "loss of function" (LOF) variants have not been described. Family-based genetic analysis of GME individuals with cardiomyopathic disease identified an Iranian patient with dilated cardiomyopathy (DCM) as a carrier of a novel, homozygous single nucleotide insertion in JPH2 resulting in a stop codon (JPH2-p.E641*). A second Iranian family with consanguineous parents hosting an identical heterozygous variant had 2 children die in childhood from cardiac failure. To characterize ethnicity-dependent genetic variability in JPH2 and to identify homozygous JPH2 variants associated with cardiac disease, we identified variants in JPH2 in a worldwide control cohort (gnomAD) and 2 similar cohorts from the Greater Middle East (GME Variome, Iranome). These were compared against ethnicity-matched clinical whole exome sequencing (WES) referral tests and a case cohort of individuals with hypertrophic cardiomyopathy (HCM) based on comprehensive review of the literature. Worldwide, 1.45% of healthy individuals hosted a rare JPH2 variant with a significantly higher proportion among GME individuals (4.45%); LOF variants were rare overall (0.04%) yet were most prevalent in GME (0.21%). The increased prevalence of LOF variants in GME individuals was corroborated among region-specific, clinical WES cohorts. In conclusion, we report ethnic-specific differences in JPH2 rare variants, with GME individuals being at higher risk of hosting homozygous LOF variants. This conclusion is supported by the identification of a novel JPH2 LOF variant confirmed by segregation analysis resulting in autosomal recessive pediatric DCM due to presumptive JPH2 truncation.

Association of human leukocyte antigen-DRB haplotype in multiple sclerosis population of Khuzestan, Iran.

Background: One of the demyelinating and inflammatory diseases of the central nervous system (CNS) is multiple sclerosis (MS). Though pathogenesis of MS is still unknown, both genetic and environmental factors are involved. The human leukocyte antigen (HLA) class-II alleles including HLA-DRB5*01, DQB1*0602, DRB1*1501, and DQA1*0102 may have remarkable effect in MS risk although it is controversial in studies. As there is no data with respect to the HLA-DRB1*1501-DRB5*01 correlation with MS in Khuzestan Province, Iran, the goal of the survey was to investigate the association of this haplotype with MS in this population. Methods: The study focused on DRB5*01-DRB1*1501 haplotype association with MS in 200 patients and 200 healthy individuals. Typing of HLA was carried out by polymerase chain reaction (PCR) amplification with sequence-specific primers (SSP) method. SPSS software was used for the statistical analyses. Results: No association between DRB5*01+-DRB1*1501+ and MS was found (P = 0.156). Distribution of DRB1*1501+-DRB5*01- (carrying DRB1*1501+ but not DRB5*01-) and DRB1*1501--DRB5*01- haplotypes was statistically different between patients and controls (29.73% vs. 11.81%, P < 0.001) and (42.16% vs. 68.50%, P < 0.001), respectively. However, DRB1*1501--DRB5*01+ revealed no association with MS (15.13% vs. 11.81%, P = 0.403). HLA-DRB1*1501--DRB5*01+ was significantly more frequent among female patients with MS (16.19% vs. 6.12%, P = 0.019) and Persian group (17.11% vs. 5.79%, P = 0.027). Positive correlation of HLA-DRB1*1501+-DRB5*01- haplotype with the expanded disability status scale (EDSS) steps from 5 to 10 was observed (62.50% vs. 25.76%, P = 0.026). Moreover, no meaningful association was shown among the haplotypes with EDSS, course of MS, ethnicity, and gender. Conclusion: Our findings suggest that DRB1*1501+-DRB5*01- and DRB1*1501--DRB5*01- haplotypes may have positive association with MS risk. Also, this survey indicates that HLA-DRB1*1501--DRB5*01+ is involved in susceptibility of the disease among women and Persians. DRB1*1501+-DRB5*01- genotype frequency may have a key role in MS developing.