scholarly journals Utility and Diversity: Challenges for Genomic Medicine

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Wylie Burke
Keyword(s):  
Human Population ◽  
Clinical Utility ◽  
Human Genetics ◽  
Clinical Care ◽  
Genomic Medicine ◽  
Annual Review ◽  
Publication Date ◽  
Genomic Information ◽  
European Descent ◽  
Genomic Knowledge

Genomic information is poised to play an increasing role in clinical care, extending beyond highly penetrant genetic conditions to less penetrant genotypes and common disorders. But with this shift, the question of clinical utility becomes a major challenge. A collaborative effort is necessary to determine the information needed to evaluate different uses of genomic information and then acquire that information. Another challenge must also be addressed if that process is to provide equitable benefits: the lack of diversity of genomic data. Current genomic knowledge comes primarily from populations of European descent, which poses the risk that most of the human population will be shortchanged when health benefits of genomics emerge. These two challenges have defined my career as a geneticist and have taught me that solutions must start with dialogue across disciplinary and social divides. Expected final online publication date for the Annual Review of Genomics and Human Genetics Volume 22 is August 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals Scaling Genetic Counseling in the Genomics Era

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Laura M. Amendola ◽  
Katie Golden-Grant ◽  
Sarah Scollon
Keyword(s):  
Genetic Counseling ◽  
Human Genetics ◽  
Massively Parallel Sequencing ◽  
Genomic Medicine ◽  
Genetic Counselors ◽  
Annual Review ◽  
Publication Date ◽  
Counseling Training ◽  
Key Stakeholders ◽  
Genetic Counseling Service

The development of massively parallel sequencing–based genomic sequencing tests has increased genetic test availability and access. The field and practice of genetic counseling have adapted in response to this paradigm-shifting technology and the subsequent transition to practicing genomic medicine. While the key elements defining genetic counseling remain relevant, genetic counseling service delivery models and practice settings have evolved. Genetic counselors are addressing the challenges of direct-to-consumer and consumer-driven genetic testing, and genetic counseling training programs are responding to the ongoing increased demand for genetic counseling services across a broadening range of contexts. The need to diversify both the patient and participant groups with access to genetic information, as well as the field of genetic counseling, is at the forefront of research and training program initiatives. Genetic counselors are key stakeholders in the genomics era, and their contributions are essential to effectively and equitably deliver precision medicine. Expected final online publication date for the Annual Review of Genomics and Human Genetics Volume 22 is August 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals The Role of Electronic Health Records in Advancing Genomic Medicine

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Jodell E. Linder ◽  
Lisa Bastarache ◽  
Jacob J. Hughey ◽  
Josh F. Peterson
Keyword(s):  
Electronic Health Records ◽  
Association Studies ◽  
Clinical Care ◽  
Genomic Medicine ◽  
Risk Scores ◽  
Annual Review ◽  
Publication Date ◽  
Health Records ◽  
Electronic Health

Recent advances in genomic technology and widespread adoption of electronic health records (EHRs) have accelerated the development of genomic medicine, bringing promising research findings from genome science into clinical practice. Genomic and phenomic data, accrued across large populations through biobanks linked to EHRs, have enabled the study of genetic variation at a phenome-wide scale. Through new quantitative techniques, pleiotropy can be explored with phenome-wide association studies, the occurrence of common complex diseases can be predicted using the cumulative influence of many genetic variants (polygenic risk scores), and undiagnosed Mendelian syndromes can be identified using EHR-based phenotypic signatures (phenotype risk scores). In this review, we trace the role of EHRs from the development of genome-wide analytic techniques to translational efforts to test these new interventions to the clinic. Throughout, we describe the challenges that remain when combining EHRs with genetics to improve clinical care. Expected final online publication date for the Annual Review of Genomics and Human Genetics, Volume 22 is August 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Test genetici e consenso informato

2012 ◽  
pp. 68-95
Author(s):  
Marco Seri ◽  
Claudio Graziano ◽  
Daniela Turchetti ◽  
Juri Monducci
Keyword(s):  
Dna Sequencing ◽  
Human Genetics ◽  
Ethical Issues ◽  
Clinical Care ◽  
Genomic Medicine ◽  
Genome Project ◽  
Ethical Challenges ◽  
Sequencing Technologies ◽  
The Human Genome Project

The pace of discovery in the field of human genetics has increased exponentially in the last 30 years. We have witnessed the completion of the Human Genome Project, the identification of hundreds of disease-causing genes, and the dawn of genomic medicine (clinical care based on genomic information). Reduction of DNA sequencing costs, thanks to the so-called "next generation sequencing" technologies, is driving a shift towards the era of "personal genomes", but scientific as well as ethical challenges ahead are countless. We provide an overview on the classification of genetic tests, on informed consent procedures in the context of genetic counseling, and on specific ethical issues raised by the implementation of new DNA sequencing technologies.

scholarly journals The Need for a Human Pangenome Reference Sequence

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Karen H. Miga ◽  
Ting Wang
Keyword(s):  
Human Genome ◽  
Genome Sequence ◽  
Human Genetics ◽  
Genomic Diversity ◽  
Human Genome Sequence ◽  
Reference Sequence ◽  
Annual Review ◽  
Publication Date ◽  
Reference Structure ◽  
Reference Human Genome

The reference human genome sequence is inarguably the most important and widely used resource in the fields of human genetics and genomics. It has transformed the conduct of biomedical sciences and brought invaluable benefits to the understanding and improvement of human health. However, the commonly used reference sequence has profound limitations, because across much of its span, it represents the sequence of just one human haplotype. This single, monoploid reference structure presents a critical barrier to representing the broad genomic diversity in the human population. In this review, we discuss the modernization of the reference human genome sequence to a more complete reference of human genomic diversity, known as a human pangenome. Expected final online publication date for the Annual Review of Genomics and Human Genetics, Volume 22 is August 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals The Yin and Yang of Histone Marks in Transcription

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Paul B. Talbert ◽  
Steven Henikoff
Keyword(s):  
Posttranslational Modifications ◽  
Human Genetics ◽  
Annual Review ◽  
Publication Date ◽  
Histone Marks ◽  
The Core ◽  
Core Histones ◽  
Yin And Yang ◽  
Transcriptional State ◽  
Histone Core

Nucleosomes wrap DNA and impede access for the machinery of transcription. The core histones that constitute nucleosomes are subject to a diversity of posttranslational modifications, or marks, that impact the transcription of genes. Their functions have sometimes been difficult to infer because the enzymes that write and read them are complex, multifunctional proteins. Here, we examine the evidence for the functions of marks and argue that the major marks perform a fairly small number of roles in either promoting transcription or preventing it. Acetylations and phosphorylations on the histone core disrupt histone-DNA contacts and/or destabilize nucleosomes to promote transcription. Ubiquitylations stimulate methylations that provide a scaffold for either the formation of silencing complexes or resistance to those complexes, and carry a memory of the transcriptional state. Tail phosphorylations deconstruct silencing complexes in particular contexts. We speculate that these fairly simple roles form the basis of transcriptional regulation by histone marks. Expected final online publication date for the Annual Review of Genomics and Human Genetics Volume 22 is August 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Clinical Staging for Youth Mental Disorders: Progress in Reforming Diagnosis and Clinical Care

2021 ◽  
Vol 3 (1) ◽  
Author(s):  
Patrick D. McGorry ◽  
Cristina Mei
Keyword(s):  
Mental Health ◽  
Mental Disorders ◽  
Developmental Psychology ◽  
Clinical Care ◽  
Clinical Staging ◽  
Annual Review ◽  
Publication Date ◽  
Diagnostic Systems ◽  
Illness Progression ◽  
Selection Of

Current silo-based diagnostic systems for mental disorders lack utility and fail to fulfil a fundamental purpose of diagnosis: to guide treatment planning and predict outcomes. Diagnostic reform has gained momentum, and clinical staging has emerged as a promising framework to improve the precision of diagnosis, particularly in early illness stages, and fill current gaps in linking diagnosis to more personalized and effective intervention, prognosis, and neurobiological markers. Transdiagnostic clinical staging recognizes that the early development of mental ill-health is marked by substantial fluidity and that symptoms may, although not inevitably, evolve into more stable diagnosable syndromes. Staging facilitates the selection of interventions that are proportionate to the current need and risk of illness progression and provides an efficient framework to organize biomarker data and guide service delivery. Here, we provide an overview of transdiagnostic clinical staging and summarize key evidence supporting its ability to integrate biomarkers and guide mental health care. Expected final online publication date for the Annual Review of Developmental Psychology, Volume 3 is December 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals Applications of Single-Cell DNA Sequencing

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Gilad D. Evrony ◽  
Anjali Gupta Hinch ◽  
Chongyuan Luo
Keyword(s):  
Dna Sequencing ◽  
Single Cell ◽  
Human Genetics ◽  
Single Cells ◽  
Annual Review ◽  
Publication Date ◽  
Genomic Analyses ◽  
Somatic Mutagenesis ◽  
Organismal Development ◽  
Fundamental Units

Over the past decade, genomic analyses of single cells—the fundamental units of life—have become possible. Single-cell DNA sequencing has shed light on biological questions that were previously inaccessible across diverse fields of research, including somatic mutagenesis, organismal development, genome function, and microbiology. Single-cell DNA sequencing also promises significant future biomedical and clinical impact, spanning oncology, fertility, and beyond. While single-cell approaches that profile RNA and protein have greatly expanded our understanding of cellular diversity, many fundamental questions in biology and important biomedical applications require analysis of the DNA of single cells. Here, we review the applications and biological questions for which single-cell DNA sequencing is uniquely suited or required. We include a discussion of the fields that will be impacted by single-cell DNA sequencing as the technology continues to advance. Expected final online publication date for the Annual Review of Genomics and Human Genetics Volume 22 is August 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals Avoiding Extinction: Recent Advances in Understanding Mechanisms of Mitochondrial DNA Purifying Selection in the Germline

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Swathi P. Jeedigunta ◽  
Anastasia V. Minenkova ◽  
Jonathan M. Palozzi ◽  
Thomas R. Hurd
Keyword(s):  
Mitochondrial Dna ◽  
Recent Progress ◽  
Human Genetics ◽  
Purifying Selection ◽  
Annual Review ◽  
Publication Date ◽  
Deleterious Mutations ◽  
A Genome ◽  
Selection Mechanisms ◽  
Female Germline

Mitochondria are unusual organelles in that they contain their own genomes, which are kept apart from the rest of the DNA in the cell. While mitochondrial DNA (mtDNA) is essential for respiration and most multicellular life, maintaining a genome outside the nucleus brings with it a number of challenges. Chief among these is preserving mtDNA genomic integrity from one generation to the next. In this review, we discuss what is known about negative (purifying) selection mechanisms that prevent deleterious mutations from accumulating in mtDNA in the germline. Throughout, we focus on the female germline, as it is the tissue through which mtDNA is inherited in most organisms and, therefore, the tissue that most profoundly shapes the genome. We discuss recent progress in uncovering the mechanisms of germline mtDNA selection, from humans to invertebrates. Expected final online publication date for the Annual Review of Genomics and Human Genetics, Volume 22 is August 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals Heart Development and Congenital Structural Heart Defects

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Lucile Houyel ◽  
Sigolène M. Meilhac
Keyword(s):  
Congenital Heart Defects ◽  
Heart Development ◽  
Congenital Heart ◽  
Human Genetics ◽  
Current Knowledge ◽  
Phenotypic Diversity ◽  
Heart Defects ◽  
Annual Review ◽  
Publication Date ◽  
Research Perspectives

Congenital heart disease is the most frequent birth defect and the leading cause of death for the fetus and in the first year of life. The wide phenotypic diversity of congenital heart defects requires expert diagnosis and sophisticated repair surgery. Although these defects have been described since the seventeenth century, it was only in 2005 that a consensus international nomenclature was adopted, followed by an international classification in 2017 to help provide better management of patients. Advances in genetic engineering, imaging, and omics analyses have uncovered mechanisms of heart formation and malformation in animal models, but approximately 80% of congenital heart defects have an unknown genetic origin. Here, we summarize current knowledge of congenital structural heart defects, intertwining clinical and fundamental research perspectives, with the aim to foster interdisciplinary collaborations at the cutting edge of each field. We also discuss remaining challenges in better understanding congenital heart defects and providing benefits to patients. Expected final online publication date for the Annual Review of Genomics and Human Genetics, Volume 22 is August 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals Clinical Utilization, Utility, and Reimbursement for Expanded Genomic Panel Testing in Adult Oncology

2020 ◽  
pp. 1038-1048
Author(s):  
Susan J. Hsiao ◽  
Anthony N. Sireci ◽  
Danielle Pendrick ◽  
Christopher Freeman ◽  
Helen Fernandes ◽  
...  
Keyword(s):  
Clinical Practice ◽  
High Risk ◽  
Clinical Utility ◽  
Medical Center ◽  
Clinical Care ◽  
Genomic Medicine ◽  
Tumor Board ◽  
Panel Testing ◽  
Pan Cancer ◽  
Cancer Panel

PURPOSE The routine use of large next-generation sequencing (NGS) pan-cancer panels is required to identify the increasing number of, but often uncommon, actionable alterations to guide therapy. Inconsistent coverage and variable payment is hindering NGS adoption into clinical practice. A review of test utilization, clinical utility, coverage, and reimbursement was conducted in a cohort of patients diagnosed with high-risk cancer who received pan-cancer panel testing as part of their clinical care. MATERIALS AND METHODS The Columbia Combined Cancer Panel (CCCP), a 467-gene panel designed to detect DNA variations in solid and liquid tumors, was performed in the Laboratory of Personalized Genomic Medicine at Columbia University Irving Medical Center. Utilization was characterized at test order. Results were reviewed by a molecular pathologist, followed by a multidisciplinary molecular tumor board where clinical utility was classified by consensus. Reimbursement was reviewed after payers provided final coverage decisions. RESULTS NGS was performed on 359 high-risk tumors from 349 patients. Reimbursement data were available for 246 cases. The most common reason providers ordered CCCP testing was for patients diagnosed with a treatment-resistant or recurrent tumor (n = 214; 61%). Findings were clinically impactful for 229 cases (64%). Molecular alterations that may inform future therapy in the event of progression or relapse were found in 42% of cases, and a targeted therapy was initiated in 23 cases (6.6%). The majority of tests were denied coverage by payers (n = 190; 77%). On average, insurers reimbursed 10.75% of the total NGS service charge. CONCLUSION CCCP testing identified clinically impactful alterations in 64% of cases. Limited coverage and low reimbursement remain barriers, and broader reimbursement policies are needed to adopt pan-cancer NGS testing that benefits patients into clinical practice.

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