Abdulrahman Alasiri

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

Publisher: Cold Spring Harbor Laboratory

Date: 10-08-2021

DOI: 10.1101/2021.08.09.455694

Abstract: 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 in iduals. 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. We have developed the Loss-of-Function ToolKit (LoFTK), which allows efficient and automated prediction of LoF variants from both genotyped 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. LoFTK is an open source software and is freely available to non-commercial users at github.com/CirculatoryHealth/LoFTK j.vansetten@umcutrecht.nl Supplementary data are available at Bioinformatics online.

Learning to teach from the student’s point of view: an ethical call from transformative learning

Publisher: Informa UK Limited

Date: 16-09-2020

DOI: 10.1080/14623943.2020.1821628

Analysis of CCR5 gene polymorphisms in 321 healthy Saudis using Next Generation Sequencing

Publisher: Elsevier BV

Date: 04-2017

DOI: 10.1016/J.HUMIMM.2017.03.003

Abstract: To investigate the extent of CCR5 polymorphism in the healthy Saudi population. A total of 321 healthy Saudi in iduals were sequenced using the ion Ampliseq™ Exome kit (Life Technologies, USA) on genomic DNA following manufacturer's protocol. Whole Exome Sequencing (WES) reads were aligned to the human reference genome (hg19 build) with Torrent Suite Software (v5.0.2) and the variants were called using the Torrent Variant Caller plugin (v5.0) and imported into Ion Reporter Server (v5.0) for the annotation. CCR5 coding exons variants were filtered and checked against the NHLBI GO Exome Sequencing Project (NHLBI), NCBI Reference dbSNPs database, 1000 genomes and Exome Aggregation Consortium datasets (ExAC). A total of 475 variants were identified. Table 1 shows polymorphisms/mutations detected within exons that introduced an amino acid change, deletion or copy number variants (CNV). Three mutations are predicted to influence CCR5 function, including the 32bp deletion (Rs333). Four polymorphisms were detected, plus two CNV. This is the first report on sequencing the full CCR5 gene using NGS in the Saudi population. Here we demonstrate seven polymorphisms/mutations that were reported before. All were detected within very low frequency including the delta 32 mutation. However, we report for the first time copy number variants at two CCR5 gene locations 45072265 and 38591712.

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

Publisher: MDPI AG

Date: 27-08-2021

DOI: 10.3390/GENES12091326

Abstract: 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.

Cardiac MRI to guide heart failure and atrial fibrillation drug discovery: a Mendelian randomization analysis

Publisher: Research Square Platform LLC

Date: 02-02-2023

DOI: 10.21203/RS.3.RS-2449265/V1

Abstract: Background drug development and disease prevention of heart failure (HF) and atrial fibrillation (AF) are impeded by a lack of robust early-stage surrogates. We determined to what extent cardiac magnetic resonance (CMR) measurements act as surrogates for the development of HF or AF in healthy in iduals. Methods Genetic data was sourced on the association with 22 atrial and ventricular CMR measurements. Mendelian randomization was used to determine CMR associations with atrial fibrillation (AF), heart failure (HF), non-ischemic cardiomyopathy (CMP), and dilated cardiomyopathy (DCM). Additionally, for the CMR surrogates of AF and HF, we explored their association with non-cardiac traits. Results In total we found that 9 CMR measures were associated with the development of HF, 7 with development of non-ischemic CMP, 6 with DCM, and 12 with AF. biventricular ejection fraction (EF), biventricular or end-systolic volumes (ESV) and left-ventricular (LV) end diastolic volume (EDV) were associated with all 4 cardiac outcomes. Increased LV-MVR (mass to volume ratio) affected HF (odds ratio (OR) 0.83, 95%CI 0.79 0.88), and DCM (OR 0.26, 95%CI 0.20 0.34. We were able to identify 9 CMR surrogates for HF and/or AF (including LV-MVR, biventricular EDV, ESV, and right-ventricular EF) which associated with non-cardiac traits such as blood pressure, lung function traits, BMI, cardioembolic stroke, and late-onset Alzheimer’s disease. Conclusion CMR measurements may act as surrogate endpoints for the development of HF (including non-ischemic CMP and DCM) or AF. Additionally, we show that changes in cardiac function and structure measured through CMR, may affect diseases of other organs leading to lung disease or late-onset Alzheimer’s disease.

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

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 12-2022

DOI: 10.1161/CIRCGEN.122.003704

Abstract: 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. We identified pathogenic and likely pathogenic variants associated with ARVC, DCM and/or HCM in 200 643 UK Biobank in iduals, who underwent whole exome sequencing. We calculated the prevalence of G+ and analyzed the frequency of cardiomyopathy/heart failure diagnosis. In undiagnosed in iduals, we analyzed early signs of disease expression using available electrocardiography and cardiac magnetic resonance imaging data. 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 in iduals, left ventricular ejection fraction was reduced in DCM G+ ( P =0.009). 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.

Atypical influenza A(H1N1)pdm09 strains caused an influenza virus outbreak in Saudi Arabia during the 2009–2011 pandemic season

Publisher: Elsevier BV

Date: 07-2019

DOI: 10.1016/J.JIPH.2019.01.067

Abstract: The triple assortment influenza A(H1N1) virus emerged in spring 2009 and disseminated worldwide, including Saudi Arabia. This study was carried out to characterize Saudi influenza isolates in relation to the global strains and to evaluate the potential role of mutated residues in transmission, adaptation, and the pathogenicity of the virus. Nasopharyngeal s les (n = 6492) collected between September 2009 to March 2011 from patients with influenza-like illness were screened by PCR for influenza A(H1N1). Phylogenetic and Molecular evolutionary analysis were carried out to place the Saudi strains in relation to the global strains followed by Mutation analysis of surface and internal proteins. Concatenated whole-genome phylogenetic analysis along with hemagglutinin (HA) signature changes, that is, Aspartic Acid (D) at position 187, P83S, S203T, and R223Q confirmed that the Saudi strains belong to the antigenic category of A/California/07/2009. However, phylogenetic analysis revealed unusual strains of A(H1N1) circulating in Saudi Arabia, not belonging to any of known clades, appearing in five distinct groups well supported by group-specific mutations and novel mutation complexes. These cases had characteristic inter- and intragroup substitution patterns while few of their closest matches showed up as sporadic cases the world over. Specific mutation patterns were detected within the functional domains of internal proteins PB2, PB1, PA, NP, NS1, and M2 having a putative role in viral fitness and virulence. Bayesian coalescent MCMC analysis revealed that Saudi strains belonged to cluster 2 of A(H1N1)pdm09 and spread a month later as compared to other strains of this cluster. Influenza outbreak in Saudi Arabia during 2009-2011 was caused by atypical strains of influenza A(H1N1)pdm09, probably introduced in this community on multiple occasions. To understand the antigenic significance of these novel point mutations and mutation complexes require functional studies, which will be crucial for risk assessment of emergent strains and defining infection control measures.

Prevalence and disease expression of pathogenic and likely pathogenic variants associated with inherited cardiomyopathies in the general population

Publisher: Cold Spring Harbor Laboratory

Date: 06-01-2022

DOI: 10.1101/2022.01.06.22268837

Abstract: 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. We identified pathogenic and likely pathogenic variants associated with ARVC, DCM and/or HCM in 200,643 UK Biobank in iduals, who underwent whole exome sequencing. We calculated the prevalence of G+ and analysed the frequency of cardiomyopathy/heart failure diagnosis. In undiagnosed in iduals, we analysed early signs of disease expression using available electrocardiography and cardiac magnetic resonance imaging data. 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 to controls, cardiovascular mortality was higher in DCM G+ (OR 1.67 [95% CI 1.04 .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+ (OR 3.66 [95% CI 2.24 .81], p=4.9×10 −7 ) and HCM G+ (OR 3.03 [95% CI 1.98 .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 in iduals, left ventricular ejection fraction was reduced in DCM G+ (p=0.009). 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.

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

Publisher: American Association for the Advancement of Science (AAAS)

Date: 28-04-2023

DOI: 10.1126/SCIADV.ADD4984

Abstract: 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.

Targeted SLC19A3 gene sequencing of 3000 Saudi newborn: a pilot study toward newborn screening

Publisher: Wiley

Date: 26-09-2019

DOI: 10.1002/ACN3.50898

La Trobe University

Location: Australia

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Bond University

Location: Australia

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University Medical Center Utrecht

Location: Netherlands

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King Abdullah International Medical Research Center

Location: Saudi Arabia

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