Occupational safety risk analysis in construction sites based on fuzzy analytic hierarchy process: A case study in a large construction project.

BACKGROUND: Construction projects are one of the most critical occupational sectors that experienced many challenges in occupational accidents and safety performance. OBJECTIVE: This study was designed to assess safety risk in construction projects based on fuzzy analytic hierarchy process. METHODS: This study was conducted with 12 construction and occupational safety experts in one of the largest construction projects in Tehran-Iran in 2020. The process of this study included (1) risk identification, (2) measurement of risk parameters and sub-parameters, and (3) risk assessment based on a fuzzy analytic hierarchy process. Risk-forming parameters in this study included the probability and severity of the event. The probability of occurrence was estimated based on four sub-parameters of technical inspection, accident experience, detection probability, and human reliability. Sub-parameters of severity included human injury, cost imposition, tarnishing the organization's esteem, and impact on project timing and work stoppage. RESULTS: Twenty-eight identified hazards were examined in the studied construction project, including falling from a height (9-hazard), falling objects (2-hazard), electric shock (6-hazard), falling crane or load (6-hazard), elevator crashes (2-hazard), and soil fall (3-hazard). Safety risk assessment revealed that 27 risk sources were at the tolerable level and one risk source was unacceptable. CONCLUSION: This study demonstrated that the risk levels in the studied construction project were tolerable and unacceptable. The obtained model in this study demonstrated that using parameters that determine the probability and severity of risk according to the nature of the working environments can be a practical step in risk evaluating and implementing control measures.

A biallelic variant in POLR2C is associated with congenital hearing loss and male infertility: Case report.

BACKGROUND: DNA-directed RNA polymerase II subunit 3 (RPB3) is the third largest subunit of RNA polymerase II and is encoded by the POLR2C (OMIM:180663). A large Iranian family with congenital hearing loss and infertility is described here with genetic and clinical characterizations of five male patients. METHODS: After doing clinical examinations, the proband was subjected to karyotyping and GJB2/6 sequencing to rule out the most evident chromosomal and gene abnormalities for male infertility and hearing loss, respectively. A custom-designed next-generation sequencing panel was also used to detect mutations in deafness-related genes. Finally, to reveal the underlying molecular cause(s) justifying hearing loss and male infertility, five male patients and 2 healthy male controls within the family were subjected to paired-end whole-exome sequencing (WES). Linkage analysis was also performed based on the data. RESULTS: All male patients showed prelingual sensorineural hearing loss and also decreased sperm motility. Linkage analysis determined 16q21 as the most susceptible locus in which a missense variant in exon 7 of POLR2C-NM_032940.3:c.545T>C;p.(Val182Ala)-was identified as a 'likely pathogenic' variant co-segregated with phenotypes. CONCLUSIONS: Using segregation and in silico analyses, for the first time, we suggested that the NM_032940.3:c.545T>C; p.(Val182Ala) in POLR2C is associated with hearing loss and male infertility.

Kabuki Syndrome: Identification of Two Novel Variants in KMT2D and KDM6A.

Kabuki syndrome (KS) is a rare genetic disorder characterized by the following 5 crucial symptoms: dysmorphic facial features, growth retardation, skeletal abnormalities, intellectual disability, and dermatoglyphic malformations. Studies show that most of the KS cases are caused by mutations or large deletions in the KMT2D gene, while the other cases show mutations in KDM6A. We studied 2 patients with suspected KS in 2 unrelated families by whole-exome sequencing to identify the possible genetic cause(s) and by Sanger sequencing to validate the identified variants and check the segregation in other members of the families. Finally, the potential effects of the variants on the structure and function of respective proteins were tested using in silico predictions. Both affected members of the families showed typical manifestations of KS including intellectual disability, developmental delay, and abnormal facial characteristics. A novel heterozygous frameshift variant in the KMT2D gene, c.4981del; p.(Glu1661Serfs*61), and a novel hemizygote missense variant in the KDM6A gene, c.3301G>A; p.(Glu1101Lys), were detected in patients 1 and 2, respectively. The frameshift variant identified in the first family was de novo, while in the second family, the mother was also heterozygous for the missense variant. The frameshift variant in KMT2D is predicted to lead to a truncated protein which is functionally impaired. The Glu1101 residue of KDM6A (UTX) affected in the second patient is located in a conserved region on the surface of the Jumonji domain and predicted to be causative. Our findings provide evidence on the possible pathogenicity of these 2 variants; however, additional functional studies are necessary to confirm their impacts.

Crystallographic modeling of the PNPT1:c.1453A>G variant as a cause of mitochondrial dysfunction and autosomal recessive deafness; expanding the neuroimaging and clinical features.

Deficiency of the proteins involved in oxidative phosphorylation (OXPHOS) can lead to mitochondrial dysfunction. Polyribonucleotide nucleotidyltransferase 1 (PNPT1) is one of the genes involved in the OXPHOS and encodes the mitochondrial polynucleotide phosphorylase (PNPase) which is implicated in RNA-processing exoribonuclease activity. Herein, we report a 34-month-old boy who presented with global developmental delay, muscular hypotonia, hearing impairment, and movement disorders including chorea and dystonia. Mitochondrial genome sequencing and whole-exome sequencing (WES) were performed and a variant in PNPT1:c.1453A>G; p. (Met485Val) was identified. A number of patient's neurologic problems had been already reported in previous studies, however, lower limbs spasticity and bulbar dysfunction were novel phenotypic findings. In addition, delayed myelination during infancy, progressive basal ganglia atrophy, and brain stem abnormal signals including transverse pontine fibers and superior colliculus involvement were also novel neuroimaging findings in this case. Different crystallographic modeling and stereochemical analysis of the c.1453A>G; p. (Met485Val) variant showed this variant affects the active site of the protein and disrupts the normal protein function.

Novel variants in critical domains of ATP8A2 and expansion of clinical spectrum.

ATP8A2 is a P4-ATPase that flips phosphatidylserine across membranes to generate and maintain transmembrane phospholipid asymmetry. Loss-of-function variants cause severe neurodegenerative and developmental disorders. We have identified three ATP8A2 variants in unrelated Iranian families that cause intellectual disability, dystonia, below-average head circumference, mild optic atrophy, and developmental delay. Additionally, all the affected individuals displayed tooth abnormalities associated with defects in teeth development. Two variants (p.Asp825His and p.Met438Val) reside in critical functional domains of ATP8A2. These variants express at very low levels and lack ATPase activity. Inhibitor studies indicate that these variants are misfolded and degraded by the cellular proteasome. We conclude that Asp825, which coordinates with the Mg2+ ion within the ATP binding site, and Met438 are essential for the proper folding of ATP8A2 into a functional flippase. We also provide evidence on the association of tooth abnormalities with defects in ATP8A2, thereby expanding the clinical spectrum of the associated disease.

Novel homozygous variants in the TMC1 and CDH23 genes cause autosomal recessive nonsyndromic hearing loss.

BACKGROUND: Hereditary hearing loss (HL) is a heterogeneous and most common sensory neural disorder. At least, 76 genes have been reported in association with autosomal recessive nonsyndromic HL (ARNSHL). Herein, we subjected two patients with bilateral sensorineural HL in two distinct consanguineous Iranian families to figure out the underlying genetic factors. METHODS: Physical and sensorineural examinations were performed on the patients. Imaging also was applied to unveil any abnormalities in anatomical structures of the middle and inner ear. In order to decipher the possible genetic causes of the verified GJB2-negative samples, the probands were subjected to whole-exome sequencing and, subsequently, Sanger sequencing was applied for variant confirmation. RESULTS: Clinical examinations showed ARNSHL in the patients. After doing whole exome sequencing, two novel variants were identified that were co-segregating with HL that were absent in 100 ethnically matched controls. In the first family, a novel homozygous variant, NM_138691.2: c.530T>C; p.(lle177Thr), in TMC1 gene co-segregated with prelingual ARNSHL. In the second family, NM_022124.6: c.2334G>A; p.(Trp778*) was reported as a nonsense variant causing prelingual ARNSHL. CONCLUSION: These findings can, in turn, endorse how TMC1 and CDH23 screening is critical to detecting HL in Iranian patients. Identifying TMC1 and CDH23 pathogenic variants doubtlessly help in the detailed genotypic characterization of HL.

A novel variant of ST3GAL3 causes non-syndromic autosomal recessive intellectual disability in Iranian patients.

BACKGROUND: The number of reported genes causing non-syndromic autosomal recessive intellectual disability (NS-ARID) is increasing. For example, mutations in the ST3GAL3 gene have been reported to be associated with NS-ARID. In the present study, we aimed to determine the genetic cause of the NS-ARID in a five-generation consanguineous Iranian family. METHODS: We subjected four patients with an initial diagnosis of NS-ID in an Iranian family. To identify the possible genetic cause(s), whole-exome sequencing was performed on the proband and Sanger sequencing was applied to investigate co-segregation analysis. Using in silico predictive tools, the possible impacts of the variant on the structure and function of ST3Gal-III were predicted. RESULTS: The common clinical features were detected in all affected members who were suffering from a severe ID. Using whole-exome sequencing, a novel variant, c.704C>T or p.(Thr235Met), in exon 9 of the ST3GAL3 gene (NM_001270461.2, OMIM# 606494) was identified and verified by Sanger sequencing. This variant is located next to the VS motif of ST3Gal-III, which is a vital part of the catalytical domains. CONCLUSIONS: In the present study, we identified a novel missense variant, c.704C>T or p.(Thr235Met), in the ST3GAL3. To our knowledge, is the third variant in this gene to be associated with NS-ARID. Our findings highlight the need for further investigations into the mechanisms by which variants in ST3GAL3 contribute to neurological dysfunction.

Three Novel Variants identified in FBN1 and TGFBR2 in seven Iranian families with suspected Marfan syndrome.

BACKGROUND: Marfan syndrome (MFS) is a multi-systemic autosomal dominant disease of the connective tissue characterized by the early development of thoracic aneurysms/dissections, along with various manifestations of the ocular and skeletal systems. Due to the genetic and clinical heterogeneity, the clinical diagnosis of this disorder is challenging. Loss-of-function mutations in FBN1 (encodes fibrillin-1) lead to MFS type 1. Also, similar mutations in transforming growth factor ß receptor 2 (TGFBR2) gene cause MFS type 2. Both proteins involve in TGF-ß signaling. METHODS: In this study, genetic screening using a panel involving 14 genes, especially FBN1 and TGFBR2, were performed on seven representatives affected members of seven unrelated Iranian families suspected with MFS. To confirm the variants, Sanger sequencing was applied to other affected/unaffected members of the families. RESULTS: A total of 13 patients showed MFS manifestations. Using genetic screening, two novel and three previously reported variants in FBN1 were identified. We also detected two variants (a novel and a previously reported variant) in the TGFBR2 gene. CONCLUSION: In this study, we introduce three novel variants identified through gene screening in seven Iranian MFS families. This report is expected to considerably improve genetic counseling for Iranian MFS families. Early precise molecular diagnosis can be helpful for better management and improving the life expectancy of these patients.