Reclassifying variations of unknown significance in diseases affecting Saudi Arabia’s population reveal new associations

Introduction: Physicians face diagnostic dilemmas upon reports indicating disease variants of unknown significance (VUS). The most puzzling cases are patients with rare diseases, where finding another matched genotype and phenotype to associate their results is challenging. This study aims to prove the value of updating patient files with new classifications, potentially leading to better assessment and prevention.Methodology: We recruited retrospective phenotypic and genotypic data from King Saud Medical City, Riyadh, Kingdom of Saudi Arabia. Between September 2020 and December 2021, 1,080 patients’ genetic profiles were tested in a College of American Pathologists accredited laboratory. We excluded all confirmed pathogenic variants, likely pathogenic variants and copy number variations. Finally, we further reclassified 194 VUS using different local and global databases, employing in silico prediction to justify the phenotype–genotype association.Results: Of the 194 VUS, 90 remained VUS, and the other 104 were reclassified as follows: 16 pathogenic, 49 likely pathogenic, nine benign, and 30 likely benign. Moreover, most of these variants had never been observed in other local or international databases.Conclusion: Reclassifying the VUS adds value to understanding the causality of the phenotype if it has been reported in another family or population. The healthcare system should establish guidelines for re-evaluating VUS, and upgrading VUS should reflect on individual/family risks and management strategies

The Importance of Preventive Medicine in Family Practice: A Review of Current Guidelines and Recommendations

Prevention is seen as a critical topic in family practice. Primordial prevention, primary prevention, secondary prevention, tertiary prevention, and quaternary prevention are all part of this strategy to disease prevention. To avoid the formation and development of risk factors, primary prevention focuses on addressing the fundamental causes and social determinants of disease. Primary prevention is the practice of preventing illnesses before they arise via the use of treatments such as immunizations and health education. Secondary prevention focuses on illness identification and intervention as early as possible to avoid disease development. Tertiary prevention addresses illness outcomes by restoring health and offering rehabilitation. Finally, quaternary prevention seeks to safeguard patients against needless medical treatments and the harm caused by over-medicating. Risks frequently rise in tandem with frailty and comorbidities. In contrast, advantages frequently drop as life expectancy increases. Preventive management strategies should consider the patient's viewpoint and be mutually agreed upon. Healthcare providers must prioritize the deployment of preventive care services, even when clinical treatments are required, in order to overcome preventive care hurdles. Healthcare practitioners may play a critical role in illness prevention and contribute to family well-being by investing in preventive care and executing these measures

Druggable proteins influencing cardiac structure and function: Implications for heart failure therapies and cancer cardiotoxicity

Dysfunction of either the right or left ventricle can lead to heart failure (HF) and subsequent morbidity and mortality. We performed a genome-wide association study (GWAS) of 16 cardiac magnetic resonance (CMR) imaging measurements of biventricular function and structure. Cis-Mendelian randomization (MR) was used to identify plasma proteins associating with CMR traits as well as with any of the following cardiac outcomes: HF, non-ischemic cardiomyopathy, dilated cardiomyopathy (DCM), atrial fibrillation, or coronary heart disease. In total, 33 plasma proteins were prioritized, including repurposing candidates for DCM and/or HF: IL18R (providing indirect evidence for IL18), I17RA, GPC5, LAMC2, PA2GA, CD33, and SLAF7. In addition, 13 of the 25 druggable proteins (52%; 95% confidence interval, 0.31 to 0.72) could be mapped to compounds with known oncological indications or side effects. These findings provide leads to facilitate drug development for cardiac disease and suggest that cardiotoxicities of several cancer treatments might represent mechanism-based adverse effects

Identification of CSF3R Mutations in B-Lineage Acute Lymphoblastic Leukemia Using Comprehensive Cancer Panel and Next-Generation Sequencing

B-lineage acute lymphocytic leukemia (B-ALL) is characterized by different genetic aberrations at a chromosomal and gene level which are very crucial for diagnosis, prognosis and risk assessment of the disease. However, there is still controversial arguments in regard to disease outcomes in specific genetic abnormalities, e.g., 9p-deletion. Moreover, in absence of cytogenetic abnormalities it is difficult to predict B-ALL progression. Here, we use the advantage of Next-generation sequencing (NGS) technology to study the mutation landscape of 12 patients with B-ALL using Comprehensive Cancer Panel (CCP) which covers the most common mutated cancer genes. Our results describe new mutations in CSF3R gene including S661N, S557G, and Q170X which might be associated with disease progression

Impact of Clinical Pharmacist Running Anticoagulation Clinic in Saudi Arabia

Despite the effectiveness of warfarin in extended anticoagulation, its narrow therapeutic index requires frequent dose adjustments and careful patient monitoring. Thus, we aimed to evaluate the outcomes of clinical pharmacists’ intervention in warfarin therapy management in terms of International Normalized Ratio (INR) control, reduction of bleeding, and hospitalization in a tertiary care hospital. An observational retrospective cohort study was conducted on 96 patients taking warfarin therapy in a clinical pharmacist-led anticoagulation clinic. We observed that 39.6% of patients required dose adjustments at their first and second visits. However, dose adjustments during the third, fourth, and fifth weeks were required at 31.1%, 20.8%, and 4.2%, respectively, to achieve INR levels. We also observed that 36.46% of the patients attained the target INR at baseline, which was increased over the first week to the fifth week to 57.29%, 61.46%, 61.46%, 68.75%, and 85.42%, respectively. No one reported the ADR between the third and fifth weeks. Based on our findings, the study strongly suggests that pharmacists’ interventions can improve the health-related quality of life of patients undergoing warfarin therapy. Thus, competent pharmacy personnel must be a priority in both usual patient care and critical care among primary care networks

LoFTK: a framework for fully automated calculation of predicted Loss-of-Function variants and genes

Abstract Background Loss-of-Function (LoF) variants in human genes are important due to their impact on clinical phenotypes and frequent occurrence in the genomes of healthy individuals. The association of LoF variants with complex diseases and traits may lead to the discovery and validation of novel therapeutic targets. Current approaches predict high-confidence LoF variants without identifying the specific genes or the number of copies they affect. Moreover, there is a lack of methods for detecting knockout genes caused by compound heterozygous (CH) LoF variants. Results We have developed the Loss-of-Function ToolKit (LoFTK), which allows efficient and automated prediction of LoF variants from genotyped, imputed and sequenced genomes. LoFTK enables the identification of genes that are inactive in one or two copies and provides summary statistics for downstream analyses. LoFTK can identify CH LoF variants, which result in LoF genes with two copies lost. Using data from parents and offspring we show that 96% of CH LoF genes predicted by LoFTK in the offspring have the respective alleles donated by each parent. Conclusions LoFTK is a command-line based tool that provides a reliable computational workflow for predicting LoF variants from genotyped and sequenced genomes, identifying genes that are inactive in 1 or 2 copies. LoFTK is an open software and is freely available to non-commercial users at https://github.com/CirculatoryHealth/LoFTK

Prevalence and Disease Expression of Pathogenic and Likely Pathogenic Variants Associated With Inherited Cardiomyopathies in the General Population

BACKGROUND: Pathogenic and likely pathogenic variants associated with arrhythmogenic right ventricular cardiomyopathy (ARVC), dilated cardiomyopathy (DCM), and hypertrophic cardiomyopathy (HCM) are recommended to be reported as secondary findings in genome sequencing studies. This provides opportunities for early diagnosis, but also fuels uncertainty in variant carriers (G+), since disease penetrance is incomplete. We assessed the prevalence and disease expression of G+ in the general population. METHODS: We identified pathogenic and likely pathogenic variants associated with ARVC, DCM and/or HCM in 200 643 UK Biobank individuals, who underwent whole exome sequencing. We calculated the prevalence of G+ and analyzed the frequency of cardiomyopathy/heart failure diagnosis. In undiagnosed individuals, we analyzed early signs of disease expression using available electrocardiography and cardiac magnetic resonance imaging data. RESULTS: We found a prevalence of 1:578, 1:251, and 1:149 for pathogenic and likely pathogenic variants associated with ARVC, DCM and HCM respectively. Compared with controls, cardiovascular mortality was higher in DCM G+ (odds ratio 1.67 [95% CI 1.04; 2.59], P =0.030), but similar in ARVC and HCM G+ ( P ≥0.100). Cardiomyopathy or heart failure diagnosis were more frequent in DCM G+ (odds ratio 3.66 [95% CI 2.24; 5.81], P =4.9×10 −7 ) and HCM G+ (odds ratio 3.03 [95% CI 1.98; 4.56], P =5.8×10 −7 ), but comparable in ARVC G+ ( P =0.172). In contrast, ARVC G+ had more ventricular arrhythmias ( P =3.3×10 −4 ). In undiagnosed individuals, left ventricular ejection fraction was reduced in DCM G+ ( P =0.009). CONCLUSIONS: In the general population, pathogenic and likely pathogenic variants associated with ARVC, DCM, or HCM are not uncommon. Although G+ have increased mortality and morbidity, disease penetrance in these carriers from the general population remains low (1.2–3.1%). Follow-up decisions in case of incidental findings should not be based solely on a variant, but on multiple factors, including family history and disease expression

APPROACH TO HEADACHE IN THE ER

Introduction: Acute severe headache is always serious and demands care and usually patients present to to the emergency department (ED). There are many medications available, and many hazards to be avoided, both regarding the diagnosis and the management. It represents an agonizingly painful and disturbing event for the patients, families, as well as the medical team. Usually, these patients have done many methods with expert doctors to no benefit. Inpatient assessment and management could be helpful in some patients. The major diagnostic difficulties in diagnosing the cases of severe acute headache in the ED are misdiagnosis of primary headache syndromes and undiagnosed secondary causes of headache. Missing the correct diagnosis will decrease the chances of correct management. Red flags such as meningismus, fever, neurologic signs, and concurrent medical illnesses should raise the attention. Aim of work: In this review, we will discuss the most recent evidence regarding the recent approach to the emergency management of patients with headache. We will also discuss options for the management. Methodology: We did a systematic search for approach to headache in the emergency department using PubMed search engine (http://www.ncbi.nlm.nih.gov/) and Google Scholar search engine (https://scholar.google.com). We only included full articles. Conclusions: Most cases of headache are evaluated in EDs have migraine, however some of them have other primary and secondary headache disorders that must be excluded. When this is performed, many medications are available to relief of headache, involving parenteral ketorolac, neuroleptic antiemetics, DHE, triptans, and magnesium sulfate. Opioids, while commonly employed, are generally less useful, and may lead to readmission to the ED. Even though most chronic headache problems could be treated in the outpatient setting, inpatient management can offer many benefits, especially in patients who are overusing medications. Intravenous DHE has good evidence for efficacy. Few commonly proposed managements plans for acute headache relief in the ED have been studied in that setting; similarly, most inpatient IV treatment protocols are not clearly established to be effective. Problems to further research include lack of funding and individual differences between refractory headache patients, making comparison studies difficult. Key words: Headache, emergency department, management