Person: Amr, Sami
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Amr
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Sami
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Amr, Sami
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Publication Empirical comparison of reduced representation bisulfite sequencing and Infinium BeadChip reproducibility and coverage of DNA methylation in humans(Nature Publishing Group UK, 2017) Carmona, Juan J.; Accomando, William P.; Binder, Alexandra M.; Hutchinson, John; Pantano, Lorena; Izzi, Benedetta; Just, Allan C.; Lin, Xihong; Schwartz, Joel; Vokonas, Pantel S.; Amr, Sami; Baccarelli, Andrea; Michels, KarinWe empirically examined the strengths and weaknesses of two human genome-wide DNA methylation platforms: rapid multiplexed reduced representation bisulfite sequencing and Illumina’s Infinium BeadChip. Rapid multiplexed reduced representation bisulfite sequencing required less input DNA, offered more flexibility in coverage, and interrogated more CpG loci at a higher regional density. The Infinium covered slightly more protein coding, cancer-associated and mitochondrial-related genes, both platforms covered all known imprinting clusters, and rapid multiplexed reduced representation bisulfite sequencing covered more microRNA genes than the HumanMethylation450, but fewer than the MethylationEPIC. Rapid multiplexed reduced representation bisulfite sequencing did not always interrogate exactly the same CpG loci, but genomic tiling improved overlap between different libraries. Reproducibility of rapid multiplexed reduced representation bisulfite sequencing and concordance between the platforms increased with CpG density. Only rapid multiplexed reduced representation bisulfite sequencing could genotype samples and measure allele-specific methylation, and we confirmed that Infinium measurements are influenced by nearby single-nucleotide polymorphisms. The respective strengths and weaknesses of these two genome-wide DNA methylation platforms need to be considered when conducting human epigenetic studies.Publication Recurrent variants in OTOF are significant contributors to prelingual nonsydromic hearing loss in Saudi patients(Nature Publishing Group, 2018) Almontashiri, Naif; Alswaid, Abdulrahman; Oza, Andrea; Al-Mazrou, Khalid A; Elrehim, Omnia; Tayoun, Ahmad Abou; Rehm, Heidi; Amr, SamiPurpose Hearing loss is more prevalent in the Saudi Arabian population than in other populations; however, the full range of genetic etiologies in this population is unknown. We report the genetic findings from 33 Saudi hearing-loss probands of tribal ancestry, with predominantly prelingual severe to profound hearing loss. Methods: Testing was performed over the course of 2012–2016, and involved initial GJB2 sequence and GJB6-D13S1830 deletion screening, with negative cases being reflexed to a next-generation sequencing panel with 70, 71, or 87 hearing-loss genes. Results: A “positive” result was reached in 63% of probands, with two recurrent OTOF variants (p.Glu57* and p.Arg1792His) accountable for a third of all “positive” cases. The next most common cause was pathogenic variants in MYO7A and SLC26A4, each responsible for three “positive” cases. Interestingly, only one “positive” diagnosis had a DFNB1-related cause, due to a homozygous GJB6-D13S1830 deletion, and no sequence variants in GJB2 were detected. Conclusion: Our findings implicate OTOF as a potential major contributor to hearing loss in the Saudi population, while highlighting the low contribution of GJB2, thus offering important considerations for clinical testing strategies for Saudi patients. Further screening of Saudi patients is needed to characterize the genetic spectrum in this population.Publication VisCap: inference and visualization of germ-line copy-number variants from targeted clinical sequencing data(Nature Publishing Group, 2016) Pugh, Trevor J.; Amr, Sami; Bowser, Mark J.; Gowrisankar, Sivakumar; Hynes, Elizabeth; Mahanta, Lisa M.; Rehm, Heidi; Funke, Birgit; Lebo, MatthewPurpose: To develop and validate VisCap, a software program targeted to clinical laboratories for inference and visualization of germ-line copy-number variants (CNVs) from targeted next-generation sequencing data. Genet Med 18 7, 712–719. Methods: VisCap calculates the fraction of overall sequence coverage assigned to genomic intervals and computes log2 ratios of these values to the median of reference samples profiled using the same test configuration. Candidate CNVs are called when log2 ratios exceed user-defined thresholds. Genet Med 18 7, 712–719. Results: We optimized VisCap using 14 cases with known CNVs, followed by prospective analysis of 1,104 cases referred for diagnostic DNA sequencing. To verify calls in the prospective cohort, we used droplet digital polymerase chain reaction (PCR) to confirm 10/27 candidate CNVs and 72/72 copy-neutral genomic regions scored by VisCap. We also used a genome-wide bead array to confirm the absence of CNV calls across panels applied to 10 cases. To improve specificity, we instituted a visual scoring system that enabled experienced reviewers to differentiate true-positive from false-positive calls with minimal impact on laboratory workflow. Genet Med 18 7, 712–719. Conclusions: VisCap is a sensitive method for inferring CNVs from targeted sequence data from targeted gene panels. Visual scoring of data underlying CNV calls is a critical step to reduce false-positive calls for follow-up testing. Genet Med 18 7, 712–719.Publication Novel frameshift variant in the IDUA gene underlies Mucopolysaccharidoses type I in a consanguineous Yemeni pedigree(Elsevier, 2017) Azab, Belal; Dardas, Zain; Hamarsheh, Mohannad; Alsalem, Mohammad; Kilani, Zaid; Kilani, Farah; Awidi, Abdalla; Jafar, Hanan; Amr, SamiMucopolysaccharidosis type I (MPS I) is an autosomal recessive storage disorder that result as a consequence of a deficiency in the lysosomal hydrolase, a-L-iduronidase enzyme encoded by IDUA gene. Over a hundred causative variants in IDUA have been identified, which result in a progressive multi-systemic disease with a broad range of severity and disease progression reported across affected individuals. The aim of this study was the detection and interpretation of IDUA mutation in a family with two children affected with lethal MPS I. The IDUA gene was sequenced in the parents of two deceased children who had a clinical diagnosis of MPS I, to assess their carrier status and to help inform on risk in future children. The sequencing analysis was performed by PCR and bidirectional Sanger sequencing of the coding region and exon-intron splice junctions at Labor MVZ Westmecklenburg molecular diagnostics laboratory. A heterozygous c.657delA variant in exon 6 was identified in each parent, which is the most likely explanation for disease in their children. This report represents the first Yemeni family to have a molecular diagnosis for MPS I.Publication The Translational Genomics Core at Partners Personalized Medicine: Facilitating the Transition of Research towards Personalized Medicine(MDPI, 2016) Blau, Ashley; Brown, Alison; Mahanta, Lisa; Amr, SamiThe Translational Genomics Core (TGC) at Partners Personalized Medicine (PPM) serves as a fee-for-service core laboratory for Partners Healthcare researchers, providing access to technology platforms and analysis pipelines for genomic, transcriptomic, and epigenomic research projects. The interaction of the TGC with various components of PPM provides it with a unique infrastructure that allows for greater IT and bioinformatics opportunities, such as sample tracking and data analysis. The following article describes some of the unique opportunities available to an academic research core operating within PPM, such the ability to develop analysis pipelines with a dedicated bioinformatics team and maintain a flexible Laboratory Information Management System (LIMS) with the support of an internal IT team, as well as the operational challenges encountered to respond to emerging technologies, diverse investigator needs, and high staff turnover. In addition, the implementation and operational role of the TGC in the Partners Biobank genotyping project of over 25,000 samples is presented as an example of core activities working with other components of PPM.Publication Next generation sequencing‐based copy number analysis reveals low prevalence of deletions and duplications in 46 genes associated with genetic cardiomyopathies(John Wiley and Sons Inc., 2015) Ceyhan‐Birsoy, Ozge; Pugh, Trevor J.; Bowser, Mark J.; Hynes, Elizabeth; Frisella, Ashley L.; Mahanta, Lisa M.; Lebo, Matt S.; Amr, Sami; Funke, BirgitAbstract Background: Diagnostic testing for genetic cardiomyopathies has undergone dramatic changes in the last decade with next generation sequencing (NGS) expanding the number of genes that can be interrogated simultaneously. Exon resolution copy number analysis is increasingly incorporated into routine diagnostic testing via cytogenomic arrays and more recently via NGS. While NGS is an attractive option for laboratories that have no access to array platforms, its higher false positive rate requires weighing the added cost incurred by orthogonal confirmation against the magnitude of the increase in diagnostic yield. Although copy number variants (CNVs) have been reported in various cardiomyopathy genes, their contribution has not been systematically studied. Methods: We performed single exon resolution NGS‐based deletion/duplication analysis for up to 46 cardiomyopathy genes in >1400 individuals with cardiomyopathies including HCM, DCM, ARVC, RCM, and LVNC. Results and Conclusion Clinically significant deletions and duplications were identified in only 9 of 1425 (0.63%) individuals. The majority of those (6/9) represented intragenic events. We conclude that the added benefit of exon level deletion/duplication analysis is low for currently known cardiomyopathy genes and may not outweigh the increased cost and complexity of incorporating it into routine diagnostic testing for these disorders.