MiR-6721-5p as a natural regulator of Meta-VCL is upregulated in the serum of patients with coronary artery disease.

Background: Coronary artery disease (CAD), the leading cause of mortality globally, arises from atherosclerotic blockage of the coronary arteries. Meta-vinculin (meta-VCL), a large spliced isoform of VCL, co-localizes in muscular adhesive structures and plays significant roles in cardiac physiology and pathophysiology. This study aimed to identify microRNAs (miRNAs) regulating meta-VCL expression and investigate the expression alterations of the miRNAs of interest and meta-VCL as potential biomarkers in the serum of CAD patients. Methods: Bioinformatics tools were employed to select miRNAs targeting meta-VCL. Cell-based ectopic expression analysis and a dual-luciferase assay were used to examine the interactions between miRNAs and meta-VCL. An ELISA assessed the concentrations of interleukin-6 (IL-6), IL-10, and tumor necrosis factor-α (TNF-α). MiRNA and meta-VCL expression patterns and biomarker suitability were evaluated in serum samples from CAD and non-CAD individuals using real-time PCR. A cardiac cell-line data set and CAD blood exosome samples were analyzed using bioinformatics and ROC curve analyses, respectively. Results: miR-6721-5p directly interacted with the putative target sites at the 3'-UTR of meta-VCL and regulated its expression. IL-10 and TNF-α concentrations, which may act as anti-inflammatory factors, decreased following miR-6721-5p upregulation and meta-VCL downregulation. Bioinformatics and experimental expression analyses confirmed downregulated meta-VCL expression and upregulated miR-6721-5p expression in CAD samples. ROC curve analysis yielded an AUC score of 0.705 (P = 0.018), indicating the potential suitability of miR-6721-5p as a biomarker for CAD. Conclusions: miR-6721-5p plays a regulatory role in meta-VCL expression and may contribute to CAD development by reducing anti-inflammatory factors. These findings suggest that miR-6721-5p could serve as a novel biomarker in the pathogenesis of CAD.

Outcomes of STEMI Patients in COVID-19 Pandemic: A Systematic Review and Meta-Analysis.

Background: The global SARS-CoV-2 pandemic has disrupted health systems and put a huge strain on hospitals and healthcare workers. Prioritizing COVID-19 patients in hospitals caused irreversible harm to cardiac patients. Although multiple studies have shown that ST-segment elevation myocardial infarction (STEMI) patients have worse admission circumstances than before the pandemic, the hospital outcomes of these patients have remained limited. This systematic review and meta-analysis examined STEMI patient outcomes during the COVID-19 epidemic. Methods: We conducted systematic searches of MEDLINE (through PubMed), Web of Science, Scopus, and Embase through Jan 10, 2021. All studies with reporting in-hospital mortality, length of stay, and door-to-balloon time with over twenty participants were included. Articles without clear definitions or results were excluded. The study followed PRISMA guidelines. The outcomes of interest were door-to-balloon time, death, and hospital stay during COVID-19 pandemic compared prior. Results: Our meta-analysis included 12 studies and 21170 people (115-6609). The pooled analysis showed significantly more pandemic mortality (OR=1.24; 95% CI: 1.07-1.43). Ten studies (13,091) recorded door-to-balloon times. Door-to-balloon time (in minutes) significantly increased during the pandemic (Standardized Mean Difference [SMD]= 0.46; 95% CI: 0.03-0.89). The length of hospital stay was reported by five studies (n=9448). Length of hospital stay (in days) was not significantly longer during the pandemic than before the outbreak (SMD= 0.04; 95% CI: -0.19-0.26). Conclusion: The COVID-19 pandemic is associated with increased mortality and door-to-balloon delay that might be attributable to the strict infection control measures in outbreak. Studies with a longer follow-up time are needed to investigate the outcomes of STEMI patients.

Ultraslow low-dose thrombolytic therapy in patients with acute mechanical prosthetic heart valve thrombosis - A prospective cohort study.

BACKGROUND: While surgery still remains the gold standard treatment for mechanical prosthetic valve thrombosis (MPVT) by many guidelines, the ultraslow low-dose thrombolytic regimen has been reported as a promising alternative. METHODS: In this prospective single-center cohort, patients with acute MPVT were treated with an ultraslow low-dose thrombolytic regimen consisting of 25 mg infusion of recombinant tissue-type plasminogen activator (rtPA) over 25 h. The regimen could be repeated in case of failure until resolution/occurrence of adverse events or a maximum cumulative dose of 150 mg. The primary outcome was the complete MPVT resolution rate; other outcomes included first-dose success rate, major bleeding, thromboembolic events, mortality, and total thrombolytic dose/duration. RESULTS: Between April 2018 to January 2024, 135 episodes of acute MPVT were treated with an ultraslow low-dose thrombolytic regimen in 118 patients. In 118/135 (87.4 %) episodes, right-sided prosthetic valve was involved. Complete success was achieved in 88.1 % of cases, with 39.5 % responding after the first dose. The median total dose was 50 mg over a median of 30 h. Only one fatal intracranial hemorrhage occurred (0.7 %), with no other bleeding or thromboembolic complications. CONCLUSION: The ultraslow low-dose thrombolytic regimen appears to exhibit high efficacy and acceptable safety in treating acute MPVT. Further large clinical trials are essential for validating these preliminary findings.

Exploring the role of non-coding RNAs in atrial septal defect pathogenesis: A systematic review.

BACKGROUND: Extensive research has recognized the significant roles of non-coding RNAs (ncRNAs) in various cellular pathophysiological processes and their association with diverse diseases, including atrial septal defect (ASD), one of the most prevalent congenital heart diseases. This systematic review aims to explore the intricate involvement and significance of ncRNAs in the pathogenesis and progression of ASD. METHODS: Four databases (PubMed, Embase, Scopus, and the Web of Science) were searched systematically up to June 19, 2023, with no year restriction. The risk of bias assessment was evaluated using the Newcastle-Ottawa scale. RESULTS: The present systematic review included thirteen studies with a collective study population of 874 individuals diagnosed with ASD, 21 parents of ASD patients, and 22 pregnant women carrying ASD fetuses. Our analysis revealed evidence linking five long ncRNAs (STX18-AS1, HOTAIR, AA709223, BX478947, and Moshe) and several microRNAs (hsa-miR-19a, hsa-miR-19b, hsa-miR-375, hsa-miR-29c, miR-29, miR-143/145, miR-17-92, miR-106b-25, and miR-503/424, miR-9, miR-30a, miR-196a2, miR-139-5p, hsa-let-7a, hsa-let-7b, and hsa-miR-486) to ASD progression, corresponding to previous studies. CONCLUSIONS: NcRNAs play a crucial role in unraveling the underlying mechanisms of ASD, contributing to both biomarker discovery and therapeutic advancements. This systematic review sheds light on the mechanisms of action of key ncRNAs involved in ASD progression, providing valuable insights for future research in this field.

Combination of FLNC and JUP variants causing arrhythmogenic cardiomyopathy in an Iranian family with different clinical features.

BACKGROUND: Arrhythmogenic cardiomyopathy (ACM) characterized by progressive myocardial loss and replacement with fibro-fatty tissue is a major cause of sudden cardiac death (SCD). In particular, ACM with predominantly left ventricular involvement, known as arrhythmogenic left ventricular cardiomyopathy (ALVC), has a poor prognosis. METHODS: The proband underwent whole-exome sequencing (WES) to determine the etiology of ALVC. Family members were then analyzed using PCR and Sanger sequencing. Clinical evaluations including 12-lead ECG, transthoracic echocardiography, and cardiac MRI were performed for all available first-degree relatives. RESULTS: WES identified two variants in the FLNC (c.G3694A) and JUP (c.G1372A) genes, the combination of which results in ALVC and SCD. CONCLUSION: The present study comprehensively investigates the involvement of two discovered variants of FLNC and JUP in the pathogenesis of ALVC. More study is necessary to elucidate the genetic factors involved in the etiology of ALVC.

Identification of a novel likely pathogenic TPM1 variant linked to hypertrophic cardiomyopathy in a family with sudden cardiac death.

AIMS: Hypertrophic cardiomyopathy (HCM) is an autosomal dominant genetic cardiac disorder characterized by unexplained left ventricular hypertrophy. It can cause a wide spectrum of clinical manifestations, ranging from asymptomatic to heart failure and sudden cardiac death (SCD). Approximately half of HCM cases are caused by variants in sarcomeric proteins, including α-tropomyosin (TPM1). In this study, we aimed to characterize the clinical and molecular phenotype of HCM in an Iranian pedigree with SCD. METHODS AND RESULTS: The proband and available family members underwent comprehensive clinical evaluations, including echocardiography, cardiac magnetic resonance (CMR) imaging and electrocardiography (ECG). Whole-exome sequencing (WES) was performed in all available family members to identify the causal variant, which was validated, and segregation analysis was conducted via Sanger sequencing. WES identified a novel missense variant, c.761A>G:p.D254G (NM_001018005.2), in the TPM1 gene, in the proband, his father and one of his sisters. Bioinformatic analysis predicted it to be likely pathogenic. Clinical features in affected individuals were consistent with HCM. CONCLUSIONS: The identification of a novel TPM1 variant in a family with HCM and SCD underscores the critical role of genetic screening in at-risk families. Early detection of pathogenic variants can facilitate timely intervention and management, potentially reducing the risk of SCD in individuals with HCM.

Detection of a novel pathogenic variant in KCNH2 associated with long QT syndrome 2 using whole exome sequencing.

BACKGROUND: Long QT syndrome (LQTS) is a cardiac channelopathy characterized by impaired myocardial repolarization that predisposes to life-threatening arrhythmias. This study aimed to elucidate the genetic basis of LQTS in an affected Iranian family using whole exome sequencing (WES). METHODS: A 37-year-old woman with a personal and family history of sudden cardiac arrest and LQTS was referred for genetic study after losing her teenage daughter due to sudden cardiac death (SCD). WES was performed and variants were filtered and prioritized based on quality, allele frequency, pathogenicity predictions, and conservation scores. Sanger sequencing confirmed segregation in the family. RESULTS: WES identified a novel heterozygous frameshift variant (NM_000238.4:c.3257_3258insG; pGly1087Trpfs*32) in the KCNH2 encoding the α-subunit of the rapid delayed rectifier potassium channel responsible for cardiac repolarization. This variant, predicted to cause a truncated protein, is located in the C-terminal region of the channel and was classified as likely pathogenic based on ACMG guidelines. The variant was absent in population databases and unaffected family members. CONCLUSION: This study reports a novel KCNH2 frameshift variant in an Iranian family with LQTS, expanding the spectrum of disease-causing variants in this gene. Our findings highlight the importance of the C-terminal region in KCNH2 for proper channel function and the utility of WES in identifying rare variants in genetically heterogeneous disorders like LQTS. Functional characterization of this variant is warranted to fully elucidate its pathogenic mechanisms and inform personalized management strategies.

Applying a Computer-based Warfarin Management System at a Large Tertiary Cardiovascular Center in Iran.

BACKGROUND: Regarding adjustments to warfarin dosage, numerous studies have shown that computerized methods are superior to those based on personal experience. OBJECTIVES: To report the efficacy of a computer-based warfarin management system (WMS) in the Iranian population. METHODS: By utilizing the existing dosing algorithms and obtaining expert opinions, we developed a computer-based WMS at a large tertiary cardiovascular center. The time in therapeutic range and the number of international normalized ratio (INR) tests of clinic patients were compared before and after the implementation of WMS. RESULTS: Overall, 803 patients with 5407 INR tests were included in the before phase and 679 patients with 4189 INR tests in the after phase. The mean time in therapeutic range was 57.3% before and 59% after WMS implementation [mean difference, 1.64; 95% confidence interval (CI), -1.12-4.40]. In the before phase, the mean number of INR tests was 6.7, which dropped to 6.1 tests in the after phase (mean difference, -0.61; 95% CI, -0.97 to -0.24). Only 54.5% of the warfarin dosing prescriptions were consistent with the dosing recommendations of the WMS, and adherence to the WMS was poorest in the highest INR target range. CONCLUSIONS: For the first time in Iran, we demonstrated that a computerized system was as effective as a traditional experience-based method to monitor INR in VKA-anticoagulated patients. Furthermore, it could reduce both the number of INR tests and that of visits.

Whole-exome sequencing revealed a likely pathogenic variant in NF1 causing neurofibromatosis type I and Arrhythmogenic Cardiomyopathy.

BACKGROUND: Neurofibromatosis type I (NF1) is a genetic disorder characterized by the tumor's development in nerve tissue. Complications of NF1 can include pigmented lesions, skin neurofibromas, and heart problems such as cardiomyopathy. In this study, we performed whole-exome sequencing (WES) on an Iranian patient with NF1 to identify the genetic cause of the disease. METHODS: Following clinical assessment, WES was used to identify genetic variants in a family with a son suffering from NF1. No symptomatic manifestations were observed in other family members. In the studied family, in silico and segregation analysis were applied to survey candidate variants. RESULTS: Clinical manifestations were consistent with arrhythmogenic cardiomyopathy (ACM). WES detected a likely pathogenic heterozygous missense variant, c.3277G > A:p.Val1093Met, in the NF1 gene, confirmed by PCR and Sanger sequencing. The patient's parents and brother had a normal sequence at this locus. CONCLUSIONS: Although there is no cure for NF1, genetic tests, such as WES, can detect at-risk asymptomatic family members. Furthermore, cardiac evaluation could also help these patients before heart disease development.

A novel homozygous variant (c.5876T > C: p. Leu1959Pro) in DYSF segregates with limb-girdle muscular dystrophy: a case report.

BACKGROUND: Limb girdle muscular dystrophies (LGMDs) constitute a heterogeneous group of neuromuscular disorders with a very variable clinical presentation and overlapping traits. The clinical symptoms of LGMD typically appear in adolescence or early adulthood. Genetic variation in the dysferlin gene (DYSF) has been associated with LGMD. METHODS: We characterized a recessive LGMD in a young adult from consanguineous Irani families using whole-exome sequencing (WES) technology. Sanger sequencing was performed to verify the identified variant. Computational modeling and protein-protein docking were used to investigate the impact of the variant on the structure and function of the DYSF protein. RESULTS: By WES, we identified a novel homozygous missense variant in DYSF (NM_003494.4: c.5876T > C: p. Leu1959Pro) previously been associated with LGMD phenotypes. CONCLUSIONS: The identification and validation of new pathogenic DYSF variant in the present study further highlight the importance of this gene in LGMD.

Exploring TTN variants as genetic insights into cardiomyopathy pathogenesis and potential emerging clues to molecular mechanisms in cardiomyopathies.

The giant protein titin (TTN) is a sarcomeric protein that forms the myofibrillar backbone for the components of the contractile machinery which plays a crucial role in muscle disorders and cardiomyopathies. Diagnosing TTN pathogenic variants has important implications for patient management and genetic counseling. Genetic testing for TTN variants can help identify individuals at risk for developing cardiomyopathies, allowing for early intervention and personalized treatment strategies. Furthermore, identifying TTN variants can inform prognosis and guide therapeutic decisions. Deciphering the intricate genotype-phenotype correlations between TTN variants and their pathologic traits in cardiomyopathies is imperative for gene-based diagnosis, risk assessment, and personalized clinical management. With the increasing use of next-generation sequencing (NGS), a high number of variants in the TTN gene have been detected in patients with cardiomyopathies. However, not all TTN variants detected in cardiomyopathy cohorts can be assumed to be disease-causing. The interpretation of TTN variants remains challenging due to high background population variation. This narrative review aimed to comprehensively summarize current evidence on TTN variants identified in published cardiomyopathy studies and determine which specific variants are likely pathogenic contributors to cardiomyopathy development.

A novel likely pathogenic homozygous RBCK1 variant in dilated cardiomyopathy with muscle weakness.

AIMS: Polyglucosan body myopathy 1 (PGBM1) is a type of glycogen storage disease where polyglucosan accumulation leads to cardiomyopathy and skeletal muscle myopathy. Variants of RBCK1 is related with PGBM1. We present a newly discovered pathogenic RBCK1 variant resulting in dilated cardiomyopathy (DCM) and a comprehensive literature review. METHODS AND RESULTS: Whole-exome sequencing (WES) was utilized to detect genetic variations in a 7-year-old girl considered the proband. Sanger sequencing was performed to validate the variant in the patient and all the available family members, whether affected or unaffected. The variant's pathogenicity was assessed by conducting a cosegregation analysis within the family with in silico predictive software. WES showed that the proband's RBCK1 gene contained a missense likely pathogenic homozygous nucleotide variant, c.598_599insT: p.His200LeufsTer14 (NM_001323956.1), in exon 8. The computational analysis supported the variant's pathogenicity. The variant was identified in a heterozygous form among all the healthy members of the family. Variants with changes in N-terminal part of the protein were more likely to manifest immunodeficiency and auto-inflammation than those with C-terminal protein modifications according to prior variations of RBCK1 reported in the literature. CONCLUSIONS: Our study offers novel findings indicating an RBCK1 variant in individuals of Iranian ancestry presenting with DCM leading to heart transplantation and myopathy without immunodeficiency or auto-inflammation.

Associations between low serum levels of ANRIL and some common gene SNPs in Iranian patients with premature coronary artery disease.

Coronary artery disease (CAD) is the major cause of mortality in the world. Premature development of CAD can be attributed to women under 55 and men under 45. Many genetic factors play a part in premature CAD. Among them, ANRIL, a long noncoding RNA is located at the 9p21 risk locus, and its expression seems to be correlated with CAD. In the current study, premature CAD and control blood samples, with and without Type 2 Diabetes (T2D), were genotyped for six SNPs at the 9p21 locus. Additionally, ANRIL serum expression was assessed in both groups using real-time PCR. It was performed using different primers targeting exons 1, 5-6, and 19. The χ2 test for association, along with t-tests and ANOVA, was employed for statistical analysis. In this study, we did not find any significant correlation between premature coronary artery disease and rs10757274, rs2383206, rs2383207, rs496892, rs10757278 and rs10738605. However, a lower ANRIL expression was correlated with each SNP risk genotype. Despite the correlation between lower ANRIL expression and CAD, Type 2 diabetes was associated with higher ANRIL expression. Altogether, the correlation between ANRIL expression and the genotypes of the studied SNPs indicated that genetic variants, even those in intronic regions, affect long noncoding RNA expression levels. In conclusion, we recommend combining genetic variants with expression analysis when developing screening strategies for families with premature CAD. To prevent the devastating outcomes of CAD in young adults, it is crucial to discover noninvasive genetic-based screening tests.

A novel pathogenic variant in the carnitine transporter gene, SLC22A5, in association with metabolic carnitine deficiency and cardiomyopathy features.

BACKGROUND: Primary carnitine deficiency (PCD) denotes low carnitine levels with an autosomal recessive pattern of inheritance. Cardiomyopathy is the most common cardiac symptom in patients with PCD, and early diagnosis can prevent complications. Next-generation sequencing can identify genetic variants attributable to PCD efficiently. OBJECTIVE: We aimed to detect the genetic cause of the early manifestations of hypertrophic cardiomyopathy and metabolic abnormalities in an Iranian family. METHODS: We herein describe an 8-year-old boy with symptoms of weakness and lethargy diagnosed with PCD through clinical evaluations, lab tests, echocardiography, and cardiac magnetic resonance imaging. The candidate variant was confirmed through whole-exome sequencing, polymerase chain reaction, and direct Sanger sequencing. The binding efficacy of normal and mutant protein-ligand complexes were evaluated via structural modeling and docking studies. RESULTS: Clinical evaluations, echocardiography, and cardiac magnetic resonance imaging findings revealed hypertrophic cardiomyopathy as a clinical presentation of PCD. Whole-exome sequencing identified a new homozygous variant, SLC22A5 (NM_003060.4), c.821G > A: p.Trp274Ter, associated with carnitine transport. Docking analysis highlighted the impact of the variant on carnitine transport, further indicating its potential role in PCD development. CONCLUSIONS: The c.821G > A: p.Trp274Ter variant in SLC22A5 potentially acted as a pathogenic factor by reducing the binding affinity of organic carnitine transporter type 2 proteins for carnitine. So, the c.821G > A variant may be associated with carnitine deficiency, metabolic abnormalities, and cardiomyopathic characteristics.

Left main and three vessels spontaneous coronary artery dissection as an incidental finding in young man with history of Hodgkin's lymphoma-a case report.

BACKGROUND: Spontaneous coronary artery dissection is a rare and important cause of myocardial infarction, especially in young women without other coronary artery disease. This arterial dissection can occur within or between any of the 3 layers. Its predisposing factors include connective tissue diseases (Marfone syndrome, Ehlers-Danlos syndrome), vasculitis (polyarteritis nodosa, systemic lupus erythematosus, and Kawasaki disease), atherosclerosis and fibromuscular dysplasia. Clinical presentations of spontaneous coronary artery dissection are wide spectrum from asymptomatic to acute coronary disease, sustained ventricular arrhythmia and sudden cardiac death. CASE PRESENTATION: We describe A 33-year-old man with history of Hodgkin's lymphoma five years earlier that became a candidate for Patent foramen ovale closure due to recurrent embolic cerebrovascular accident. Before the intervention, coronary angiography incidentally showed dissection in the left main and all major coronary arteries. CONCLUSIONS: Based on our hypothesis, chemoradiotherapy-induced arteriopathies could be consider as a predisposing factor for spontaneous coronary artery dissection.

Catecholaminergic polymorphic ventricular tachycardia (and seizure) caused by a novel homozygous likely pathogenic variant in CASQ2 gene.

BACKGROUND: Although structural heart disease is frequently present among patients who experience sudden cardiac death (SCD), inherited arrhythmia syndromes can also play an important role in the occurrence of SCD. CPVT2, which is the second-most prevalent form of CPVT, arises from an abnormality in the CASQ2 gene. OBJECTIVE: We represent a novel CASQ2 variant that causes CPVT2 and conduct a comprehensive review on this topic. METHODS: The proband underwent Whole-exome sequencing (WES) in order to ascertain the etiology of CPVT. Subsequently, the process of segregating the available family members was carried out through the utilization of PCR and Sanger Sequencing. We searched the google scholar and PubMed/Medline for studies reporting CASQ2 variants, published up to May 10,2023. We used the following mesh term "Calsequestrin" and using free-text method with terms including "CASQ2","CASQ2 variants", and "CASQ2 mutation". RESULTS: The CASQ2 gene was found to contain an autosomal recessive nonsense variant c.268_269insTA:p.Gly90ValfsTer4, which was identified by WES. This variant was determined to be the most probable cause of CPVT in the pedigree under investigation. CONCLUSION: CASQ2 variants play an important role in pathogenesis of CPVT2. Notabely, based on results of our study and other findings in the literature the variant in this gene may cause an neurological signs in the patients with CPVT2. Further studies are needed for more details about the role of this gene in CPVT evaluation, diagnosis, and gene therapy.

Whole-exome sequencing reveals a likely pathogenic LMNA variant causing hypertrophic cardiomyopathy.

OBJECTIVE: We studied the clinical and molecular features of a family with hypertrophic cardiomyopathy (HCM). BACKGROUND: A very heterogeneous disease affecting the heart muscle, HCM is mostly caused by variants in the proteins of sarcomeres. The detection of HCM pathogenic variants can affect the handling of patients and their families. METHODS: Whole-exome sequencing (WES) was performed to assess the genetic cause(s) of HCM in a consanguineous Iranian family. RESULTS: Missense likely pathogenic variant c.1279C>T (p.Arg427Cys) within exon 7 of the LMNA gene (NM_170707) was found. The segregations were confirmed by polymerase chain reaction-based Sanger sequencing. CONCLUSIONS: Variant c.1279C>T (p.Arg427Cys) in the LMNA gene seemed to have been the cause of HCM in the family. A few LMNA gene variants related to HCM phenotypes have been recognized so far. Identifying HCM genetic basis confers significant opportunities to understand how the disease can develop and, by extension, how this progression can be arrested. Our study supports WES effectiveness for first-tier variant screening of HCM in a clinical setting.

Whole-exome sequencing uncovers a novel EFEMP2 gene variant (c.C247T) associated with dominant nonsyndromic thoracic aortic aneurysm.

BACKGROUND: Thoracic aortic aneurysm (TAA) is a multifactorial disorder. Familial TAA, which is more clinically aggressive, is associated with a high risk of lethal dissection or rupture. Genetic evaluation can provide TAA patients with personalized treatment and help in predicting risk to family members. OBJECTIVE: The purpose of this investigation was to report a likely pathogenic variant in the EFEMP2 gene that may contribute to TAA in a family with a documented history of the condition. METHODS: In the index patient, the causative genetic predisposition was identified using whole-exome sequencing. The potential likely pathogenic effect of the candidate variant was further analyzed through bioinformatics analysis, homology modeling, and molecular docking. RESULTS: The results revealed a likely pathogenic heterozygous variant, c.247C>T p.Arg83Cys, in exon 4 of the EFEMP2 gene (NM_016938), which was predicted to have disease-causing effects by MutationTaster, PROVEAN, SIFT, and CADD (phred score = 27.6). CONCLUSION: In this study, a likely pathogenic variant in the EFEMP2 gene was identified in an Iranian family with a dominant pattern of autosomal inheritance of TAA. This finding underscores the importance of conducting molecular genetic evaluations in families with nonsyndromic TAA and the significance of early detection of at-risk family members.

Genetic Variations in the Human Angiotensin-ConvertingEnzyme 2 and Susceptibility to Coronavirus Disease-19.

Background: Health and economies are both affected by the coronavirus disease-19 (COVID-19) global pandemic. Angiotensin-converting enzyme 2 (ACE2) is a polymorphic enzyme that is a part of the renin-angiotensin system, and it plays a crucial role in viral entry. Previous investigations and studies revealed that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and ACE2 have a considerable association. Recently, ACE2 variants have been described in human populations in association with cardiovascular and pulmonary conditions. In this study, genetic susceptibility to COVID-19 in different populations was investigated. Methods and Results: We evaluated the identified variants based on the predictive performance of 5 deleteriousness-scoring methods and the 2015 American College of Medical Genetics and Genomics (ACMG) guidelines. The results indicated 299 variants within the ACE2 gene. The variants were analyzed by different in-silico analysis tools to assess their functional effects. Ultimately, 5 more deleterious variants were found in the ACE2 gene. Conclusions: Collecting more information about the variations in binding affinity between SARS-CoV-2 and host-cell receptors due to ACE2 variants leads to progress in treatment strategies for COVID-19. The evidence accumulated in this study showed that ACE2 variants in different populations may be associated with the genetic susceptibility, symptoms, and outcome of SARS-CoV-2 infection.

SARS-Cov-2 Cycle Threshold Value and Olfactory Dysfunction in COVID-19 Patients.

Introduction: Considering the inconsistent results regarding the association between the severity and duration of olfactory dysfunction (OD), and the viral load in coronavirus disease 2019 (COVID-19) patients, we aimed to conduct this study. Materials and Methods: This is a prospective cohort study in which COVID-19 patients were evaluated for the initial cycle threshold value (Ct values) measured by the nasopharyngeal samples along with olfactory function measured by the University of Pennsylvania Smell Identification Test (UPSIT) within 2 months of COVID-19 onset. Results: Among 309 COVID-19 patients who were included in this study, 108 (34.9%), 112 (36.2%) and 89 (28.8%) were normosmic, hyposmic, and anosmic, respectively based on the UPSIT. The severity of COVID-19 and the rate of hospitalization were higher in anosmic patients (p<0.0001, and p<0.0001, respectively). Moreover, significant associations between the initial Ct value and the severity of OD at admission and follow-ups were detected (p<0.0001 and p<0.0001, respectively). Anosmic patients had higher Ct values in comparison with hyposmic (approx. 3-fold) and normosmic (approx. 12-fold) patients. The recovery rate after one- and two-month follow-ups was 47% and 84%, respectively. At the follow-ups, OD-recovered patients significantly had lower Ct values (mean Ct value: 27.79 ± 2 and 28.21 ± 2.08) in comparison with those who have not recovered yet (mean Ct value: 30.19 ± 3.36, and 33.6 ± 3.37) (p<0.0001, and p<0.0001, respectively). Conclusions: Ct value seems to be a significant factor not only in predicting OD severity in COVID-19 patients but also in the OD recovery duration. This finding may be helpful to investigate the underlying mechanisms of OD in COVID-19 patients.