Showing papers in "Current Genetic Medicine Reports in 2014"

Late-Onset Alzheimer's Disease Genes and the Potentially Implicated Pathways.

Abstract: Late-onset Alzheimer’s disease (LOAD) is a devastating neurodegenerative disease with no effective treatment or cure. In addition to APOE, recent large genome-wide association studies have identified variation in over 20 loci that contribute to disease risk: CR1, BIN1, INPP5D, MEF2C, TREM2, CD2AP, HLA-DRB1/HLA-DRB5, EPHA1, NME8, ZCWPW1, CLU, PTK2B, PICALM, SORL1, CELF1, MS4A4/MS4A6E, SLC24A4/RIN3,FERMT2, CD33, ABCA7, CASS4. In addition, rare variants associated with LOAD have also been identified in APP, TREM2 and PLD3 genes. Previous research has identified inflammatory response, lipid metabolism and homeostasis, and endocytosis as the likely modes through which these gene products participate in Alzheimer’s disease. Despite the clustering of these genes across a few common pathways, many of their roles in disease pathogenesis have yet to be determined. In this review, we examine both general and postulated disease functions of these genes and consider a comprehensive view of their potential roles in LOAD risk.

Closing the Gap: Genetic and Genomic Continuum from Syndromic to Nonsyndromic Craniosynostoses

Abstract: Craniosynostosis, a condition that includes the premature fusion of one or multiple cranial sutures, is a relatively common birth defect in humans and the second most common craniofacial anomaly after orofacial clefts. There is a significant clinical variation among different sutural synostoses as well as significant variation within any given single-suture synostosis. Craniosynostosis can be isolated (i.e., nonsyndromic) or occurs as part of a genetic syndrome (e.g., Crouzon, Pfeiffer, Apert, Muenke, and Saethre-Chotzen syndromes). Approximately 85 % of all cases of craniosynostosis are nonsyndromic. Several recent genomic discoveries are elucidating the genetic basis for nonsyndromic cases and implicate the newly identified genes in signaling pathways previously found in syndromic craniosynostosis. Published epidemiologic and phenotypic studies clearly demonstrate that nonsyndromic craniosynostosis is a complex and heterogeneous condition supporting a strong genetic component accompanied by environmental factors that contribute to the pathogenetic network of this birth defect. Large population, rather than single-clinic or hospital-based studies is required with phenotypically homogeneous subsets of patients to further understand the complex genetic, maternal, environmental, and stochastic factors contributing to nonsyndromic craniosynostosis. Learning about these variables is a key in formulating the basis of multidisciplinary and lifelong care for patients with these conditions.

Copy Number Variation in Congenital Heart Defects

Abstract: Congenital heart defects (CHDs) are the most common birth defect and a major contributor to mortality, morbidity, and healthcare costs throughout the world. Although improvements in surgical advances and cardiac care have increased the lifespan of individuals with CHDs, the underlying etiologies of disease remain elusive and there have been no interventions that decrease disease incidence. Genetic, epigenetic, and environmental factors all influence the development of CHDs, and an improved understanding of causation is a prerequisite for prevention. Genetic causes of CHDs include both structural chromo- some abnormalities and single gene disorders. Copy num- ber variation (CNV), or submicroscopic chromosomal deletions or duplications, has emerged as an important contributor to congenital genetic disorders, including CHDs, and has identified critical dosage sensitive genes important for cardiac development. Common CNVs asso- ciated with highly penetrant CHDs were first identified in genomic disorders such as 22q11.2 deletion syndrome and Williams-Beuren syndrome. More recently, research investigations and clinical diagnostic testing support a role for CNVs in CHDs with extracardiac abnormalities (ECAs) as well as isolated CHD. It is estimated that CNVs con- tribute to 3-25 % of CHDs with ECAs and 3-10 % of isolated CHDs. While somewhat less clear, new evidence suggests that there is an increase in rare, large, genic CNVs in patients with CHDs, indicating that the overall CNV burden may also be an important factor in disease. As genetic testing for CHDs moves forward, CNVs will play an important role in diagnosis and gene discovery.

CNVs in Epilepsy.

Abstract: Copy number variants (CNVs) are deletions or duplications of DNA. CNVs have been increasingly recognized as an important source of both normal genetic variation and pathogenic mutation. Technologies for genome-wide discovery of CNVs facilitate studies of large cohorts of patients and controls to identify CNVs that cause increased risk for disease. Over the past 5 years, studies of patients with epilepsy confirm that both recurrent and non-recurrent CNVs are an important source of mutation for patients with various forms of epilepsy. Here, we will review the latest findings and explore the clinical implications.

After Myriad: Genetic Testing in the Wake of Recent Supreme Court Decisions about Gene Patents

Abstract: Genetic testing is becoming more common and more powerful by the day. The costs of the underlying DNA sequencing technology are plummeting, making it likely that tests based on it will become even more pervasive. The use of tests to determine DNA sequence to help make clinical decisions is here to stay. DNA sequencing is also finding new uses in forensics, determination of ancestry, understanding the history and genetic lineages of human populations and many other applications.

Cross-Disorder Comparison of Four Neuropsychiatric CNV Loci

Abstract: Copy number variants (CNVs) have been identified as a major risk factor in neuropsychiatric disorders. In this review, we describe the phenotypes and syndromic features associated with CNVs at four of the best-characterized risk loci for these disorders: 15q11.2-13.1, 22q11.2, 16p11.2, and 7q11.23. By considering the reported prevalence of these CNVs in autism, intellectual disability, schizophrenia, and controls, we demonstrate a pattern of asymmetric shared risk in which CNVs increase the risk of multiple disorders but to differing degrees. This asymmetric risk sharing is incompatible with a model in which CNVs observed in autism or schizophrenia are secondary to a reduction in IQ, but favors a more complex relationship between individual CNVs and specific neuropsychiatric phenotypes. Finally, we discuss how the lessons learned from CNVs in neuropsychiatric disorders will translate to the expanding list of genes being associated with these disorders through exome sequencing.

The Critical Challenge of Educating the Public About Genetics

Abstract: The translation of genomics into medicine would benefit from a public that has a strong foundation in core genetics principles and that is able to access, identify, and use reliable information. Unfortunately, public understanding of genetics is generally poor, a condition that can be traced to deficiencies in formal science education, weaknesses in representations of genetics in the media and on the Internet, and the limited knowledge and involvement of health care providers in patient education. Notwithstanding these challenges, the Internet, media, and health professionals likely will remain major sources of public education. Whether those sources contribute positively or negatively will depend, in part, on the public’s ability to discriminate high-quality from low-quality information and on health providers’ understanding of genetics and their willingness to engage in the genetics education of their patients.

The Influences of Genetic and Environmental Factors on Methylome-Wide Association Studies for Human Diseases

Abstract: DNA methylation (DNAm) is an essential epigenetic mechanism for normal development, and its variation may be associated with diseases. High-throughput technology allows robust measurement of DNA methylome in population studies. Methylome-wide association studies (MWAS) scan DNA methylome to detect new epigenetic loci affecting disease susceptibility. MWAS is an emerging approach to unraveling the mechanism linking genetics, environment, and human diseases. Here I review the recent studies of genetic determinants and environmental modifiers of DNAm, and the concept for partitioning genetic and environmental contribution to DNAm. These studies establish the correlation maps between genome and methylome, and enable the interpretation of epigenetic association with disease traits. Recent findings suggested that MWAS was a promising genomic method to identify epigenetic predictors accounting for unexplained disease risk. However, new study designs, analytical methods and shared resources need to be implemented to address the limitations and challenges in future epigenomic epidemiologic studies.

Genetic Counseling for Diabetes Mellitus.

Abstract: Most diabetes is polygenic in etiology, with (type 1 diabetes, T1DM) or without (type 2 diabetes, T2DM) an autoimmune basis. Genetic counseling for diabetes generally focuses on providing empiric risk information based on family history and/or the effects of maternal hyperglycemia on pregnancy outcome. An estimated one to five percent of diabetes is monogenic in nature, e.g., maturity onset diabetes of the young, with molecular testing and etiology-based treatment available. However, recent studies show that most monogenic diabetes is misdiagnosed as T1DM or T2DM. While efforts are underway to increase the rate of diagnosis in the diabetes clinic, genetic counselors and clinical geneticists are in a prime position to identify monogenic cases through targeted questions during a family history combined with working in conjunction with diabetes professionals to diagnose and assure proper treatment and familial risk assessment for individuals with monogenic diabetes.

Genomic Variation: Lessons Learned from Whole-Genome CNV Analysis

Abstract: One of the most fundamental goals of the study of human genetics was to determine the relationship between genomic variation and human disease. The effects of large-scale structural variation, such as aneuploidy and other cytogenetically visible imbalances, as well as sequence-level variation, have been studied for several decades. However, compared to these, the impact of submicroscopic copy number variants (CNV) has only recently been appreciated. Despite this, lessons learned from the study of CNVs have already proven significant and broadly applicable. From expanding the concept of normal human variation to providing concrete examples of the utility of genomics in clinical care and challenging notions of the genetic architecture of complex disease, CNVs have provided valuable insights into the genomics of human health and development.

Genome-Wide Association Studies of Cardiovascular Disease in European and Non-European Populations

Abstract: Genome-wide association studies (GWASs) for coronary artery disease (CAD) have identified more than 40 variants robustly associated with CAD risk in European white populations. Overall, the majority of GWAS-identified CAD loci are in non-coding regions of the genome and may encompass multiple signals of variable effect. Most of these are not associated with conventional risk factors but highlight novel pathways, including extracellular matrix integrity, proliferative response to cellular injury and immune regulation. Many but not all of these CAD-associated loci have been found to replicate in South Asian and East Asian populations although with variable effect size in South Asians. The significantly shorter haplotype blocks in populations of African ethnicity may be helpful in fine mapping association signals identified in European populations and also in identifying new signals that may be ethnic specific. However, differential linkage disequilibrium between tag SNPs and functional variants contribute significantly to diluting the effect sizes, and few significant CAD loci identified in European populations have been replicated in African Americans.

Genetic discoveries in AD using CSF amyloid and tau

Abstract: The use of cerebrospinal fluid (CSF) levels of Aβ42 and Tau phosphorylated at threonine 181 (pTau181) as endophenotypes for genetic studies of Alzheimer’s disease (AD) has led to successful identification of both rare and common AD risk variants. In addition, this approach has provided meaningful hypotheses for the biological mechanisms by which known AD risk variants modulate the disease process. In this article, we discuss these successes and outline challenges to effective and continued applications of this approach. We contrast the statistical power of this approach with traditional case-control designs and discuss solutions to address challenges in quality control and data analysis for these phenotypes. Finally, we discuss the potential for the use of this approach with larger samples as well as the incorporation of next generation sequencing and for future work with other endophenotypes for AD.

The Role of Genetic Counselors for Patients with Familial Hypercholesterolemia

Abstract: Familial hypercholesterolemia (FH) is the most common inherited cause of premature coronary heart disease and leads to significant morbidity and mortality. Genetic counselors are specialized health care professionals with advanced degrees and training in both medical genetics and psychosocial counseling. FH patients and their families require focused education regarding the heritable nature of their disease, the risk to family members, the necessity of cascade screening, and the availability of genetic testing. Patients and families may also benefit from additional services genetic counselors provide, such as psychosocial support and other resources. All of these services are well-established components of the genetic counseling process. Therefore, genetic counselors can serve as a valuable resource to FH patients, their families, and the multidisciplinary team of clinicians providing care for these patients.

Genetics of Psychosis in Alzheimer Disease

Abstract: Psychosis occurs in approximately half of patients with Alzheimer disease (AD with psychosis, AD + P). AD + P patients have more rapid cognitive decline, greater behavioral symptoms, and higher mortality than do AD patients without psychosis. Studies in three independent cohorts have shown that psychosis in AD aggregates in families, with estimated heritability of 29.5–60.8 %. These findings have motivated studies to investigate and uncover the genes responsible for the development of psychosis, with the ultimate goal of identifying potential biologic mechanisms that may serve as leads to specific therapies. Linkage analyses have implicated loci on chromosomes 2, 6–8, 15, and 21 with AD + P. Association studies on apolipoprotein E do not support it as a risk gene for psychosis in AD. No other candidate genes, such as neurodegenerative and monoamine genes, show conclusive evidence of association with AD + P. However, a recent genome-wide association study has produced some promising leads, including among them genes that have been associated with schizophrenia. This review summarizes the current knowledge on the genetic basis of AD + P.

Rare Variants and Transcriptomics in Alzheimer disease.

Abstract: Alzheimer disease (AD) is the most common dementia in the elderly, still without effective treatment. Early-onset AD (EOAD) is caused by mutations in the genes APP, PSEN1 and PSEN2. Genome-wide association studies have identified >20 late-onset AD (LOAD) susceptibility genes with common variants of small risk, with the exception of APOE. We review rare susceptibility variants in LOAD with larger effects that have been recently identified in the EOAD gene APP and the newly discovered AD genes TREM2 and PLD3. Human genetic studies now consistently support the amyloid hypothesis of AD for both EOAD and LOAD. Moreover, they identified biological processes that overlap with human transcriptomics studies in AD across different tissues, such as inflammation, cytoskeletal organization, synaptic functions, etc. Transcriptomic profiles of pre-symptomatic AD-associated variant carriers already reflect specific molecular mechanisms reminiscent to those of AD patients. This might provide an avenue for personalized medicine.

Subtle Psychosocial Sequelae of Genetic Test Results

Abstract: Research using standard psychological measures has not revealed a dramatic psychological reaction to receipt of predictive genetic test results. Qualitative research, however, indicates that there are subtle psychosocial sequelae of receiving such results that should be considered by individuals and their clinicians prior to testing. Among these more subtle, but burdensome sequelae of testing are (i) changed social relationships (including relationships with clinicians), (ii) the impact of test results on important life decisions (e.g., career and reproductive choices), and (iii) altered self-concept among those tested. This review examines these more subtle sequelae, as well as the inadequacy of existing quantitative measures for assessing their impact, and discusses the relevance of such sequelae for decision-making about predictive genetic testing.

Pragmatic and Ethical Challenges of Incorporating the Genome into the Electronic Health Record

Abstract: Recent successes in the use of gene sequencing for patient care highlight the potential of genomic medicine. For genomics to become a part of usual care, pertinent elements of a patient’s genomic test must be communicated to the most appropriate care providers. Electronic health records may serve as a useful tool for storing and disseminating genomic data. Yet, the structure of existing EHRs and the nature of genomic data pose a number of pragmatic and ethical challenges in their integration. Through a review of the recent genome-EHR integration literature, we explore concrete examples of these challenges, categorized under four key questions: What data will we store? How will we store it? How will we use it? How will we protect it? We conclude that genome-EHR integration requires a rigorous, multi-faceted, and interdisciplinary approach of study. Problems facing the field are numerous, but few are intractable.

The Rapidly Emerging Role for Whole Exome Sequencing in Clinical Genetics

Abstract: Sequencing of the exome, the protein-coding region of the human genome, has quickly grown into a new approach for clinical diagnosis of disease. Enabled by next- generation sequencing technologies, clinical exomes accompanied by clinical interpretation of the genome variants are used today to guide health care providers in understanding and diagnosing their patient's disease. Continuing improvement in both sequencing technology and exome approaches, as well as interpretation of the variation identified, will be required to fully realize the power of this new science. This review provides a glimpse into the value and complexities we all face in this quest.

Stem Cell Transplantation: Genetic Counselors as a Critical Part of the Process

Abstract: Genetic counselors bring unique and important expertise to health care teams that serve patients with genetic conditions treated by hematopoietic stem cell transplantation (HSCT). Genetic counselors are master’s-trained allied health care professionals who work in collaboration with physicians to guide patients through the complexities of heritable conditions and emerging technologies, including through the diagnostic, HSCT treatment, and post-HSCT processes. This article will review the history of HSCT for genetic conditions, the role of the genetic counselor throughout the HSCT process, and the evolving and expanding role of genetic counselors in current and future stem cell therapies.

Advances in Genetic Discovery and Implications for Counseling of Patients and Families with Autism Spectrum Disorders.

Abstract: The prevalence of autism spectrum disorders (ASD) continues to increase. Genetic factors play an important role in the etiology of ASD, although specific genetic causes are identified in only a minority of cases. Recent advances have accelerated the discovery of genes implicated in ASD through convergent genomic analysis of genome-wide association studies, chromosomal microarray, exome sequencing, genome sequencing, and gene networks. Hundreds of candidate genes for ASD have been reported, yet only a handful have proven causative. Symptoms are complex and highly variable, and most cases are likely due to cumulative genetic factors, the interactions among them, as well as environmental factors. Here we summarize recent findings in genomic research regarding discovery of candidate genes, describe the major molecular processes in neural development that may be disrupted in ASD, and discuss the implication of research findings in clinical genetic diagnostic testing and counseling. Continued advances in genetic research will eventually translate into innovative approaches to prevention and treatment of ASD.

Clinical Management of Pediatric Genomic Testing.

Abstract: As sequencing becomes integrated into clinical medicine, many complex ethical questions arise regarding the return of genomic information, especially in pediatrics. Issues center on the best interests of the child, particularly in return of information about adult-onset conditions. These include the child's future autonomous decision-making and access to knowledge about treatable conditions, the child in the family unit, and benefit to family members of learning information which could impact them personally. This article first discusses the framework for returning genomic information, and then ethical issues regarding return of results. Finally it discusses potential harms and benefits, while recognizing that little is known about what these actually are. A new era of genomic information is in its infancy; handling genomic information in a way that provides patients and their families with knowledge that is helpful without causing distress is the greatest challenge.

Blood Pressure Genetics and Hypertension: Genome-Wide Analysis and Role of Ancestry

Abstract: Genome-wide association studies have been successful in identifying an increasing number of loci as associated with blood pressure and hypertension. However, most studies undertaken to date have only included individuals of European-ancestry for discovery of loci. Although there are differences in the prevalence and incidence of cardiovascular diseases between ancestries, it is expected that a common set of genomic loci will have an underlying involvement in blood pressure across ancestries with differences in genetic effect sizes due to ancestry-related differences in linkage disequilibrium (with the true causal variant) and environmental interactions. The differences in genetic variation between ancestries, for example, linkage disequilibrium structure and allele frequencies, can be exploited to identify additional loci associated with blood pressure traits and also to fine-map signals. This review will summarise the findings to date and discuss approaches for testing association with blood pressure across different ancestries.

Ethical and Policy Issues in Genetic Prediction of Violence: Implications for Clinicians

Abstract: This paper reviews the ethical and policy issues raised by current biomedical research into violent behavior. Increasing awareness of the environmental mediation of genetic influence may not reduce the risks of social control and stigmatization. The review concludes that (1) public anxiety about mass killings and mental illness will increase pressure to detect individual biological features that predispose to crime. The pressure to find such individual differences may be even greater than it was in the 1990s, when more pervasive violent crime was easier to attribute to “shared environment.” Further, it concludes (2) that the recognition of early environmental factors in predispositions to violent crime may increase pressures on parents to ensure the good behavior of their children; and (3) that these first two developments will sharpen role conflicts for clinicians expected to serve as both protectors of their patients’ health and protectors of public safety.

The Genetics of Common Epilepsy Disorders: Lessons Learned from the Channelopathy Era

Abstract: Idiopathic epilepsies are thought to be almost entirely the result of genetic determinants, most of which remain undiscovered. It was once widely accepted that mutations that change the amino acid sequence of ion channel proteins were the major cause of these epilepsies, making epilepsy in general a ''channelopathy.'' Since then, more comprehensive analysis of ion channel-encoding genes has largely rejected this hypothesis for common forms of epilepsy. Here, we discuss some of the assump- tions that led to the channelopathy hypothesis and propose ways to avoid similar mistakes going forward. We also offer insight into promising genetic candidates that we believe play a major role in susceptibility to common forms of idiopathic epilepsy.

Pharmacogenomics for Precision Medicine in the Era of Collaborative Co-creation and Crowdsourcing

Abstract: The whole gamut of new technologies in the past decade has revolutionized DNA sequencing, making it cheaper, efficient, and scalable. The consequent big-data in genomics have posed new challenges and opportunities. The transformation of internet as a fabric that intertwines multiple technological and social layers and the rise of platforms that can organize and integrate massively parallel human activities have transformed the workplaces in many industries and offers a new opportunity in the area of genomics. In this short review, we discuss the state-of-the art of crowdsourcing in genomics research with special focus on pharmacogenomics. We discuss the field, starting with an overview of technology and the major challenges. We also discuss a number of ongoing crowdsourcing approaches in the area of pharmacogenomics and personal genomics. We conclude with deliberating on the issues in genomics and how crowdsourcing could offer a plausible alternative to conventional approaches in genomics.

Management Strategies for Ethics in International Research

Abstract: PERSPECTIVE is a large-scale, international research project that aims to develop a risk stratification approach for breast cancer screening. This project involving many researchers as well as samples and data from 30 different countries creates novel ethical challenges. We discuss some specific issues that have arisen in the context of the PERSPECTIVE project as well as the innovative strategies conceived to address them. Even in the absence of an overarching international organization for the ethics review of multisite research projects, an adapted, flexible ethical framework, together with customized sample and data sharing tools, and a multi-step process for ethics approvals were successful strategies.

New Innovations: Therapies for Genetic Conditions

Abstract: New, mechanistic understanding of genetic disease is prompting the rapid advancement of treatments for these diseases. Treatment strategies for monogenic hereditary disorders and complex genetic disorders are evolving with novel uses of traditional medications, targeted therapies for biochemical deficiencies including enzyme replacement, and pathology-targeted pharmacologic approaches to enhance normal function. There is also tangible progress in the development of nucleic acid-derived therapies, utilizing both DNA and RNA to modify gene expression and to correct a genetic disease process. Technologies that use antisense oligonucleotides, RNA interference, gene transfer, and stem cell transplantation are resulting in promising treatment breakthroughs. Though serious challenges remain in the safe and successful implementation of these technologies in clinical practice, the exciting prospect of treatment for previously untreatable genetic conditions is now within sight, providing hope for both patients and providers. Current options and evolving therapies are reviewed for the broad category of genetic disease.

Incidental Finding in Copy Number Variation (CNV) Analysis

Abstract: When interrogating the human genome, the most significant finding at times might not even be the one related to the referring diagnosis. Such incidental findings (IFs) can pose challenges with regard to which results should be revealed? Such issues have begun to be addressed with the recent American College of Medical Genetics and Genomics (ACMG) recommendations for reporting IFs in clinical exome and genome sequencing; however, copy number variants (CNV) were not specifically addressed. The recommendations found that while some incidental CNV findings are currently of uncertain clinical significance, others are medically actionable. The reporting of the incidental CNVs can have a significant impact on risk counseling for future pregnancies and other family members at risk as well as enabling interventions to improve health outcomes. According to the ACMG recommendations, in the course of performing chromosomal microarray analysis in 3,500 “normal” parental samples for interpretation of variants of unknown clinical significance in the proband, we incidentally found 28 (0.8 %) clinically relevant CNVs that were reported back to the physician to be communicated to the patient. Reporting of IFs is not new to medicine, so should reporting IF in whole genome analysis be any different? Should the current ACMG recommendations for reporting IFs be updated to incorporate incidental CNVs?

Understanding the Paradigm Challenges Posed by Multiplex Panel Testing for Cancer Susceptibility

Abstract: Massively parallel (“next generation”) sequencing (MPS) is a technology that has revolutionized genetics In clinical cancer genetics, MPS affords the opportunity to concurrently analyze the sequence of an arbitrary number of genes that may be related to a clinical presentation, such as breast cancer This multiplex panel testing may identify germ line pathogenic variants in genes that would not have been tested on phenotypic grounds While this type of testing may be beneficial in specific circumstances, broad application introduces challenges that cannot easily be addressed by conventional pre-test counseling models Newer approaches are required to preserve the tradition of shared decision-making that has guided clinical cancer genetics since its inception