Browsing by Author "Tayoun, Ahmad N. Abou"

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Comprehensive Genomic Sequencing–Based Screening for Hearing Loss in the Neonatal Intensive Care Setting—Is It Time?
(2022) Tayoun, Ahmad N. Abou
Introduction: Zhu et al assessed the utility of combining expanded genomic sequencing with traditional physiological newborn hearing screening (NBHS) in the neonatal intensive care unit (NICU). The benefits associated with combining genetic and physiological screening, as illustrated by Zhu et al1 and elsewhere,2 include the identification of babies at risk for hearing loss who can benefit from early intervention yet are missed by NBHS, as well as genetic factors that may help improve the management of hearing loss in confirmed cases. In a cohort of 8078 patients admitted to the NICU, Zhu et al1 show that exome sequencing identified 7 patients with hearing loss who already had a negative NBHS test result (false negatives), thus increasing the total number of patients with confirmed hearing loss by 13.5% (7 of 52) in this setting. Furthermore, of all patients with confirmed hearing loss, 75.0% (39 of 52) had genetic findings, thus also providing important genetic information for a substantial proportion of patients.
Elevated ASCL1 activity creates de novo regulatory elements associated with neuronal diferentiation
(2022) Ali, Fahad R; Gomez, Roshna Lawrence; Tayoun, Ahmad N. Abou
Background: The pro-neural transcription factor ASCL1 is a master regulator of neurogenesis and a key factor necessary for the reprogramming of permissive cell types to neurons. Endogenously, ASCL1 expression is often associated with neuroblast stem-ness. Moreover, ASCL1-mediated reprogramming of fibroblasts to differentiated neurons is commonly achieved using artificially high levels of ASCL1 protein, where ASCL1 acts as an “on-target” pioneer factor. However, the genome-wide effects of enhancing ASCL1 activity in a permissive neurogenic environment has not been thoroughly investigated. Here, we overexpressed ASCL1 in the neuronally-permissive context of neuroblastoma (NB) cells where modest endogenous ASCL1 supports the neuroblast program. Results: Increasing ASCL1 in neuroblastoma cells both enhances binding at existing ASCL1 sites and also leads to creation of numerous additional, lower affinity binding sites. These extensive genome-wide changes in ASCL1 binding result in significant reprogramming of the NB transcriptome, redirecting it from a proliferative neuroblastic state towards one favoring neuronal differentiation. Mechanistically, ASCL1-mediated cell cycle exit, and differentiation can be increased further by preventing its multi-site phosphorylation, which is associated with additional changes in genome-wide binding and gene activation profiles. Conclusions: Our findings show that enhancing ASCL1 activity in a neurogenic environment both increases binding at endogenous ASCL1 sites and also results in additional binding to new low affinity sites that favors neuronal differentiation over the proliferating neuroblast program supported by the endogenous protein. These findings have important implications for controlling processes of neurogenesis in cancer and cellular reprogramming.
Evaluating the impact of in silico predictors on clinical variant classification
(2021) Tayoun, Ahmad N. Abou
Background: In silico evidence is important to consider when interpreting genetic variants. According to the ACMG/AMP, in silico evidence is applied at the supporting strength level using the PP3 and BP4 criteria, for pathogenic and benign evidence, respectively. While PP3 has been determined to be one of the most commonly applied criteria, less is known about the effect of these two criteria on variant classification outcomes. Methods: In this study, a total of 727 missense variants curated by Clinical Genome Resource (ClinGen) Variant Curation Expert Panels (VCEPs) were analyzed to determine how often PP3 and BP4 were applied and how often they influenced final variant classifications. The current categorical system of variant classification was compared with a point-based system being developed by the ClinGen Sequence Variant Interpretation Working Group. In addition, the performance of four in silico tools (REVEL, VEST, FATHMM, and MPC) was assessed by using a gold set of 237 variants (classified as benign or pathogenic independent of PP3 or BP4) to calculate pathogenicity likelihood ratios. Results: Collectively, the PP3 and BP4 criteria were applied by ClinGen VCEPs to 55% of missense variants in this data set. Removing in silico criteria from variants where they were originally applied caused variants to change classification from pathogenic to likely pathogenic (14%), likely pathogenic to variant of uncertain significance (VUS) (24%), or likely benign to VUS (64%). The proportion of downgrades with the categorical classification system was similar to that of the point-based system, though the latter resolved borderline classifications. REVEL and VEST performed at a level consistent with moderate strength towards either benign or pathogenic evidence, while FATHMM performed at the supporting level. Conclusions: Overall, this study demonstrates that in silico criteria PP3 and BP4 are commonly applied in variant classification and often affect the final classification. Our results suggest that when sufficient thresholds for in silico predictors are established, PP3 and BP4 may be appropriate to use at a moderate strength. However, further calibration with larger datasets is needed to optimize the performance of current in silico tools given the impact they have on clinical variant classification.
Genetic variation in the Middle East—an opportunity to advance the human genetics field
(2020) Tayoun, Ahmad N. Abou
Abstract: We highlight the current lack of representation of the Middle East from large genomic studies and emphasize the expected high impact of cataloging its variation. We discuss the limiting factors and possible solutions to generating and accessing research and clinical sequencing data from this part of the world.
Genomic medicine in the Middle East
(2021) Tayoun, Ahmad N. Abou; Alsheikh-Ali, Alawi
Abstract: We discuss the current state of genomic medicine in Arab countries of the Middle East, a region with outsized contribution to Mendelian genetics due to inbreeding yet has poor representation in global variome datasets. We focus on genomic testing, clinical genetics, and genetic counseling services along with associated training and research programs. Finally, we highlight opportunities for improvement in genomic medicine services in this region.
Genomic medicine in the Middle East
(2021) Tayoun, Ahmad N. Abou; Alsheikh-Ali, Alawi
Abstract: We discuss the current state of genomic medicine in Arab countries of the Middle East, a region with outsized contribution to Mendelian genetics due to inbreeding yet has poor representation in global variome datasets. We focus on genomic testing, clinical genetics, and genetic counseling services along with associated training and research programs. Finally, we highlight opportunities for improvement in genomic medicine services in this region.
Rapid whole genome sequencing of critically ill pediatric patients from genetically underrepresented populations
(2022) Alsheikh-Ali, Alawi; Tayoun, Ahmad N. Abou
Abstract: We describe a case series of fve infants (age range: 1–90 days; 4 females and 1 male) who presented to Al Jalila Chil dren’s intensive care units (ICU) with complex multisystem disorders. Patients were Emirati, Kenyan, Jordanian, Filipino, or Pakistani. Trio rapid whole genome sequencing (rWGS) was performed on all fve patients and their parents within the hospital’s genomics facility. Results were returned within ~37 h from blood sample draws and were diagnostic in 3 out of 5 patients. Positive fndings were a homozygous pathogenic variant in POMT1 gene causing muscular dystro phydystroglycanopathy, a mosaic tetrasomy of the short arm of chromosome 12 (12p13.33p11.1) causing PallisterKillian syndrome, and compound heterozygous pathogenic variants in the LIPA gene causing lysosomal acid lipase defciency and Wolman disease. The rWGS analysis provided fast and precise diagnostic fndings in those 3 patients and also aided in devising better management plans for them in the intensive care setting. For example, the 3-monthold infant with pathogenic variants in the LIPA gene is now a candidate for an FDA-approved, potentially lifesaving enzyme replacement therapy (sebelipase alfa). Our case series emphasize the feasibility and utility of rWGS in pedi atric intensive care setting, in a diverse population that has long been underserved in genomic services. Signifcant investments in local healthcare infrastructure are needed, globally, for more equitable access of genomic medicine among vulnerable patients.