A Mutation in the CACNA1F Gene Found by Whole Exome Sequencing (WES) and In Silico Analysis in an Iranian Family with Consanguineous Relationships.

BACKGROUND: X-linked mutations are highly important in clinical diagnosis, and at least 533 disorders are related to the genes located on the X chromosome. CASE PRESENTATION: A 21-year-old Caucasian woman with a 24-year-old Caucasian man as her fiancé referred Clinical genetic lab for premarital genetic counseling (carrier screening). None of them had any abnormal manifestations. Following genetic counseling, Whole Exome Sequencing (WES) test performed to find the possible pathogenic mutations. Also, after drawing the couple's pedigree, candidate mutations were examined in the woman's parents as well as her uncles. Additionally, in silico investigations were performed through SWISS-MODEL, MolProbity, ProSA, Py- Mol, and FATCAT tools. The most important mutation diagnosed in the woman (R1362Q in the 35th exon of CACNA1F), was observed in her mother and her two uncles. The mutation was also screened in both her father and her fiancé, but they had no mutations. After medical examinations of carriers, there was no sign of any eye impairment. Other mutations were TCTN2 (c.1613-2A>G), TARS (p.K319E), SPEG (p.E3020K), CPS1 (p.A1180V), MYO3A (p.I736M), NNT (p.R968Q), MED23 (p.K406T). Bioinformatics analyses indicated no alteration in the mutant structure of CACNA1F (Q1362) compared with the normal structure (R1362). CONCLUSION: Conclusively, the current study emphasizes the non-pathogenic effect of missense mutation R1362Q in the 35th exon of CACNA1F in association with ocular diseases. This will ensure the reports of this mutation as healthy instead of uncertain in the literature and databanks.

A Novel Mutation (Lys31Arg) in the DMD Gene Impacts on Neuromuscular Dysfunctions Found by Whole Exome Sequencing and In Silico Analyses in an Iranian Family.

BACKGROUND: Duchene Muscular Disorder (DMD) is a severe X-linked recessive neuromuscular disease. Previous reports predicted that one-third of cases with a fatal X-linked recessive disease will be caused by a novel mutation, and the mutation rate for DMD seems to be higher in males. OBJECTIVE: A novel mutation in the DMD gene DMD (NM_004006.3):c.92A>G (p.Lys31Arg) is suggested for males because of their heterozygous mothers carrying the mutant alleles. METHOD: Whole Exome Sequencing (WES) was done for a 25-year-old female followed by the screening of the novel mutation in her parents and her brother by the Sanger sequencing technique. Some in silico analyses were run to find the putative alterations in wild-type and mutant structures by PolyPhen-2 and Mupro. Notably, SWISS-MODEL was performed to build a reliable model for the mutant allele based on the PDB ID: 1DXX structure. Also, superimposition was done by PyMol. RESULTS: WES analysis revealed three novel mutations including DLD (exon13:c.G1382A:p. G461E), ABCA3 (exon12:c.G1404C:p.W468C), and DMD (exon2:c.A92G:p.K31R) in the case. Focusing on DMD mutation, Sanger sequencing of the patient's parents and brother indicated no mutant allele in her mother and brother but a mutant allele in her father as a hemizygous pattern. In silico analyses showed no considerable change regarding pathogenic impact. CONCLUSION: In conclusion, our findings revealed no pathogenic effect of the new mutation (K31R) of the DMD gene in an Iranian 25-year-old woman. Because of the DMD importance in preclinical diagnosis, these data may shed a light on the diagnosis of this mutation in future pregnancies.

Analysis of Interleukin-6 Gene Variants (rs1800795, rs1800796, rs1554606, rs1800797, rs2069840, rs12700386, and rs2069861) as Prognostic Markers in Breast Cancer: A Systematic Review, Meta-Analysis, and Network Analysis.

Interleukin-6 (IL-6) has obviously tumor-promoting and tumor-inhibitory effects and can induce an epithelial-mesenchymal transition phenotype in human breast cancer (BC) cells and implicate its potential to promote BC metastasis. Herein, we aimed to evaluate the association of IL-6 variants (rs1800795, rs1800796, rs1554606, rs1800797, rs2069840, rs12700386, and rs2069861) with the susceptibility to BC. The databases of PubMed/Medline, Web of Science, Scopus, and Cochrane Library were searched until December 19, 2022, without any restrictions. The quality assessment of each study was performed based on the Newcastle-Ottawa Scale tool. The Review Manager 5.3 software presented the effect sizes including odds ratio (OR) along with a 95% confidence interval (CI). Both publication bias and sensitivity analyses were carried out by the Comprehensive Meta-Analysis version 2.0 software. A total of 2,508 records were identified among databases and at last, 27 articles were entered into the meta-analysis. Seven polymorphisms of IL-6 were entered into the analyses. Just rs1800797 polymorphism in the dominant model (OR = 1.51; 95% CI = 1.15-2.00; P = 0.003) and rs2069840 polymorphism in heterozygous (OR = 0.89; 95% CI = 0.81-0.97; P = 0.008) and dominant (OR = 0.91; 95% CI = 0.84-0.99; P = 0.02) models had a significant association with the BC risk. In conclusion, among 7 polymorphisms and despite a few included cases, the present meta-analysis recommended that the AA+GA genotype of rs1800797 polymorphism had a significantly elevated risk and the GC and the CC+GC genotypes of rs2069840 polymorphism had a protective role in the BC patients.

A Novel Arg120Pro Mutation in the RP2 Gene in an Iranian Family with X-linked Retinitis Pigmentosa: A Case Report.

As the most common type of inherited retinal degenerative disease, retinitis pigmentosa (RP) has taken clinical and prenatal attention. Considering the clinical importance of consanguineous marriages, new mutations in this type of pregnancy have a high risk and increase the importance of Prenatal Diagnosis (PND). In vitro analysis was done through Whole Exome Sequencing (WES) for a 36-year-old woman who was referred to a genetic laboratory in Kermanshah in 2021 for PND. The woman had consanguineous marriage and was pregnant with twins (a boy and a girl). Mutation confirmation tests were also performed on her husband and both fetuses to find mutations. Moreover, in silico analyses were performed by SWISS-MODEL, ProSA, Molprobity, Swiss-Pdb Viewer, and ERRAT. The WES analysis showed a novel mutation of the RP2 gene (exon2:c. 359G>C: p.R120P) in the 36-year-old pregnant woman. Mutations identified in her husband and her twins revealed changes in protein conformations. Further modeling and validation evaluations showed the replacement of Arg by Pro at the 120th residue site of the cognate protein. For the first time, our report introduced a novel missense mutation in the RP2 gene associated with severe signs of RP in an Iranian family based on an X-linked recessive pattern of genetic inheritance. These findings may pave the way for a better diagnosis of RP in genetic counseling and PND.

Changes in liver enzymes and association with prognosis in patients with COVID-19: a retrospective case-control study.

OBJECTIVE: COVID-19 has recently emerged as a serious threat to global health. This study examined the laboratory investigations of patients with COVID-19, with an emphasis on liver enzymes. METHODS: This retrospective, single-center study was performed on patients with COVID-19 who were admitted to Imam Reza Hospital, Iran from March 2020 to February 2021. Laboratory tests included a complete blood cell count, white blood cell (WBC) count, neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), lymphocyte/monocyte ratio, and levels of aspartate aminotransferase, alanine aminotransferase (ALT), and alkaline phosphatase. Patient survival was among the outcome measures investigated in association with laboratory findings. RESULTS: We enrolled 77 patients with COVID-19 and 63 healthy controls. In comparison with the control group, patients with COVID-19 showed COVID-19 increased ALT, WBC, neutrophils, NLR, and PLR, and decreased platelet counts and lymphocytes. CONCLUSION: Although elevated levels of AST, NLR, PLR, and LMR were found in patients with COVID-19, they were not linked to mortality. Given the presence of AST in other tissues, the influence of SARS-CoV-2 on the liver should be interpreted with caution.