Browsing by Author "Tayoun, Ahmad Abou"

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Association of Dromedary Camels and Camel Ticks with Reassortant Crimean-Congo Hemorrhagic Fever Virus, United Arab Emirates
(2021) Ramaswamy, Sathiskumar; Karuvantevida, Noushad; Tayoun, Ahmad Abou; Loney, Tom; Nowotny, Norbert
Abstract: We previously detected a potentially novel reassortant of Crimean-Congo hemorrhagic fever virus in camels at the largest livestock market in the United Arab Emirates. A broader survey of large mammals at the site indicated zoonotic transmission is associated with dromedaries and camel ticks. Seroprevalence in cattle, sheep, and goats is minimal.
Case Report: CMV-Associated Congenital Nephrotic Syndrome
(2020) Tayoun, Ahmad Abou
Background: Congenital nephrotic syndrome, historically defined by the onset of large proteinuria during the first 3 months of life, is a rare clinical disorder, generally with poor outcome. It is caused by pathogenic variants in genes associated with this syndrome or by fetal infections disrupting podocyte and/or glomerular basement membrane integrity. Here we describe an infant with congenital CMV infection and nephrotic syndrome that failed to respond to targeted antiviral therapy. Case and literature survey highlight the importance of the “tetrad” of clinical, virologic, histologic, and genetic workup to better understand the pathogenesis of CMV-associated congenital and infantile nephrotic syndromes. Case Presentation: A male infant was referred at 9 weeks of life with progressive abdominal distention, scrotal edema, and vomiting. Pregnancy was complicated by oligohydramnios and pre-maturity (34 weeks). He was found to have nephrotic syndrome and anemia, normal platelet and white blood cell count, no splenomegaly, and no syndromic features. Diagnostic workup revealed active CMV infection (positive CMV IgM/PCR in plasma) and decreased C3 and C4. Maternal anti-CMV IgG was positive, IgM negative. Kidney biopsy demonstrated focal mesangial proliferative and sclerosing glomerulonephritis with few fibrocellular crescents, interstitial T- and B-lymphocyte infiltrates, and fibrosis/tubular atrophy. Immunofluorescence was negative. Electron microscopy showed diffuse podocyte effacement, but no cytomegalic inclusions or endothelial tubuloreticular arrays. After 4 weeks of treatment with valganciclovir, plasma and urine CMV PCR were negative, without improvement of the proteinuria. Unfortunately, the patient succumbed to fulminant pneumococcal infection at 7 months of age. Whole exome sequencing and targeted gene analysis identified a novel homozygous, pathogenic variant (2071+1G>T) in NPHS1. Literature Review and Discussion: The role of CMV infection in isolated congenital nephrotic syndrome and the corresponding pathological changes are still debated. A search of the literature identified only three previous reports of infants with congenital nephrotic syndrome and evidence of CMV infection, who also underwent kidney biopsy and genetic studies. Conclusion: Complete workup of congenital infections associated with nephrotic syndrome is warranted for a better understanding of their pathogenesis (“diagnostic triad” of viral, biopsy, and genetic studies).Molecular testing is essential for acute and long-term prognosis and treatment plan.
Clinical evaluation and etiologic diagnosis of hearing loss: A clinical practice resource of the American College of Medical Genetics and Genomics (ACMG)
(2022-07) Tayoun, Ahmad Abou
Abstract: Hearing loss is a common and complex condition that can occur at any age, can be inherited or acquired, and is associated with a remarkably wide array of etiologies. The diverse causes of hearing loss, combined with the highly variable and often overlapping presentations of different forms of hearing loss, challenge the ability of traditional clinical evaluations to arrive at an etiologic diagnosis for many deaf and hard-of-hearing individuals. However, identifying the etiology of hearing loss may affect clinical management, improve prognostic accuracy, and refine genetic counseling and assessment of the likelihood of recurrence for relatives of deaf and hard-of-hearing individuals. Linguistic and cultural identities associated with being deaf or hardof-hearing can complicate access to and the effectiveness of clinical care. These concerns can be minimized when genetic and other health care services are provided in a linguistically and culturally sensitive manner. This clinical practice resource offers information about the frequency, causes, and presentations of hearing loss and suggests approaches to the clinical and genetic evaluation of deaf and hard-of-hearing individuals aimed at identifying an etiologic diagnosis and providing informative and effective patient education and genetic counseling.
Correction: Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19
(2024-01) Tayoun, Ahmad Abou
Abstract: Background: We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15–20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in ~ 80% of cases. Methods: We report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded. Results: No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5–528.7, P = 1.1 × 10−4) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR = 3.70[95%CI 1.3–8.2], P = 2.1 × 10−4). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR = 19.65[95%CI 2.1–2635.4], P = 3.4 × 10−3), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR = 4.40[9%CI 2.3–8.4], P = 7.7 × 10−8). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD] = 43.3 [20.3] years) than the other patients (56.0 [17.3] years; P = 1.68 × 10−5). Conclusions: Rare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old.
Detection of copy number variants and genes by chromosomal microarray in an Emirati neurodevelopmental disorders cohort
(2022) Nassir, Nasna; Al Shaibani, Shaiban; Ahmed, Awab; Tayoun, Ahmad Abou; Uddin, Mohammed; Albanna, Ammar
Abstract: Copy number variations (CNVs) are highly implicated in the etiology of neurodevelopmental disorders (NDDs), and chromosomal microarray analysis (CMA) has been recommended as a frst-tier test for many NDDs. We undertook a study to identify clinically relevant CNVs and genes in an ethnically homogenous population of the United Arab Emirates. We genotyped 98 patients with NDDs using genome-wide chromosomal microarray analysis, and observed 47.1% deletion and 52.9% duplication CNVs, of which 11.8% are pathogenic, 23.5% are likely pathogenic, and 64.7% VOUS. The average size of copy number losses (3.9 Mb) was generally higher than of gains (738.4 kb). Analysis of VOUS CNVs for constrained genes (enrichment for brain critical exons and high pLI genes) yielded 7 unique genes. Among these 7 constrained genes, we propose FNTA and PXK as potential candidate genes for neurodevelopmental disorders, which warrants further investigation. Thirty-two overlapping CNVs (Decipher and ClinVar) containing the FNTA gene were previously identifed in NDD patients and 6 overlapping CNVs (Decipher and ClinVar) containing the PXK gene were previously identifed in NDD patients. Our study supports the utility of CMA for CNV profling which aids in precise genetic diagnosis and its integration into therapeutics and management of NDD patients.
Diagnosing Cornelia de Lange syndrome and related neurodevelopmental disorders using RNA sequencing
(2020) Tayoun, Ahmad Abou
Purpose: Neurodevelopmental disorders represent a frequent indication for clinical exome sequencing. Fifty percent of cases, however, remain undiagnosed even upon exome reanalysis. Here we show RNA sequencing (RNA-seq) on human B-lymphoblastoid cell lines (LCL) is highly suitable for neurodevelopmental Mendelian gene testing and demonstrate the utility of this approach in suspected cases of Cornelia de Lange syndrome (CdLS). Methods: Genotype–Tissue Expression project transcriptome data for LCL, blood, and brain were assessed for neurodevelopmental Mendelian gene expression. Detection of abnormal splicing and pathogenic variants in these genes was performed with a novel RNA-seq diagnostic pipeline and using a validation CdLS-LCL cohort (n = 10) and test cohort of patients who carry a clinical diagnosis of CdLS but negative genetic testing (n = 5). Results: LCLs share isoform diversity of brain tissue for a large subset of neurodevelopmental genes and express 1.8-fold more of these genes compared with blood (LCL, n = 1706; whole blood, n = 917). This enables testing of more than 1000 genetic syndromes. The RNA-seq pipeline had 90% sensitivity for detecting pathogenic events and revealed novel diagnoses such as abnormal splice products in NIPBL and pathogenic coding variants in BRD4 and ANKRD11. Conclusion: The LCL transcriptome enables robust frontline and/ or reflexive diagnostic testing for neurodevelopmental disorders.
Effect of Common Medications on the Expression of SARS-CoV-2 Entry Receptors in Kidney Tissue
(2020) Tayoun, Ahmad Abou; Loney, Tom; Uddin, Mohammed; Senok, Abiola; Al Heialy, Saba; Alsheikh-Ali, Alawi
Abstract: Besides the respiratory system, severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection was shown to affect other essential organs such as the kidneys. Early kidney involvement during the course of infection was associated with worse outcomes, which could be attributed to the direct SARS-CoV-2 infection of kidney cells. In this study, the effect of commonly used medications on the expression of SARS-CoV-2 receptor, angiotensin-converting enzyme (ACE)2, and TMPRSS2 protein in kidney tissues was evaluated. This was done by in silico analyses of publicly available transcriptomic databases of kidney tissues of rats treated with multiple doses of commonly used medications. Of 59 tested medications, 56% modified ACE2 expression, whereas 24% modified TMPRSS2 expression. ACE2 was increased with only a few of the tested medication groups, namely the renin-angiotensin inhibitors, such as enalapril, antibacterial agents, such as nitrofurantoin, and the proton pump inhibitor, omeprazole. The majority of the other medications decreased ACE2 expression to variable degrees with allopurinol and cisplatin causing the most noticeable downregulation. The expression level of TMPRSS2 was increased with a number of medications, such as diclofenac, furosemide, and dexamethasone, whereas other medications, such as allopurinol, suppressed the expression of this gene. The prolonged exposure to combinations of these medications could regulate the expression of ACE2 and TMPRSS2 in a way that may affect kidney susceptibility to SARS-CoV-2 infection. Data presented here suggest that we should be vigilant about the potential effects of commonly used medications on kidney tissue expression of ACE2 and TMPRSS2.
Genetic and Clinical Characteristics of Patients in the Middle East With Multisystem Inflammatory Syndrome in Children
(2022) Uddin, Mohammed; Al Suwaidi, Hanan; Al-Hammadi, Suleiman; Loney, Tom; Nowotny, Norbert; Alsheikh-Ali, Alawi; Tayoun, Ahmad Abou
Importance: Clinical, genetic, and laboratory characteristics of Middle Eastern patients with multisystem in‐ flammatory syndrome in children (MIS-C) have not yet been documented. Objective: To assess the genetic and clinical characteristics of patients with MIS-C of primarily Arab and Asian origin. Design, Setting, and Participants : A prospective, multicenter cohort study was conducted from September 1, 2020, to August 31, 2021, in the United Arab Emirates and Jordan. Forty-five patients with MIS-C and a matched control group of 25 healthy children with a confirmed SARS-CoV-2 infection status were re‐ cruited. Whole exome sequencing in all 70 participants was performed to identify rare, likely deleterious variants in patients with MIS-C and to correlate genetic findings with the clinical course of illness. Exposures: SARS-CoV-2. Main Outcomes and Measures: Fever, organ system complications, laboratory biomarkers, whole exome sequencing findings, treatments, and clinical outcomes were measured. The Mann-Whitney U test was used to as‐ sess the association between genetic variants and MIS-C attributes. The Fisher exact test was used to compute the genetic burden in MIS-C relative to controls. Results: A total of 45 patients with MIS-C (23 [51.1%] male; 30 [66.7%] of Middle Eastern origin; mean [SD] age, 6.7 [3.6] years) and 25 controls (17 [68.0%] male; 24 [96.0%] of Middle Eastern ori‐ gin; mean [SD] age 7.4 [4.0] years) participated in the study. Key inflammatory markers were significantly dysregulated in all patients with MIS-C. Mucocutaneous and gastrointestinal mani‐ festations were each reported in 36 patients (80.0%; 95% CI, 66.1%-89.1%), cardiac findings were reported in 22 (48.9%; 95% CI, 35.0%-63.0%), and neurologic findings were reported in 14 (31.1%; 95% CI, 19.5%-45.6%). Rare, likely deleterious heterozygous variants in immunerelated genes, including TLR3, TLR6, IL22RA2, IFNB1, and IFNA6, were identified in 19 patients (42.2%; 95% CI, 29.0%-56.7%), of whom 7 had multiple variants. There was higher enrichment of genetic variants in patients relative to controls (29 vs 3, P < .001). Patients with those vari‐ ants tended to have earlier disease onset (7 patients [36.8%; 95% CI, 19.1%-58.9%] with ge‐ netic findings vs 2 [7.7%; 95% CI, 2.1%-24.1%] without genetic findings were younger than 3 years at onset) and resistance to treatment (8 patients [42.1%; 95% CI, 23.1%-63.7%] with ge‐ netic findings vs 3 patients [11.5%; 95% CI, 4.0%-29.0%] without genetic findings received 2 doses of intravenous immunoglobulin). Conclusions and Relevance: The results of this cohort study suggest that rare, likely deleterious genetic variants may con‐ tribute to MIS-C disease. This finding paves the way for additional studies with larger, diverse populations to fully characterize the genetic contribution to this new disease entity.
Genetic determinants of severe COVID 19 in young Asian and Middle Eastern patients: a case series
(2023) Badla, Beshr Abdulaziz; Hanifa, Mohamed Samer; Al Suwaidi, Hanan; Nowotny, Norbert; Popatia, Rizwana; Alsheikh-Ali, Alawi; Loney, Tom; Tayoun, Ahmad Abou
Abstract: Studies of genetic factors associated with severe COVID-19 in young adults have been limited in non-Caucasian populations. Here, we clinically characterize a case series of patients with COVID19, who were otherwise healthy, young adults (N= 55; mean age 34.1 ±SD 5.0 years) from 16 Asian, Middle Eastern, and North African countries. Using whole exome sequencing, we identify rare, likely deleterious variants afecting 16 immune-related genes in 17 out of 55 patients (31%), including 7 patients (41% of all carriers or 12.7% of all patients) who harbored multiple such variants mainly in interferon and toll-like receptor genes. Protein network analysis as well as transcriptomic analysis of nasopharyngeal swabs from an independent COVID-19 cohort (N= 50; 42% Asians and 22% Arabs) revealed that most of the altered genes, as identifed by whole exome sequencing, and the associated molecular pathways were signifcantly altered in COVID-19 patients. Genetic variants tended to be associated with mortality, intensive care admission, and ventilation support. Our clinical cases series, genomic and transcriptomic fndings suggest a possible role for interferon pathway genes in severe COVID-19 and highlight the importance of extending genetic studies to diverse populations to better understand the human genetics of disease.
The Genomic Landscape of Pediatric Rheumatology Disorders in the Middle East
(2020) Tayoun, Ahmad Abou
Abstract: Genetic investigations for patients with pediatric rheumatological disorders have been limited to classic genotyping testing, mainly MEFV hotspot mutation analysis, for periodic fever. Therefore, the landscape and clinical utility of comprehensive genomic investigations for a wider range of pediatric rheumatological disorders have not been fully characterized in the Middle East. Here seventy-one pediatric patients, of diverse Arab origins, were clinically and genetically assessed for a spectrum of rheumatology-related disease at the only dedicated tertiary children’s hospital in the United Arab Emirates. Clinical genomic investigations included mainly (76%) next generation sequencing-based gene panels and whole exome sequencing, along with rapid sequencing in the intensive care unit (ICU) and urgent setting. The overall positive yield was 46.5% (16.7%-66.7% for specific indications), while dual diagnoses were made in 2 cases (3%). Although the majority (21/33, 64%) of positive findings involved the MEFV gene, the remaining (12/33, 36%) alterations were attributed to eleven other genes/loci. Copy number variants contributed substantially (5/33, 15.2%) to the overall diagnostic yield. Sequencing-based testing, specifically rapid sequencing, had high positive rate and delivered timely results. Genetic findings guided clinical management plans and interventions in most cases (27/33, 81.8%). We highlight unique findings and provide additional evidence that heterozygous loss of function of the IFIH1 gene increases susceptibility to recurrent fevers. Our study highlights the importance of comprehensive genomic investigations in patients with pediatric rheumatological disorders, and provides new insights into the pathogenic variation landscape in this group of disorders.
Genotype-phenotype correlation identified a novel SARS-CoV-2 variant possibly linked to severe disease
(2021) Loney, Tom; Al Suwaidi, Hanan; Uddin, Mohammed; Senok, Abiola; Nowotny, Norbert; Alsheikh-Ali, Alawi; Tayoun, Ahmad Abou
Abstract: The geographic location and heterogeneous multi-ethnic population of Dubai (United Arab Emirates; UAE) provide a unique setting to explore the global molecular epidemiology of SARS-CoV-2 and relationship between different viral strains and disease severity. We systematically selected (i.e. every 100th individual in the central Dubai COVID-19 database) 256 patients by age, sex, disease severity and month to provide a representative sample of laboratory-confirmed COVID-19 patients (nasopharyngeal swab PCR positive) during the first wave of the UAE outbreak (January to June 2020). Sociodemographic and clinical data were extracted from medical records and full SARS-CoV-2 genome sequences extracted from nasopharyngeal swabs were analysed. Older age was significantly associated with COVID-19-associated hospital admission and mortality. Overweight/obese or diabetic patients were 3–4 times more likely to be admitted to hospital and intensive care unit (ICU). Sequencing data showed multiple independent viral introductions into the UAE from Europe, Iran and Asia (29 January–18 March), and these early strains seeded significant clustering consistent with almost exclusive community-based transmission between April and June 2020. Majority of sequenced strains (N = 60, 52%) were from the European cluster consistent with the higher infectivity rates associated with the D614G mutation carried by most strains in this cluster. A total of 986 mutations were identified in 115 genomes, 272 were unique (majority were missense, n = 134) and 20/272 mutations were novel. A missense (Q271R) and synonymous (R41R) mutation in the S and N proteins, respectively, were identified in 2/27 patients with severe COVID-19 but not in patients with mild or moderate disease (0/86; p = .05, Fisher's Exact Test). Both patients were women (51–64 years) with no significant underlying health conditions. The same two mutations were identified in a healthy 37-year-old Indian man who was hospitalized in India due to COVID-19. Our findings provide evidence for continued communitybased transmission of the European strains in the Dubai population and highlight new mutations that might be associated with severe disease in otherwise healthy adults.
Host transcriptomic profiling of COVID-19 patients with mild, moderate, and severe clinical outcomes
(2021) Uddin, Mohammed; Loney, Tom; Nowotny, Norbert; Alsuwaidi, Hanan; Alsheikh-Ali, Alawi; Tayoun, Ahmad Abou
Abstract: Characterizing key molecular and cellular pathways involved in COVID-19 is essential for disease prognosis and management. We perform shotgun transcriptome sequencing of human RNA obtained from nasopharyngeal swabs of patients with COVID-19, and identify a molecular signature associated with disease severity. Specifically, we identify globally dysregulated immune related pathways, such as cytokinecytokine receptor signaling, complement and coagulation cascades, JAK-STAT, and TGF- b signaling pathways in all, though to a higher extent in patients with severe symptoms. The excessive release of cytokines and chemokines such as CCL2, CCL22, CXCL9 and CXCL12 and certain interferons and interleukins related genes like IFIH1, IFI44, IFIT1 and IL10 were significantly higher in patients with severe clinical presentation compared to mild and moderate presentations. Differential gene expression analysis identified a small set of regulatory genes that might act as strong predictors of patient outcome. Our data suggest that rapid transcriptome analysis of nasopharyngeal swabs can be a powerful approach to quantify host molecular response and may provide valuable insights into COVID-19 pathophysiology.
MERS-CoV Found in Hyalomma dromedarii Ticks Attached to Dromedary Camels at a Livestock Market, United Arab Emirates, 2019
(2023) Loney, Tom; Mazrooei, Hessa; Karuvantevida, Noushad; Tayoun, Ahmad Abou; Alsheikh-Ali, Alawi; Nowotny, Norbert
Abstract: The main mode of transmission of Middle East respiratory syndrome-related coronavirus (MERS-CoV) between dromedaries is likely via the respiratory route. However, there must be other modes to explain how the infection is brought to MERS-CoV-negative closed herds, such as transmission by ticks. Here, we present a study performed at three different locations in the United Arab Emirates (UAE) involving 215 dromedary camels (Camelus dromedarius) and the ticks attached to them. We tested the camels and ticks via RT-(q)PCR for the presence of MERS-CoV nucleic acids, as well as flaviviruses that may be present in the region (e.g., Alkhumra hemorrhagic fever virus). Camel sera were additionally analyzed for evidence of previous exposure to MERS-CoV. In total, 8 out of 242 tick pools were positive for MERS-CoV RNA (3.3%; Ct 34.6–38.3), 7 of which contained Hyalomma dromedarii ticks, and one contained a Hyalomma sp. tick (species not identified). All of the virus-positive ticks’ host camels were also positive for MERS-CoV RNA in their nasal swab samples. Short sequences established in the N gene region from two positive tick pools were identical to viral sequences from their hosts’ nasal swabs. In total, 59.3% of dromedaries at the livestock market had MERS-CoV RNA in their nasal swabs (Ct 17.7–39.5). While dromedaries at all locations were negative for MERS-CoV RNA in their serum samples, antibodies were detected in 95.2% and 98.7% of them (tested by ELISA and indirect immunofluorescence test, respectively). Given the probably transient and/or low level of MERS-CoV viremia in dromedaries and the rather high Ct values observed in the ticks, it seems unlikely that Hyalomma dromedarii is a competent vector for MERS-CoV; however, its role in mechanical or fomite transmission between camels should be investigated.
MERS-CoV in sheep, goats, and cattle, United Arab Emirates, 2019: Virological and serological investigations reveal an accidental spillover from dromedaries
(2021) Loney, Tom; Tayoun, Ahmad Abou
Abstract: The recent COVID-19 pandemic has demonstrated again the global threat posed by emerging zoonotic coronaviruses. During the past two decades alone, humans have experienced the emergence of several coronaviruses, such as SARS-CoV in 2003, MERS-CoV in 2012, and SARS-CoV-2 in 2019. To date, MERS-CoV has been detected in 27 countries, with a case fatality ratio of approximately 34.5 %. Similar to other coronaviruses, MERS-CoV presumably originated from bats; however, the main reservoir and primary source of human infections are dromedary camels. Other species within the Camelidae family, such as Bactrian camels, alpacas, and llamas, seem to be susceptible to the infection as well, although to a lesser extent. In contrast, susceptibility studies on sheep, goats, cattle, pigs, chickens, and horses obtained divergent results. In the present study, we tested nasal swabs and/or sera from 55 sheep, 45 goats, and 52 cattle, collected at the largest livestock market in the United Arab Emirates, where dromedaries are also traded, for the presence of MERS-CoV nucleic acid by RT-qPCR and for specific antibodies by immunouorescence assay (IFA). All sera were negative for MERS-CoV-reactive antibodies, but the nasal swab of one sheep (1.8 %) was positive for MERS-CoV nucleic acid. Next generation sequencing (NGS) of the complete N gene of the sheep-derived MERS-CoV revealed >99 % nucleotide identity to MERS-CoV sequences of five dromedaries in nearby pens and to three reference sequences. The NGS sequence of the sheep-derived MERS-CoV was confirmed by conventional RT-PCR of a part of the N gene and subsequent Sanger sequencing. All MERS-CoV sequences clustered within clade B, lineage 5. In conclusion, our study shows that non-camelid livestock, such as sheep, goats, and cattle do not play a major role in MERS-CoV epidemiology. The one sheep that tested positive most likely reflects an accidental viral spillover event from infected dromedaries in nearby pens.
Middle Eastern Genetic Variation Improves Clinical Annotation of the Human Genome
(2022) Tayoun, Ahmad Abou
Abstract: Genetic variation in populations of Middle Eastern origin remains highly underrepresented in most comprehensive genomic databases. This underrepresentation hampers the functional annotation of the human genome and challenges accurate clinical variant interpretation. To highlight the importance of capturing genetic variation in the Middle East, we aggregated whole exome and genome sequencing data from 2116 individuals in the Middle East and established the Middle East Variation (MEV) database. Of the high-impact coding (missense and loss of function) variants in this database, 53% were absent from the most comprehensive Genome Aggregation Database (gnomAD), thus representing a unique Middle Eastern variation dataset which might directly impact clinical variant interpretation. We highlight 39 variants with minor allele frequency >1% in the MEV database that were previously reported as rare disease variants in ClinVar and the Human Gene Mutation Database (HGMD). Furthermore, the MEV database consisted of 281 putative homozygous loss of function (LoF) variants, or complete knockouts, of which 31.7% (89/281) were absent from gnomAD. This set represents either complete knockouts of 83 unique genes in reportedly healthy individuals, with implications regarding disease penetrance and expressivity, or might affect dispensable exons, thus refining the clinical annotation of those regions. Intriguingly, 24 of those genes have several clinically significant variants reported in ClinVar and/or HGMD. Our study shows that genetic variation in the Middle East improves functional annotation and clinical interpretation of the genome and emphasizes the need for expanding sequencing studies in the Middle East and other underrepresented populations.
Multiple early introductions of SARS‑CoV‑2 into a global travel hub in the Middle East
(2020) Tayoun, Ahmad Abou; Loney, Tom; Uddin, Mohammed; Senok, Abiola; Nowotny, Norbert; Alsheikh-Ali, Alawi; Al Suwaidi, Hanan
Abstract: International travel played a significant role in the early global spread of SARS-CoV-2. Understanding transmission patterns from different regions of the world will further inform global dynamics of the pandemic. Using data from Dubai in the United Arab Emirates (UAE), a major international travel hub in the Middle East, we establish SARS-CoV-2 full genome sequences from the index and early COVID-19 patients in the UAE. The genome sequences are analysed in the context of virus introductions, chain of transmissions, and possible links to earlier strains from other regions of the world. Phylogenetic analysis showed multiple spatiotemporal introductions of SARS-CoV-2 into the UAE from Asia, Europe, and the Middle East during the early phase of the pandemic. We also provide evidence for early community-based transmission and catalogue new mutations in SARS-CoV-2 strains in the UAE. Our findings contribute to the understanding of the global transmission network of SARS-CoV-2.
Regulation of Angiotensin- Converting Enzyme 2 in Obesity: Implications for COVID-19
(2020) Al Heialy, Saba; Hachim, Mahmood Yaseen; Senok, Abiola; Tayoun, Ahmad Abou; Alsheikh-Ali, Alawi
Abstract: The ongoing COVID-19 pandemic is caused by the novel coronavirus SARS-CoV-2. Age, smoking, obesity, and chronic diseases such as cardiovascular disease and diabetes have been described as risk factors for severe complications and mortality in COVID-19. Obesity and diabetes are usually associated with dysregulated lipid synthesis and clearance, which can initiate or aggravate pulmonary inflammation and injury. It has been shown that for viral entry into the host cell, SARS-CoV-2 utilizes the angiotensin-converting enzyme 2 (ACE2) receptors present on the cells. We aimed to characterize how SARS-CoV-2 dysregulates lipid metabolism pathways in the host and the effect of dysregulated lipogenesis on the regulation of ACE2, specifically in obesity. In our study, through the re-analysis of publicly available transcriptomic data, we first found that lung epithelial cells infected with SARS-CoV-2 showed upregulation of genes associated with lipid metabolism, including the SOC3 gene, which is involved in the regulation of inflammation and inhibition of leptin signaling. This is of interest as viruses may hijack host lipid metabolism to allow the completion of their viral replication cycles. Furthermore, a dataset using a mouse model of diet-induced obesity showed a significant increase in Ace2 expression in the lungs, which negatively correlated with the expression of genes that code for sterol response element-binding proteins 1 and 2 (SREBP). Suppression of Srebp1 showed a significant increase in Ace2 expression in the lung. Moreover, ACE2 expression in human subcutaneous adipose tissue can be regulated through changes in diet. Validation of the in silico data revealed a higher expression of ACE2, TMPRSS2 and SREBP1 in vitro in lung epithelial cells from obese subjects compared to non-obese subjects. To our knowledge this is the first study to show upregulation of ACE2 and TMPRSS2 in obesity. In silico and in vitro results suggest that the dysregulated lipogenesis and the subsequently high ACE2 expression in obese patients might be the mechanism underlying the increased risk for severe complications in those patients when infected by SARS-CoV-2.
SARS-CoV-2 Whole Genome Amplification and Sequencing for Effective Population-Based Surveillance and Control of Viral Transmission
(2020) Loney, Tom; Al Suwaidi, Hanan; Nowotny, Norbert; Alsheikh-Ali, Alawi; Tayoun, Ahmad Abou
BACKGROUND: With the gradual reopening of economies and resumption of social life, robust surveillance mechanisms should be implemented to control the ongoing COVID-19 pandemic. Unlike RT-qPCR, SARSCoV- 2 whole genome sequencing (cWGS) has the added advantage of identifying cryptic origins of the virus, and the extent of community-based transmissions versus new viral introductions, which can in turn influence public health policy decisions. However, the practical and cost considerations of cWGS should be addressed before it is widely implemented. METHODS: We performed shotgun transcriptome sequencing using RNA extracted from nasopharyngeal swabs of patients with COVID-19, and compared it to targeted SARS-CoV-2 genome amplification and sequencing with respect to virus detection, scalability, and cost-effectiveness. To track virus origin, we used opensource multiple sequence alignment and phylogenetic tools to compare the assembled SARS-CoV-2 genomes to publicly available sequences. RESULTS: We found considerable improvement in whole genome sequencing data quality and viral detection using amplicon-based target enrichment of SARSCoV- 2. With enrichment, more than 99% of the sequencing reads mapped to the viral genome, compared to an average of 0.63% without enrichment. Consequently, an increase in genome coverage was obtained using substantially less sequencing data, enabling higher scalability and sizable cost reductions. We also demonstrated how SARS-CoV-2 genome sequences can be used to determine their possible origin through phylogenetic analysis including other viral strains. CONCLUSIONS: SARS-CoV-2 whole genome sequencing is a practical, cost-effective, and powerful approach for population-based surveillance and control of viral transmission in the next phase of the COVID-19 pandemic.
SARS-CoV-2–related MIS-C: A key to the viral and genetic causes of Kawasaki disease?
(2021) Tayoun, Ahmad Abou
Abstract: Multisystem inflammatory syndrome in children (MIS-C) emerged in April 2020 in communities with high COVID-19 rates. This new condition is heterogenous but resembles Kawasaki disease (KD), a well-known but poorly understood and clinically heterogenous pediatric inflammatory condition for which weak associations have been found with a myriad of viral illnesses. Epidemiological data clearly indicate that SARS-CoV-2 is the trigger for MIS-C, which typically occurs about 1 mo after infection. These findings support the hypothesis of viral triggers for the various forms of classic KD. We further suggest that rare inborn errors of immunity (IEIs) altering the immune response to SARS-CoV-2 may underlie the pathogenesis of MIS-C in some children. The discovery of monogenic IEIs underlying MIS-C would shed light on its pathogenesis, paving the way for a new genetic approach to classic KD, revisited as a heterogeneous collection of IEIs to viruses.
A Simple Practical Guide to Genomic Diagnostics in a Pediatric Setting
(2021) Tayoun, Ahmad Abou
Abstract: With limited access to trained clinical geneticists and/or genetic counselors in the majority of healthcare systems globally, and the expanding use of genetic testing in all specialties of medicine, many healthcare providers do not receive the relevant support to order the most appropriate genetic test for their patients. Therefore, it is essential to educate all healthcare providers about the basic concepts of genetic testing and how to properly utilize this testing for each patient. Here, we review the various genetic testing strategies and their utilization based on different clinical scenarios, and test characteristics, such as the types of genetic variation identified by each test, turnaround time, and diagnostic yield for different clinical indications. Additional considerations such as test cost, insurance reimbursement, and interpretation of variants of uncertain significance are also discussed. The goal of this review is to aid healthcare providers in utilizing the most appropriate, fastest, and most cost-effective genetic test for their patients, thereby increasing the likelihood of a timely diagnosis and reducing the financial burden on the healthcare system by eliminating unnecessary and redundant testing.