scholarly journals The Science and Art of Clinical Genetic Variant Classification and Its Impact on Test Accuracy

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Hunter H. Giles ◽  
Madhuri R. Hegde ◽  
Elaine Lyon ◽  
Christine M. Stanley ◽  
Iain D. Kerr ◽  
...  
Keyword(s):  
Genetic Variant ◽  
Human Genetics ◽  
Classification Systems ◽  
Annual Review ◽  
Publication Date ◽  
Clinical Genetics ◽  
Test Accuracy ◽  
Variant Classification ◽  
Clinical Genetic ◽  
Science And Art

Clinical genetic variant classification science is a growing subspecialty of clinical genetics and genomics. The field's continued improvement is essential for the success of precision medicine in both germline (hereditary) and somatic (oncology) contexts. This review focuses on variant classification for DNA next-generation sequencing tests. We first summarize current limitations in variant discovery and definition, and then describe the current five- and four-tier classification systems outlined in dominant standards and guideline publications for germline and somatic tests, respectively. We then discuss measures of variant classification discordance and the field's bias for positive results, as well as considerations for panel size and population screening in the context of estimates of positive predictive value that incorporate estimated variant classification imperfections. Finally, we share opinions on the current state of variant classification from some of the authors of the most widely used standards and guideline publications and from other domain experts. 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.

Long Noncoding RNAs and Human Liver Disease

2021 ◽  
Vol 17 (1) ◽  
Author(s):  
Johanna K. DiStefano ◽  
Glenn S. Gerhard
Keyword(s):  
Liver Disease ◽  
Biological Significance ◽  
Noncoding Rnas ◽  
Classification Systems ◽  
Long Noncoding Rnas ◽  
Annual Review ◽  
Publication Date ◽  
Cholestatic Liver Disease ◽  
Diverse Range ◽  
Number Of Publications

Long noncoding RNAs (lncRNAs) are pervasively transcribed in the genome, exhibit a diverse range of biological functions, and exert effects through a variety of mechanisms. The sheer number of lncRNAs in the human genome has raised important questions about their potential biological significance and roles in human health and disease. Technological and computational advances have enabled functional annotation of a large number of lncRNAs. Though the number of publications related to lncRNAs has escalated in recent years, relatively few have focused on those involved in hepatic physiology and pathology. We provide an overview of evolving lncRNA classification systems and characteristics and highlight important advances in our understanding of the contribution of lncRNAs to liver disease, with a focus on nonalcoholic steatohepatitis, hepatocellular carcinoma, and cholestatic liver disease. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 17 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Mycotoxin Production in Fusarium According to Contemporary Species Concepts

2021 ◽  
Vol 59 (1) ◽  
Author(s):  
Gary P. Munkvold ◽  
Robert H. Proctor ◽  
Antonio Moretti
Keyword(s):  
Fusarium Species ◽  
Pathogenic Fungi ◽  
Species Concepts ◽  
Classification Systems ◽  
Individual Species ◽  
Annual Review ◽  
Publication Date ◽  
Mycotoxin Production ◽  
Depth Of Knowledge ◽  
Genus Fusarium

Fusarium is one of the most important genera of plant-pathogenic fungi in the world and arguably the world's most important mycotoxin-producing genus. Fusarium species produce a staggering array of toxic metabolites that contribute to plant disease and mycotoxicoses in humans and other animals. A thorough understanding of the mycotoxin potential of individual species is crucial for assessing the toxicological risks associated with Fusarium diseases. There are thousands of reports of mycotoxin production by various species, and there have been numerous attempts to summarize them. These efforts have been complicated by competing classification systems based on morphology, sexual compatibility, and phylogenetic relationships. The current depth of knowledge of Fusarium genomes and mycotoxin biosynthetic pathways provides insights into how mycotoxin production is distributed among species and multispecies lineages (species complexes) in the genus as well as opportunities to clarify and predict mycotoxin risks connected with known and newly described species. Here, we summarize mycotoxin production in the genus Fusarium and how mycotoxin risk aligns with current phylogenetic species concepts. Expected final online publication date for the Annual Review of Phytopathology, Volume 59 is August 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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.

scholarly journals Variant Re-interpretation in Survivors of Cardiac Arrest with Preserved Ejection Fraction (CASPER Registry) by Clinicians and Clinical Commercial Laboratories

2021 ◽  
Author(s):  
Brianna Davies ◽  
Kirsten Bartels ◽  
Julie Hathaway ◽  
Fang Xu ◽  
Jason D. Roberts ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Ejection Fraction ◽  
Genetic Variant ◽  
Clinical Care ◽  
Variant Classification ◽  
Variant Interpretation ◽  
Preserved Ejection Fraction ◽  
Periodic Review ◽  
Clinical Genetic ◽  
Over Time

Background - Following an unexplained cardiac arrest, clinical genetic testing is increasingly becoming standard of care. Periodic review of variant classification is required, as re-interpretation can change the diagnosis, prognosis, and management of patients and their relatives. Methods - This study aimed to develop and validate a standardized algorithm to facilitate clinical application of the 2015 American College of Medical Genetics and Association for Molecular Pathology (ACMG-AMP) guidelines for the interpretation of genetic variants. The algorithm was applied to genetic results in the Cardiac Arrest Survivors with Preserved Ejection Fraction Registry (CASPER), to assess the rate of variant re-classification over time. Variant classifications were then compared to the classifications of two commercial laboratories to determine the rate and identify sources of variant interpretation discordance. Results - Thirty-one percent of participants (40/131) had at least one genetic variant with a clinically significant reclassification over time. Variants of uncertain significance were more likely to be downgraded (73%) to benign than upgraded to pathogenic (27%, p= 0.03). For the second part of the study, 50% (70/139) of variants had discrepant interpretations (excluding benign variants), provided by at least one team. Conclusions - Periodic review of genetic variant classification is a key component of follow-up care given rapidly changing information in the field. There is potential for clinical care gaps with discrepant variant interpretations, based in the interpretation and application of current guidelines. The development of gene and disease specific guidelines and algorithms may provide an opportunity to further standardize variant interpretation reporting in the future.

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 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 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 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.

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