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NPJ Genomic Medicine

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https://www.readbyqxmd.com/read/30210808/user-considerations-in-assessing-pharmacogenomic-tests-and-their-clinical-support-tools
#1
REVIEW
Gouri Mukerjee, Andrea Huston, Boyko Kabakchiev, Micheline Piquette-Miller, Ron van Schaik, Ruslan Dorfman
Pharmacogenomic (PGx) testing is gaining recognition from physicians, pharmacists and patients as a tool for evidence-based medication management. However, seemingly similar PGx testing panels (and PGx-based decision support tools) can diverge in their technological specifications, as well as the genetic factors that determine test specificity and sensitivity, and hence offer different values for users. Reluctance to embrace PGx testing is often the result of unfamiliarity with PGx technology, a lack of knowledge about the availability of curated guidelines/evidence for drug dosing recommendations, and an absence of wide-spread institutional implementation efforts and educational support...
2018: NPJ Genomic Medicine
https://www.readbyqxmd.com/read/30210807/hhv-6-encoded-small-non-coding-rnas-define-an-intermediate-and-early-stage-in-viral-reactivation
#2
Bhupesh K Prusty, Nitish Gulve, Suvagata Roy Chowdhury, Michael Schuster, Sebastian Strempel, Vincent Descamps, Thomas Rudel
Human herpesvirus 6A and 6B frequently acquires latency. HHV-6 activation has been associated with various human diseases. Germ line inheritance of chromosomally integrated HHV-6 makes viral DNA-based analysis difficult for determination of early stages of viral activation. We characterized early stages of HHV-6 activation using high throughput transcriptomics studies and applied the results to understand virus activation under clinical conditions. Using a latent HHV-6A cell culture model in U2OS cells, we identified an early stage of viral reactivation, which we define as transactivation that is marked by transcription of several viral small non-coding RNAs (sncRNAs) in the absence of detectable increase in viral replication and proteome...
2018: NPJ Genomic Medicine
https://www.readbyqxmd.com/read/30155272/1q21-1-microduplication-large-verbal-nonverbal-performance-discrepancy-and-ddpcr-assays-of-hydin-hydin2-copy-number
#3
Jean Xavier, Bo Zhou, Frédéric Bilan, Xianglong Zhang, Brigitte Gilbert-Dussardier, Sylvie Viaux-Savelon, Reenal Pattni, Steve S Ho, David Cohen, Douglas F Levinson, Alexander E Urban, Claudine Laurent-Levinson
Microduplication of chromosome 1q21.1 is observed in ~0.03% of adults. It has a highly variable, incompletely penetrant phenotype that can include intellectual disability, global developmental delay, specific learning disabilities, autism, schizophrenia, heart anomalies and dysmorphic features. We evaluated a 10-year-old-male with a 1q21.1 duplication by CGH microarray. He presented with major attention deficits, phonological dysphasia, poor fine motor skills, dysmorphia and mild autistic features, but not the typical macrocephaly...
2018: NPJ Genomic Medicine
https://www.readbyqxmd.com/read/30131873/two-different-stat1-gain-of-function-mutations-lead-to-diverse-ifn-%C3%AE-mediated-gene-expression
#4
Adi Ovadia, Nigel Sharfe, Cynthia Hawkins, Suzanne Laughlin, Chaim M Roifman
Signal transducer and activator of transcription 1 (STAT1) regulates multiple biological processes downstream of a variety of cytokine receptors in many cell types. Heterozygous gain-of-function (GOF) mutations in STAT1 have been associated with a diverse phenotype encompassing chronic mucocutaneous candidiasis (CMCC) and declining immunity. There is no clear correlation between STAT1 domain-specific mutations and phenotype, and it remains unclear why GOF mutations in STAT1 result in such a wide spectrum of clinical presentations...
2018: NPJ Genomic Medicine
https://www.readbyqxmd.com/read/30131872/an-integrated-clinical-program-and-crowdsourcing-strategy-for-genomic-sequencing-and-mendelian-disease-gene-discovery
#5
REVIEW
Alireza Haghighi, Joel B Krier, Agnes Toth-Petroczy, Christopher A Cassa, Natasha Y Frank, Nikkola Carmichael, Elizabeth Fieg, Andrew Bjonnes, Anwoy Mohanty, Lauren C Briere, Sharyn Lincoln, Stephanie Lucia, Vandana A Gupta, Onuralp Söylemez, Sheila Sutti, Kameron Kooshesh, Haiyan Qiu, Christopher J Fay, Victoria Perroni, Jamie Valerius, Meredith Hanna, Alexander Frank, Jodie Ouahed, Scott B Snapper, Angeliki Pantazi, Sameer S Chopra, Ignaty Leshchiner, Nathan O Stitziel, Anna Feldweg, Michael Mannstadt, Joseph Loscalzo, David A Sweetser, Eric Liao, Joan M Stoler, Catherine B Nowak, Pedro A Sanchez-Lara, Ophir D Klein, Hazel Perry, Nikolaos A Patsopoulos, Soumya Raychaudhuri, Wolfram Goessling, Robert C Green, Christine E Seidman, Calum A MacRae, Shamil R Sunyaev, Richard L Maas, Dana Vuzman
Despite major progress in defining the genetic basis of Mendelian disorders, the molecular etiology of many cases remains unknown. Patients with these undiagnosed disorders often have complex presentations and require treatment by multiple health care specialists. Here, we describe an integrated clinical diagnostic and research program using whole-exome and whole-genome sequencing (WES/WGS) for Mendelian disease gene discovery. This program employs specific case ascertainment parameters, a WES/WGS computational analysis pipeline that is optimized for Mendelian disease gene discovery with variant callers tuned to specific inheritance modes, an interdisciplinary crowdsourcing strategy for genomic sequence analysis, matchmaking for additional cases, and integration of the findings regarding gene causality with the clinical management plan...
2018: NPJ Genomic Medicine
https://www.readbyqxmd.com/read/30131871/chemical-genetic-based-phenotypic-screen-reveals-novel-regulators-of-gluconeogenesis-in-human-primary-hepatocytes
#6
Haixia Zou, Qian Liu, Li Meng, Jingye Zhou, Chenxiao Da, Xikun Wu, Lichun Jiang, Jianyong Shou, Haiqing Hua
Insulin resistance is a pathophysiological hallmark of type 2 diabetes and nonalcoholic fatty liver disease. Under the condition of fat accumulation in the liver, suppression of hepatic glucose production by insulin is diminished. In order to gain deeper understanding of dysregulation of glucose production in metabolic diseases, in the present study, we performed an unbiased phenotypic screening in primary human hepatocytes to discover novel mechanisms that regulate gluconeogenesis in the presence of insulin...
2018: NPJ Genomic Medicine
https://www.readbyqxmd.com/read/30109124/whole-genome-analysis-for-effective-clinical-diagnosis-and-gene-discovery-in-early-infantile-epileptic-encephalopathy
#7
Betsy E P Ostrander, Russell J Butterfield, Brent S Pedersen, Andrew J Farrell, Ryan M Layer, Alistair Ward, Chase Miller, Tonya DiSera, Francis M Filloux, Meghan S Candee, Tara Newcomb, Joshua L Bonkowsky, Gabor T Marth, Aaron R Quinlan
Early infantile epileptic encephalopathy (EIEE) is a devastating epilepsy syndrome with onset in the first months of life. Although mutations in more than 50 different genes are known to cause EIEE, current diagnostic yields with gene panel tests or whole-exome sequencing are below 60%. We applied whole-genome analysis (WGA) consisting of whole-genome sequencing and comprehensive variant discovery approaches to a cohort of 14 EIEE subjects for whom prior genetic tests had not yielded a diagnosis. We identified both de novo point and INDEL mutations and de novo structural rearrangements in known EIEE genes, as well as mutations in genes not previously associated with EIEE...
2018: NPJ Genomic Medicine
https://www.readbyqxmd.com/read/30109123/exome-sequencing-for-paediatric-onset-diseases-impact-of-the-extensive-involvement-of-medical-geneticists-in-the-diagnostic-odyssey
#8
Christopher Cy Mak, Gordon Kc Leung, Gary Tk Mok, Kit San Yeung, Wanling Yang, Cheuk-Wing Fung, Sophelia Hs Chan, So-Lun Lee, Ni-Chung Lee, Rolph Pfundt, Yu-Lung Lau, Brian Hy Chung
Currently, offering whole-exome sequencing (WES) via collaboration with an external laboratory is increasingly common. However, the receipt of a WES report can be merely the beginning of a continuing exploration process rather than the end of the diagnostic odyssey. The laboratory often does not have the information the physician has, and any discrepancies in variant interpretation must be addressed by a medical geneticist. In this study, we performed diagnostic WES of 104 patients with paediatric-onset genetic diseases...
2018: NPJ Genomic Medicine
https://www.readbyqxmd.com/read/30062048/recurrent-loss-of-heterozygosity-correlates-with-clinical-outcome-in-pancreatic-neuroendocrine-cancer
#9
Ben Lawrence, Cherie Blenkiron, Kate Parker, Peter Tsai, Sandra Fitzgerald, Paula Shields, Tamsin Robb, Mee Ling Yeong, Nicole Kramer, Sarah James, Mik Black, Vicky Fan, Nooriyah Poonawala, Patrick Yap, Esther Coats, Braden Woodhouse, Reena Ramsaroop, Masato Yozu, Bridget Robinson, Kimiora Henare, Jonathan Koea, Peter Johnston, Richard Carroll, Saxon Connor, Helen Morrin, Marianne Elston, Christopher Jackson, Papaarangi Reid, John Windsor, Andrew MacCormick, Richard Babor, Adam Bartlett, Dragan Damianovich, Nicholas Knowlton, Sean Grimmond, Michael Findlay, Cristin Print
Pancreatic neuroendocrine tumors (pNETs) are uncommon cancers arising from pancreatic islet cells. Here we report the analysis of gene mutation, copy number, and RNA expression of 57 sporadic well-differentiated pNETs. pNET genomes are dominated by aneuploidy, leading to concordant changes in RNA expression at the level of whole chromosomes and chromosome segments. We observed two distinct patterns of somatic pNET aneuploidy that are associated with tumor pathology and patient prognosis. Approximately 26% of the patients in this series had pNETs with genomes characterized by recurrent loss of heterozygosity (LoH) of 10 specific chromosomes, accompanied by bi-allelic MEN1 inactivation and generally poor clinical outcome...
2018: NPJ Genomic Medicine
https://www.readbyqxmd.com/read/30062047/responsible-sharing-of-biomedical-data-and-biospecimens-via-the-automatable-discovery-and-access-matrix-ada-m
#10
REVIEW
J Patrick Woolley, Emily Kirby, Josh Leslie, Francis Jeanson, Moran N Cabili, Gregory Rushton, James G Hazard, Vagelis Ladas, Colin D Veal, Spencer J Gibson, Anne-Marie Tassé, Stephanie O M Dyke, Clara Gaff, Adrian Thorogood, Bartha Maria Knoppers, John Wilbanks, Anthony J Brookes
Given the data-rich nature of modern biomedical research, there is a pressing need for a systematic, structured, computer-readable way to capture, communicate, and manage sharing rules that apply to biomedical resources. This is essential for responsible recording, versioning, communication, querying, and actioning of resource sharing plans. However, lack of a common "information model" for rules and conditions that govern the sharing of materials, methods, software, data, and knowledge creates a fundamental barrier...
2018: NPJ Genomic Medicine
https://www.readbyqxmd.com/read/30002876/meta-analysis-of-the-diagnostic-and-clinical-utility-of-genome-and-exome-sequencing-and-chromosomal-microarray-in-children-with-suspected-genetic-diseases
#11
Michelle M Clark, Zornitza Stark, Lauge Farnaes, Tiong Y Tan, Susan M White, David Dimmock, Stephen F Kingsmore
Genetic diseases are leading causes of childhood mortality. Whole-genome sequencing (WGS) and whole-exome sequencing (WES) are relatively new methods for diagnosing genetic diseases, whereas chromosomal microarray (CMA) is well established. Here we compared the diagnostic utility (rate of causative, pathogenic, or likely pathogenic genotypes in known disease genes) and clinical utility (proportion in whom medical or surgical management was changed by diagnosis) of WGS, WES, and CMA in children with suspected genetic diseases by systematic review of the literature (January 2011-August 2017) and meta-analysis, following MOOSE/PRISMA guidelines...
2018: NPJ Genomic Medicine
https://www.readbyqxmd.com/read/29951225/signaling-pathway-screening-platforms-are-an-efficient-approach-to-identify-therapeutic-targets-in-cancers-that-lack-known-driver-mutations-a-case-report-for-a-cancer-of-unknown-primary-origin
#12
Pedro Torres-Ayuso, Sudhakar Sahoo, Garry Ashton, Elvira An, Nicole Simms, Melanie Galvin, Hui Sun Leong, Kristopher K Frese, Kathryn Simpson, Natalie Cook, Andrew Hughes, Crispin J Miller, Richard Marais, Caroline Dive, Matthew G Krebs, John Brognard
Precision medicine aims to tailor cancer therapies to target specific tumor-promoting aberrations. For tumors that lack actionable drivers, which occurs frequently in the clinic, extensive molecular characterization and pre-clinical drug efficacy studies will be required. A cell line maintained at low passage and a patient- derived xenograft model (PDX) were generated using a fresh biopsy from a patient with a poorly-differentiated neuroendocrine tumor of unknown primary origin. Next-generation sequencing, high throughput signaling network analysis, and drug efficacy trials were then conducted to identify actionable targets for therapeutic intervention...
2018: NPJ Genomic Medicine
https://www.readbyqxmd.com/read/29928512/identification-of-an-immune-gene-expression-signature-associated-with-favorable-clinical-features-in-treg-enriched-patient-tumor-samples
#13
Kevin B Givechian, Kamil Wnuk, Chad Garner, Stephen Benz, Hermes Garban, Shahrooz Rabizadeh, Kayvan Niazi, Patrick Soon-Shiong
Immune heterogeneity within the tumor microenvironment undoubtedly adds several layers of complexity to our understanding of drug sensitivity and patient prognosis across various cancer types. Within the tumor microenvironment, immunogenicity is a favorable clinical feature in part driven by the antitumor activity of CD8+ T cells. However, tumors often inhibit this antitumor activity by exploiting the suppressive function of regulatory T cells (Tregs), thus suppressing the adaptive immune response. Despite the seemingly intuitive immunosuppressive biology of Tregs, prognostic studies have produced contradictory results regarding the relationship between Treg enrichment and survival...
2018: NPJ Genomic Medicine
https://www.readbyqxmd.com/read/29760947/incorporating-epilepsy-genetics-into-clinical-practice-a-360%C3%A2-evaluation
#14
Stephanie Oates, Shan Tang, Richard Rosch, Rosalie Lear, Elaine F Hughes, Ruth E Williams, Line H G Larsen, Qin Hao, Hans Atli Dahl, Rikke S Møller, Deb K Pal
We evaluated a new epilepsy genetic diagnostic and counseling service covering a UK population of 3.5 million. We calculated diagnostic yield, estimated clinical impact, and surveyed referring clinicians and families. We costed alternative investigational pathways for neonatal onset epilepsy. Patients with epilepsy of unknown aetiology onset < 2 years; treatment resistant epilepsy; or familial epilepsy were referred for counseling and testing. We developed NGS panels, performing clinical interpretation with a multidisciplinary team...
2018: NPJ Genomic Medicine
https://www.readbyqxmd.com/read/29736260/mutation-load-estimation-model-as-a-predictor-of-the-response-to-cancer-immunotherapy
#15
Guan-Yi Lyu, Yu-Hsuan Yeh, Yi-Chen Yeh, Yu-Chao Wang
The determination of the mutation load, a total number of nonsynonymous point mutations, by whole-exome sequencing was shown to be useful in predicting the treatment responses to cancer immunotherapy. However, this technique is expensive and time-consuming, which hampers its application in clinical practice. Therefore, the objective of this study was to construct a mutation load estimation model for lung adenocarcinoma, using a small set of genes, as a predictor of the immunotherapy treatment response. Using the somatic mutation data downloaded from The Cancer Genome Atlas (TCGA) database, a computational framework was developed...
2018: NPJ Genomic Medicine
https://www.readbyqxmd.com/read/29736259/predictors-of-next-generation-sequencing-panel-selection-using-a-shared-decision-making-approach
#16
Eliza Courtney, Shao-Tzu Li, Tarryn Shaw, Yanni Chen, John Carson Allen, Joanne Ngeow
The introduction of next-generation sequencing panels has transformed the approach for genetic testing in cancer patients, however, established guidelines for their use are lacking. A shared decision-making approach has been adopted by our service, where patients play an active role in panel selection and we sought to identify factors associated with panel selection and report testing outcomes. Demographic and clinical data were gathered for female breast and/or ovarian cancer patients aged 21 and over who underwent panel testing...
2018: NPJ Genomic Medicine
https://www.readbyqxmd.com/read/29644095/rapid-whole-genome-sequencing-decreases-infant-morbidity-and-cost-of-hospitalization
#17
Lauge Farnaes, Amber Hildreth, Nathaly M Sweeney, Michelle M Clark, Shimul Chowdhury, Shareef Nahas, Julie A Cakici, Wendy Benson, Robert H Kaplan, Richard Kronick, Matthew N Bainbridge, Jennifer Friedman, Jeffrey J Gold, Yan Ding, Narayanan Veeraraghavan, David Dimmock, Stephen F Kingsmore
Genetic disorders are a leading cause of morbidity and mortality in infants. Rapid whole-genome sequencing (rWGS) can diagnose genetic disorders in time to change acute medical or surgical management (clinical utility) and improve outcomes in acutely ill infants. We report a retrospective cohort study of acutely ill inpatient infants in a regional children's hospital from July 2016-March 2017. Forty-two families received rWGS for etiologic diagnosis of genetic disorders. Probands also received standard genetic testing as clinically indicated...
2018: NPJ Genomic Medicine
https://www.readbyqxmd.com/read/29619247/cardiac-arrhythmia-and-neuroexcitability-gene-variants-in-resected-brain-tissue-from-patients-with-sudden-unexpected-death-in-epilepsy-sudep
#18
Daniel Friedman, Kasthuri Kannan, Arline Faustin, Seema Shroff, Cheddhi Thomas, Adriana Heguy, Jonathan Serrano, Matija Snuderl, Orrin Devinsky
Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related mortality in young adults. The exact mechanisms are unknown but death often follows a generalized tonic-clonic seizure. Proposed mechanisms include seizure-related respiratory, cardiac, autonomic, and arousal dysfunction. Genetic drivers underlying SUDEP risk are largely unknown. To identify potential SUDEP risk genes, we compared whole-exome sequences (WES) derived from formalin-fixed paraffin embedded surgical brain specimens of eight epilepsy patients who died from SUDEP with seven living controls matched for age at surgery, sex, year of surgery and lobe of resection...
2018: NPJ Genomic Medicine
https://www.readbyqxmd.com/read/29581887/improving-imputation-in-disease-relevant-regions-lessons-from-cystic-fibrosis
#19
Naim Panjwani, Bowei Xiao, Lizhen Xu, Jiafen Gong, Katherine Keenan, Fan Lin, Gengming He, Zeynep Baskurt, Sangook Kim, Lin Zhang, Mohsen Esmaeili, Scott Blackman, Stephen W Scherer, Harriet Corvol, Mitchell Drumm, Michael Knowles, Garry Cutting, Johanna M Rommens, Lei Sun, Lisa J Strug
Does genotype imputation with public reference panels identify variants contributing to disease? Genotype imputation using the 1000 Genomes Project (1KG; 2504 individuals) displayed poor coverage at the causal cystic fibrosis (CF) transmembrane conductance regulator ( CFTR ) locus for the International CF Gene Modifier Consortium. Imputation with the larger Haplotype Reference Consortium (HRC; 32,470 individuals) displayed improved coverage but low sensitivity of variants clinically relevant for CF. A hybrid reference that combined whole genome sequencing (WGS) from 101 CF individuals with the 1KG imputed a greater number of single-nucleotide variants (SNVs) that would be analyzed in a genetic association study ( r 2  ≥ 0...
2018: NPJ Genomic Medicine
https://www.readbyqxmd.com/read/29479477/clinical-testing-of-brca1-and-brca2-a-worldwide-snapshot-of-technological-practices
#20
Amanda Ewart Toland, Andrea Forman, Fergus J Couch, Julie O Culver, Diana M Eccles, William D Foulkes, Frans B L Hogervorst, Claude Houdayer, Ephrat Levy-Lahad, Alvaro N Monteiro, Susan L Neuhausen, Sharon E Plon, Shyam K Sharan, Amanda B Spurdle, Csilla Szabo, Lawrence C Brody
Clinical testing of BRCA1 and BRCA2 began over 20 years ago. With the expiration and overturning of the BRCA patents, limitations on which laboratories could offer commercial testing were lifted. These legal changes occurred approximately the same time as the widespread adoption of massively parallel sequencing (MPS) technologies. Little is known about how these changes impacted laboratory practices for detecting genetic alterations in hereditary breast and ovarian cancer genes. Therefore, we sought to examine current laboratory genetic testing practices for BRCA1 / BRCA2 ...
2018: NPJ Genomic Medicine
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