Disclosure of Incidental Findings From Next-Generation Sequencing in Pediatric Genomic Research

Background: With the outbreak of high throughput next-generation sequencing (NGS), the biological research of drug discovery has been directed towards the oncology and infectious disease therapeutic areas, with extensive use in biopharmaceutical development and vaccine production. Method: In this review, an effort was made to address the basic background of NGS technologies, potential applications of NGS in drug designing. Our purpose is also to provide a brief introduction of various Nextgeneration sequencing techniques. Discussions: The high-throughput methods execute Large-scale Unbiased Sequencing (LUS) which comprises of Massively Parallel Sequencing (MPS) or NGS technologies. The Next geneinvolved necessarily executes Largescale Unbiased Sequencing (LUS) which comprises of MPS or NGS technologies. These are related terms that describe a DNA sequencing technology which has revolutionized genomic research. Using NGS, an entire human genome can be sequenced within a single day. Conclusion: Analysis of NGS data unravels important clues in the quest for the treatment of various lifethreatening diseases and other related scientific problems related to human welfare.

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2443 Attitudes and preferences for return of results from next-generation sequencing

Journal of Clinical and Translational Science ◽

10.1017/cts.2018.277 ◽

2018 ◽

Vol 2 (S1) ◽

pp. 79-79

Author(s):

Matthew Neu ◽

Jaimie Richards ◽

Sara J. Knight

Keyword(s):

Next Generation Sequencing ◽

Genome Sequencing ◽

Incidental Findings ◽

Return Of Results ◽

Medical Setting ◽

Specific Gene ◽

Next Generation ◽

Inclusion Criteria ◽

Secondary Findings ◽

Generation Sequencing

OBJECTIVES/SPECIFIC AIMS: Objectives: Decreasing costs and increasing evidence for clinical utility have contributed to whole genome sequencing (WGS) becoming a clinical reality. While previous studies have surveyed the attitudes of patients and community members towards specific gene tests, an emerging literature has begun to describe the preferences of diverse recipients for WGS results. In this study, we sought to identify and synthesize the quantitative evidence on preferences for results from WGS using a systematic review of the literature. METHODS/STUDY POPULATION: We conducted a search of articles on PubMed including subject index terms WGS, whole exome sequencing, genome sequencing, secondary findings, incidental findings, attitudes, preferences, choices, utilities, stated-preferences, discrete choice experiment, and willingness-to-pay. We conducted 11 formal searches to refine the strategy and conducted a final search in December 2017. Duplicates were eliminated and a title and abstract review was conducted to select articles meeting inclusion criteria. RESULTS/ANTICIPATED RESULTS: Our search strategy identified 79 publications meeting initial search criteria with 30 manuscripts meeting inclusion criteria. Of these, most studies were conducted with patient-participants enrolled in existing sequencing studies, while few engaged members of the general public. Of the studies conducted on patients, most were on the medical setting of cancer and related syndromes. The earliest publication date of a manuscript meeting our inclusion criteria was in 2012, yet the majority were published in 2015 or later. DISCUSSION/SIGNIFICANCE OF IMPACT: Between 2012 and 2015, we saw an increasing focus in the medical literature on understanding public and patient preferences for return of results from WGS and WES. Both public and patient populations participating in surveys expressed preferences for receiving results from next-generation sequencing, even if the results are secondary or incidental findings unrelated to the primary indication for sequencing. A primary factor related to patient interest in incidental or secondary findings is the extent to which these results can inform medical intervention. Few studies surveyed representative population-based samples, and this may be an area for future investigation.

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Whole-Exome Sequencing for Diagnosis of Turner Syndrome: Toward Next-Generation Sequencing and Newborn Screening

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2016-3414 ◽

2017 ◽

Vol 102 (5) ◽

pp. 1529-1537 ◽

Cited By ~ 13

Author(s):

David R. Murdock ◽

Frank X. Donovan ◽

Settara C. Chandrasekharappa ◽

Nicole Banks ◽

Carolyn Bondy ◽

...

Keyword(s):

Next Generation Sequencing ◽

Newborn Screening ◽

Exome Sequencing ◽

Turner Syndrome ◽

Whole Exome Sequencing ◽

Genomic Research ◽

Next Generation ◽

Low Level ◽

Whole Exome ◽

Generation Sequencing

Abstract Context: Turner syndrome (TS) is due to a complete or partial loss of an X chromosome in female patients and is not currently part of newborn screening (NBS). Diagnosis is often delayed, resulting in missed crucial diagnostic and therapeutic opportunities. Objectives: This study sought to determine if whole-exome sequencing (WES) as part of a potential NBS program could be used to diagnose TS. Design, Setting, Patients: Karyotype, chromosomal microarray, and WES were performed on blood samples from women with TS (n = 27) enrolled in the Personalized Genomic Research study at the National Institutes of Health. Female control subjects (n = 37) and male subjects (n = 27) also underwent WES. Copy number variation was evaluated using EXCAVATOR2 and B allele frequency was calculated from informative single nucleotide polymorphisms. Simulated WES data were generated for detection of low-level mosaicism and complex structural chromosome abnormalities. Results: We detected monosomy for chromosome X in all 27 TS samples, including 1 mosaic for 45,X/46,XX and another with previously unreported material on chromosome Y. Sensitivity and specificity were both 100% for the diagnosis of TS with no false-positive or false-negative results. Using simulated WES data, we detected isochromosome Xq and low-level mosaicism as low as 5%. Conclusion: We present an accurate method of diagnosing TS using WES, including cases with low-level mosaicism, isochromosome Xq, and cryptic Y-chromosome material. Given the potential use of next-generation sequencing for NBS in many different diseases and syndromes, we propose WES can be used as a screening test for TS in newborns.

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Simple sequence repeats (SSRs) markers in fish genomic research and their acceleration via next-generation sequencing and computational approaches

Aquaculture International ◽

10.1007/s10499-016-9973-4 ◽

2016 ◽

Vol 24 (4) ◽

pp. 1089-1102 ◽

Cited By ~ 9

Author(s):

Jitendra Kumar Sundaray ◽

Kiran Dashrath Rasal ◽

Vemulawada Chakrapani ◽

Pranati Swain ◽

Dinesh Kumar ◽

...

Keyword(s):

Next Generation Sequencing ◽

Simple Sequence Repeats ◽

Genomic Research ◽

Next Generation ◽

Computational Approaches ◽

Ssrs Markers ◽

Generation Sequencing ◽

Simple Sequence

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Factors Associated With Declining to Participate in a Pediatric Oncology Next-Generation Sequencing Study

JCO Precision Oncology ◽

10.1200/po.19.00213 ◽

2020 ◽

pp. 202-211 ◽

Cited By ~ 3

Author(s):

Katianne M. Howard Sharp ◽

Niki Jurbergs ◽

Annastasia Ouma ◽

Lynn Harrison ◽

Elsie Gerhardt ◽

...

Keyword(s):

Next Generation Sequencing ◽

Pediatric Oncology ◽

Black Children ◽

Genomic Research ◽

Next Generation ◽

Clinical Implementation ◽

Parental Decision Making ◽

Genomics Research ◽

Race Ethnicity ◽

Generation Sequencing

PURPOSE For the advances of pediatric oncology next-generation sequencing (NGS) research to equitably benefit all children, a diverse and representative sample of participants is needed. However, little is known about demographic and clinical characteristics that differentiate families who decline enrollment in pediatric oncology NGS research. METHODS Demographic and clinical data were retrospectively extracted for 363 pediatric patients (0-21 years) with cancer approached for enrollment in Genomes for Kids (G4K), a study examining the feasibility of comprehensive clinical genomic analysis of tumors and paired normal samples. Demographic and clinical factors that significantly differentiated which families declined were subsequently compared, for 348 families, with enrollment in Clinical Implementation of Pharmacogenetics (PG4KDS), a pharmacogenomics study with more explicit therapeutic benefit examining genes affecting drug responses and metabolism. RESULTS Fifty-three families (14.6%) declined enrollment in G4K. Race/ethnicity was the only variable that significantly differentiated study refusal according to multivariable logistic regression, with families of black children more likely to decline enrollment compared with families of non-Hispanic or Hispanic white children. Reasons for declining G4K were generally consistent with other pediatric genomics research: feeling overwhelmed and insurance discrimination fears were most frequently cited. Families of black children were also more likely to decline enrollment in PG4KDS. Thirteen (3.7%) of the 348 families approached for both studies declined PG4KDS. CONCLUSION Race/ethnicity differentiated study declination across two different pediatric oncology genomics studies, suggesting enrollment disparities in the context of pediatric oncology genomics research. Genomics research participant samples that do not fully represent racial and ethnic minorities risk further exacerbating health disparities. Additional work is needed to understand the nuances of parental decision making in genomic research and facilitate enrollment of diverse patient populations.

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WHATIF: An open-source desktop application for extraction and management of the incidental findings from next-generation sequencing variant data

Computers in Biology and Medicine ◽

10.1016/j.compbiomed.2015.03.028 ◽

2016 ◽

Vol 68 ◽

pp. 165-169 ◽

Cited By ~ 1

Author(s):

Zhan Ye ◽

Christopher Kadolph ◽

Robert Strenn ◽

Daniel Wall ◽

Elizabeth McPherson ◽

...

Keyword(s):

Next Generation Sequencing ◽

Open Source ◽

Incidental Findings ◽

Next Generation ◽

Desktop Application ◽

Generation Sequencing

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Incidental findings from cancer next generation sequencing panels

npj Genomic Medicine ◽

10.1038/s41525-021-00224-6 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Nika Maani ◽

Karen Panabaker ◽

Jeanna M. McCuaig ◽

Kathleen Buckley ◽

Kara Semotiuk ◽

...

Keyword(s):

Next Generation Sequencing ◽

Incidental Findings ◽

Complete Blood Count ◽

Hematologic Malignancy ◽

Retrospective Chart Review ◽

Hematologic Malignancies ◽

Next Generation ◽

Inclusion Criteria ◽

Pathogenic Variants ◽

Generation Sequencing

AbstractNext-generation sequencing (NGS) technologies have facilitated multi-gene panel (MGP) testing to detect germline DNA variants in hereditary cancer patients. This sensitive technique can uncover unexpected, non-germline incidental findings indicative of mosaicism, clonal hematopoiesis (CH), or hematologic malignancies. A retrospective chart review was conducted to identify cases of incidental findings from NGS-MGP testing. Inclusion criteria included: 1) multiple pathogenic variants in the same patient; 2) pathogenic variants at a low allele fraction; and/or 3) the presence of pathogenic variants not consistent with family history. Secondary tissue analysis, complete blood count (CBC) and medical record review were conducted to further delineate the etiology of the pathogenic variants. Of 6060 NGS-MGP tests, 24 cases fulfilling our inclusion criteria were identified. Pathogenic variants were detected in TP53, ATM, CHEK2, BRCA1 and APC. 18/24 (75.0%) patients were classified as CH, 3/24 (12.5%) as mosaic, 2/24 (8.3%) related to a hematologic malignancy, and 1/24 (4.2%) as true germline. We describe a case-specific workflow to identify and interpret the nature of incidental findings on NGS-MGP. This workflow will provide oncology and genetic clinics a practical guide for the management and counselling of patients with unexpected NGS-MGP findings.

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Paroxysmal Movement Disorders

Frontiers in Neurology ◽

10.3389/fneur.2021.659064 ◽

2021 ◽

Vol 12 ◽

Author(s):

Susan Harvey ◽

Mary D. King ◽

Kathleen M. Gorman

Keyword(s):

Next Generation Sequencing ◽

Movement Disorders ◽

Clinical Phenotype ◽

Single Gene ◽

Copy Number Variant ◽

Genomic Research ◽

Next Generation ◽

Causative Gene ◽

Gene Testing ◽

Generation Sequencing

Paroxysmal movement disorders (PxMDs) are a clinical and genetically heterogeneous group of movement disorders characterized by episodic involuntary movements (dystonia, dyskinesia, chorea and/or ataxia). Historically, PxMDs were classified clinically (triggers and characteristics of the movements) and this directed single-gene testing. With the advent of next-generation sequencing (NGS), how we classify and investigate PxMDs has been transformed. Next-generation sequencing has enabled new gene discovery (RHOBTB2, TBC1D24), expansion of phenotypes in known PxMDs genes and a better understanding of disease mechanisms. However, PxMDs exhibit phenotypic pleiotropy and genetic heterogeneity, making it challenging to predict genotype based on the clinical phenotype. For example, paroxysmal kinesigenic dyskinesia is most commonly associated with variants in PRRT2 but also variants identified in PNKD, SCN8A, and SCL2A1. There are no radiological or biochemical biomarkers to differentiate genetic causes. Even with NGS, diagnosis rates are variable, ranging from 11 to 51% depending on the cohort studied and technology employed. Thus, a large proportion of patients remain undiagnosed compared to other neurological disorders such as epilepsy, highlighting the need for further genomic research in PxMDs. Whole-genome sequencing, deep-sequencing, copy number variant analysis, detection of deep-intronic variants, mosaicism and repeat expansions, will improve diagnostic rates. Identifying the underlying genetic cause has a significant impact on patient care, modification of treatment, long-term prognostication and genetic counseling. This paper provides an update on the genetics of PxMDs, description of PxMDs classified according to causative gene rather than clinical phenotype, highlighting key clinical features and providing an algorithm for genetic testing of PxMDs.

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