Faculty Publications (CoM)

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A draft human pangenome reference
(2023) Abou Tayoun, Ahmad
Introduction: Here the Human Pangenome Reference Consortium presents a frst draft of the human pangenome reference. The pangenome contains 47 phased, diploid assemblies from a cohort of genetically diverse individuals1 . These assemblies cover more than 99% of the expected sequence in each genome and are more than 99% accurate at the structural and base pair levels. Based on alignments of the assemblies, we generate a draft pangenome that captures known variants and haplotypes and reveals new alleles at structurally complex loci. We also add 119 million base pairs of euchromatic polymorphic sequences and 1,115 gene duplications relative to the existing reference GRCh38. Roughly 90 million of the additional base pairs are derived from structural variation. Using our draft pangenome to analyse short-read data reduced small variant discovery errors by 34% and increased the number of structural variants detected per haplotype by 104% compared with GRCh38-based workfows, which enabled the typing of the vast majority of structural variant alleles per sample.
The genomic landscape of rare disorders in the Middle East
(2023) Rabea, Fatma; Abou Tayoun, Ahmad
Background: Rare diseases collectively impose a significant burden on healthcare systems, especially in underserved regions, like the Middle East, which lack access to genomic diagnostic services and the associated personalized management plans. Methods: We established a clinical genomics and genetic counseling facility, within a multidisciplinary tertiary pediatric center, in the United Arab Emirates to locally diagnose and manage patients with rare diseases. Clinical genomic investigations included exome-based sequencing, chromosomal microarrays, and/or targeted testing. We assessed the diagnostic yield and implications for clinical management among this population. Variables were compared using the Fisher exact test. Tests were 2-tailed, and P<. 05 was considered statistically signifcant. Results: We present data on 1000 patients with rare diseases (46.2% females; average age, 4.6 years) representing 47 countries primarily from the Arabian Peninsula, the Levant, Africa, and Asia. The cumulative diagnostic yield was 32.5% (95% CI, 29.7–35.5%) and was higher for genomic sequencing-based testing than chromosomal microarrays (37.9% versus 17.2%, P = 0.0001) across all indications, consistent with the higher burden of single gene disorders. Of the 221 Mendelian disorders identifed in this cohort, the majority (N = 184) were encountered only once, and those with recessive inheritance accounted for ~ 62% of sequencing diagnoses. Of patients with positive genetic findings (N = 325), 67.7% were less than 5 years of age, and 60% were ofered modified management and/or intervention plans. Interestingly, 24% of patients with positive genetic fndings received delayed diagnoses (average age, 12.4 years; range 7–37 years), most likely due to a lack of access to genomic investigations in this region. One such genetic finding ended a 15-year-long diagnostic odyssey, leading to a life-threatening diagnosis in one patient, who was then successfully treated using an experimental allogenic bone marrow transplant. Finally, we present cases with candidate genes within regions of homozygosity, likely underlying novel recessive disorders. Conclusions: Early access to genomic diagnostics for patients with suspected rare disorders in the Middle East is likely to improve clinical outcomes while driving gene discovery in this genetically underrepresented population.
Kawasaki disease (KD) and multisystem inflammatory syndrome in children (MIS-C) in a Middle Eastern patient cohort
(2023) Abou Tayoun, Ahmad
Objective: This is a comprehensive characteristic study of Kawasaki disease (KD) and Multi system inflammatory syndrome in children (MIS-C) in the Middle East that creates a formula to differentiate between the two. Methods: We conducted a descriptive comparative study of KD and MIS-C in the United Arab Emirates. Retrospective MIS-C and KD cohorts were recruited between January 2017 until August 2021.We compared clinical and laboratory characteristics between both groups. Our data were compared with 87 patients with KD or MIS-C from the literature. Results: We report on123 patients. Sixty-seven (54%) met the criteria for KD (36 male, 43 Arab), and fifty-six (46%) met the criteria for MIS-C (28 male, 35 Arab). The median age was 2.2 years range (0.15–10.7) in the KD group and 7.3 years (0.7–15.2) in the MIS-C group (P<0.001). The clinical features on admission showed an increase in gastrointestinal manifestations in MIS-C compared with KD (84% vs. 31%, P<0.001). Laboratory tests on admission revealed a significant increase in the following tests in KD compared with MIS-C; white blood cells (mean 16.30 10(3) µcL vs. 11.56 10(3) µcL, P<0.001), absolute neutrophils (mean 10.72 10(3) µcL vs. 8.21 10(3) µcL, P 0.008), absolute lymphocytes (mean 3.92 10(3) µcL vs. 2.59 10(3) µcL, P 0.003), erythrocyte sedimentation rate (mean 73 mm/hr vs. 51 mm/hr, P<0.001). Conclusion: This study showed vast similarities between KD and MIS-C, suggesting that they lie along the same clinical spectrum. However, there are several differences between the two disease entities suggesting that MIS-C most likely represents a new severe variant of KD. Based on our findings in this study, we created a formula to differentiate between KD and MIS-C.
Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19
(2023) Abou Tayoun, Ahmad; Alosaimi, Mohammed Faraj
Background: We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7dependent 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 identifed 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 signifcance. Under a recessive model, the most signifcant 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 infuenza 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 signifcantly 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.
Super-enhancer associated core regulatory circuits mediate susceptibility to retinoic acid in neuroblastoma cells
(2022) Gomez, Roshna Lawrence; Ramachandran, Revathy; Abou Tayoun, Ahmad; Ali, Fahad R
Abstract: Neuroblastoma is a pediatric tumour that accounts for more than 15% of cancer-related deaths in children. High-risk tumours are often difficult to treat, and patients’ survival chances are less than 50%. Retinoic acid treatment is part of the maintenance therapy given to neuroblastoma patients; however, not all tumours differentiate in response to retinoic acid. Within neuroblastoma tumors, two phenotypically distinct cell types have been identified based on their super-enhancer landscape and transcriptional core regulatory circuitries: adrenergic (ADRN) and mesenchymal (MES). We hypothesized that the distinct super-enhancers in these different tumour cells mediate differential response to retinoic acid. To this end, three different neuroblastoma cell lines, ADRN (MYCN amplified and nonamplified) and MES cells, were treated with retinoic acid, and changes in the super-enhancer landscape upon treatment and after subsequent removal of retinoic acid was studied. Using ChIP-seq for the active histone mark H3K27ac, paired with RNA-seq, we compared the super-enhancer landscape in cells that undergo neuronal differentiation in response to retinoic acid versus those that fail to differentiate and identified unique super-enhancers associated with neuronal differentiation. Among the ADRN cells that respond to treatment, MYCN-amplified cells remain differentiated upon removal of retinoic acid, whereas MYCN non-amplified cells revert to an undifferentiated state, allowing for the identification of super-enhancers responsible for maintaining differentiation. This study identifies key super-enhancers that are crucial for retinoic acid-mediated differentiation.

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Browsing Faculty Publications (CoM) by Author "Abou Tayoun, Ahmad"