Points to Consider in the Clinical Use of NGS Panels for Mitochondrial Disease: An Analysis of Gene Inclusion and Consent Forms

Mitochondrial next generation sequencing (NGS) panels offer single-step analysis of the numerous nuclear genes involved in the structure, function, and maintenance of mitochondria. However, the complexities of mitochondrial biology and genetics raise points for consideration in clinical use of these tests. To understand the current status of mitochondrial genetic testing, we assessed the gene offerings and consent forms of mitochondrial NGS panels available from seven US-based clinical laboratories. The NGS panels varied markedly in number of genes (101–1204 genes), and the proportion of genes causing “classic” mitochondrial diseases and their phenocopies ranged widely between labs (18 %–94 % of panel contents). All panels included genes not associated with classic mitochondrial diseases (6 %–28 % of panel contents), including genes causing adult-onset neurodegenerative disorders, cancer predisposition, and other genetic syndromes or inborn errors of metabolism. Five of the panels included genes that are not listed in OMIM to be associated with a disease phenotype (5 %–49 % of panel contents). None of the consent documents reviewed had options for patient preference regarding receipt of incidental findings. These findings raise points of discussion applicable to mitochondrial diagnostics, but also to the larger arenas of exome and genome sequencing, including the need to consider the boundaries between clinical and research testing, the necessity of appropriate informed consent, and the responsibilities of clinical laboratories and clinicians. Based on these findings, we recommend careful evaluation by laboratories of the genes offered on NGS panels, clear communication of the predicted phenotypes, and revised consent forms to allow patients to make choices about receiving incidental findings. We hope that our analysis and recommendations will help to maximize the considerable clinical utility of NGS panels for the diagnosis of mitochondrial disease.     

心肌保护新靶点——线粒体钙激活钾通道研究进展

心肌缺血再灌注损伤与线粒体有密切的关系。其中,位于线粒体的钾通道受到了人们的广泛关注。除了已被许多研究证明的线粒体ATP敏感钾通道参与心肌缺血再灌注的保护作用外,近年来研究发现的线粒体内膜钙激活钾通道也参与心肌保护作用,而国内相关研究报道很少。本文拟就心肌细胞线粒体上的钙激活钾通道结构、生物学特性和心脏缺血再灌注中的心肌保护作用进行简要阐述。     

线粒体在糖尿病发生发展中作用的再评价

糖尿病作为一种线粒体疾病,已成为世界面临的重大健康问题,线粒体医学的发展,大大推进了对糖尿病病因及病理机制的认识,为糖尿病的干预拓宽了道路,基于线粒体糖尿病与2型糖尿病病因的不同,对线粒体糖尿病的诊断与治疗也不同。     

Environmental and Behavioral Influences on Gene Activity

The central dogma of molecular biology holds that 'information' flows from the genes to the structure of the proteins that the genes bring about through the formula DNA → RNA → protein. In this view, a set of master genes activates the DNA necessary to produce the appropriate proteins that the organism needs during development. In contrast to this view, probabilistic epigenesis holds that necessarily there are signals from the internal and external environment that activate DNA to produce the appropriate proteins. To support this view, I review a substantial body of evidence showing that external environmental influences on gene activation are normally occurring events in a large variety of organisms, including humans. This demonstrates how genes and environments work together to produce functional organisms, thus extending the model of probabilistic epigenesis.     

心理应激与DNA损害

心理应激不仅能使人的行为特征发生变化,而且也能使人的生理状况发生改变,因此,被认为是某些身心疾病的诱因。在此过程中,DNA损害是心理应激造成的最终结果之一。有关DNA损害,虽然以往的研究者以人或动物为对象进行了一系列急性应激和慢性应激的实验研究,但是,心理应激是如何造成DNA损害的过程还不清楚,具体的生理心理机制还未阐明。该文利用健康心理学提出的理论模型对此进行了分析,阐述了心理应激与DNA损害之间联系的可能的机制,强调了氧化应激在这一过程中的重要作用。同时,为临床制订预防疾病的干预措施提供了思路     

The involvement of epigenetic defects in mental retardation

Mental retardation is a group of cognitive disorders with a significant worldwide prevalence rate. This high rate, together with the considerable familial and societal burden resulting from these disorders, makes it an important focus for prevention and intervention. While the diseases associated with mental retardation are diverse, a significant number are linked with disruptions in epigenetic mechanisms, mainly due to loss-of-function mutations in genes that are key components of the epigenetic machinery. Additionally, several disorders classed as imprinting syndromes are associated with mental retardation. This review will discuss the epigenetic abnormalities associated with mental retardation, and will highlight their importance for diagnosis, treatment, and prevention of these disorders.     

Infectious and immune factors in the pathogenesis of neurodevelopmental disorders: epidemiology, hypotheses, and animal models

Both genetic and environmental factors contribute to the pathogenesis of a wide variety of neurodevelopmental disorders, including autism, mental retardation, and schizophrenia. Some heritable disorders approach 100% penetrance; nonetheless, even in these disorders, subtle aspects of clinical disease expression may be influenced by the environment. In other disorders with genetic influences, exogenous factors, and the timepoint(s) during nervous system development at which they are introduced, modulate expression of disease. Elucidation of the mechanisms guiding this intricate interplay between host response genes, environmental agents, and the neurodevelopmental context within which these interactions occur, is necessary to understand the continuum of clinical outcomes. This chapter will review the evidence that infectious and immune factors may contribute to the pathogenesis of neurodevelopmental disorders, describe an animal model of neurodevelopmental disorders based upon viral infection, identify processes by which neural circuitry may be compromised, and outline areas for future research.     

DNA

The authors predict that in a few years, many areas of psychology will be awash in specific genes responsible for the widespread influence of genetics on behavior. As the focus shifts from finding genes (genomics) to understanding how genes affect behavior (behavioral genomics), it is important for the future of psychology as a science that pathways between genes and behavior be examined not only at the molecular biological level of cells or the neuroscience level of the brain but also at the psychological level of analysis. After a brief overview of quantitative genetic research, the authors describe how genes that influence complex traits like behavioral dimensions and disorders in human and nonhuman animals are being found. Finally, the authors discuss behavioral genomics and predict that DNA will revolutionize psychological research and treatment early in the 21st century.     

Phosphorylated nerve growth factor-induced clone B (NGFI-B) translocates from the nucleus to mitochondria of stressed rat cardiomyocytes and induces apoptosis

Stress induces cardiac dysfunction and cardiomyocyte injury, and while current data indicate that mitochondria play a key role in this process, the mechanisms remain unknown. In this study, we found that in rats, restraint stress induced nerve growth factor-induced clone B (NGFI-B) translocation from the nucleus to mitochondria in cardiomyocytes. This translocation promoted cytochrome c release from mitochondria to the cytoplasm, which ultimately resulted in cardiomyocyte apoptosis. We also found that stress induced oversecretion of glucocorticoids and activated the protein kinase A (PKA) pathway in cardiomyocytes. Enhanced PKA activity increased NGFI-B serine phosphorylation, which caused NGFI-B to translocate from the nucleus to mitochondria. Moreover, a PKA peptide inhibitor blocked NGFI-B serine phosphorylation and translocation. Our data demonstrate that stress affects cardiomyocytes by inducing NGFI-B mitochondrial translocation via serine phosphorylation, which in turn initiates mitochondrial-mediated apoptosis.     

Acute starvation in C57BL/6J mice increases myocardial UCP2 and UCP3 protein expression levels and decreases mitochondrial bio-energetic function

Associations between uncoupling protein (UCP) expression and functional changes in myocardial mitochondrial bio-energetics have not been well studied during periods of starvation stress. Our aim was to study the effects of acute starvation, for 24 or 48 h, on combined cardiac mitochondrial function and UCP expression in mice. Isolated heart mitochondria from female mice starved for 48 h compared to that from mice fed revealed a significantly (p < 0.05) decreased adenosine diphosphate-to-oxygen ratio, a significantly increased proton leak and an increased GTP inhibition on palmitic acid-induced state 4 oxygen consumption (p < 0.05). These bio-energetic functional changes were associated with increases in mitochondrial UCP2 and UCP3 protein expression. In conclusion, our findings suggest that increased UCP2 and UCP3 levels may contribute to decreased myocardial mitochondrial bio-energetic function due to starvation.     

The neuropharmacology of beta adrenolytics

The paper provides a survey of neuropharmacological fundamentals for the use of beta-adrenolytics in the treatment of psychiatric and neurological diseases. In particular there are discussed results of animal- and clinical-pharmacological experiments carried out in order to assess the influence of betaadrenolytics in disorders and diseases such as anxiety, psychoses, tremor, some kinds of addiction, migraine and epilepsy. The conclusion is that in spite of some ascertained clinical indications on the one hand and a variety of neuropharmacological results on the other the mode of action of betaadrenolytics at the level of the CNS remains still insufficiently explainable.     

Genetics of emotion

Emotion is critical to most aspects of human behavior, and individual differences in systems recruited to process emotional stimuli, expressed as variation in emotionality, are characteristic of several neuropsychiatric disorders. We examine the genetic origins of individual differences in emotion processing by focusing on functional variants at five genes: catechol-O-methyltransferase (COMT), serotonin transporter (SLC6A4), neuropeptide Y (NPY), a glucocorticoid receptor-regulating co-chaperone of stress proteins (FKBP5) and pituitary adenylate cyclase-activating polypeptide receptor (ADCYAP1R1). These represent a range of effects of genes on emotion as well as the variety of mechanisms and factors, such as stress, that modify these effects. The new genomic era of genome-wide association studies (GWAS) and deep sequencing may yield a wealth of new loci modulating emotion. The effects of these genes can be validated by neuroimaging, neuroendocrine and other studies accessing intermediate phenotypes, deepening our understanding of mechanisms of emotion and variation in emotionality.     

The Practices of Apostolic Faith Healers in Mental Health Care in Zimbabwe

This study aimed to understand and interpret faith healers' explanations of the aetiology and treatment of diseases and to canvass their views regarding collaboration between Western trained health care professionals and faith healers. Fifteen female and six male faith healers from Apostolic churches in Marondera (Zimbabwe) were selected and interviewed (mean age = 42.38 years; age range = 20–69 years). All the faith healers interviewed had been practising from two to fifty years. Content analysis of the data indicated that faith healers use a variety of procedures like prayer, holy water, counselling and sacred stones during their healing sessions. Common ailments brought to the faith healers included mental disorders, infertility, substance abuse, sleep disorders, childhood problems and physical problems. Witchcraft and avenging spirits were cited as the most common causes for illness. Closer cooperation between Western trained health practitioners and traditional (faith) healers is needed in the treatment of both physical and mental illnesses.     

Controversies in counseling for mitochondrial conditions

A healthy woman sought preconceptional genetic counseling regarding a family history of a mitochondrial myopathy in her brother and retinitis pigmentosa (RP) in her two maternal aunts. Several questions were raised: (1) What is the likelihood of a familial mitochondrial condition? (2) What molecular tests or prenatal screening can we offer? (3) How would these tests help assess the likelihood of a familial mitochondrial condition? A mitochondrial mutation previously identified in the brother consisted of a heteroplasmic 2.9 kb deletion. We detected this deletion in the peripheral blood of the brother by PCR amplification of the deletion breakpoint, but not in his mother, the consultand, nor in one of the two aunts affected with RP. Although the molecular analysis was encouraging to the consultand, a familial mitochondrial disorder could not be eliminated with certainty. The pros and cons of prenatal testing for mitochondrial disorders are discussed in general, and as specifically related to this family.     

The relationship of body dysmorphic disorder and eating disorders to obsessive-compulsive disorder

Body dysmorphic disorder (BDD) and eating disorders are body image disorders that have long been hypothesized to be related to obsessive-compulsive disorder (OCD). Available data suggest that BDD and eating disorders are often comorbid with OCD. Data from a variety of domains suggest that both BDD and eating disorders have many similarities with OCD and seem related to OCD. However, these disorders also differ from OCD in some ways. Additional research is needed on the relationship of BDD and eating disorders to OCD, including studies that directly compare them to OCD in a variety of domains, including phenomenology, family history, neurobiology, and etiology.     

Coenzyme Q10: a review of its promise as a neuroprotectant

Coenzyme Q10 (CoQ10) is a powerful antioxidant that buffers the potential adverse consequences of free radicals produced during oxidative phosphorylation in the inner mitochondrial membrane. Oxidative stress, resulting in glutathione loss and oxidative DNA and protein damage, has been implicated in many neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and Huntington's disease. Experimental studies in animal models suggest that CoQ10 may protect against neuronal damage that is produced by ischemia, atherosclerosis and toxic injury. Though most have tended to be pilot studies, there are published preliminary clinical trials showing that CoQ10 may offer promise in many brain disorders. For example, a 16-month randomized, placebo-controlled pilot trial in 80 subjects with mild Parkinson's disease found significant benefits for oral CoQ10 1,200 mg/day to slow functional deterioration. However, to date, there are no published clinical trials of CoQ10 in Alzheimer's disease. Available data suggests that oral CoQ10 seems to be relatively safe and tolerated across the range of 300-2,400 mg/day. Randomized controlled trials are warranted to confirm CoQ10's safety and promise as a clinically effective neuroprotectant.     

Velo-cardio-facial syndrome: a distinctive behavioral phenotype

Velo-cardio-facial syndrome (VCFS) is the most common contiguous gene disorder and one of the most common multiple anomaly syndromes in humans. Over 180 anomalies have been delineated in the syndrome; the most common of which are the behavioral manifestations. Learning disabilities, psychiatric illness, attention deficit disorder, and a variety of developmental disorders are nearly ubiquitous findings in VCFS and are not mutually exclusive, often overlapping to create a distinctive yet confusing phenotypic picture. In addition, standard treatments for each of these separate clinical findings may not be effective, and may even be potentially harmful in individuals with VCFS, such as the use of stimulants for hyperactivity. VCFS is caused by a small deletion of DNA from the long arm of chromosome 22. Researchers are currently studying the deletion located at 22q11.2 because of the possibility that a firm genetic link to psychiatric illness and learning disorders may be found. This report describes the behavioral manifestations of VCFS, emphasizing the overlap between the cognitive and psychiatric disorders that are so common in this syndrome. MRDD Research Reviews 2000;6:142-147.     

Tangled webs: tracing the connections between genes and cognition

The rise of molecular genetics is having a pervasive influence in a wide variety of fields, including research into neurodevelopmental disorders like dyslexia, speech and language impairments, and autism. There are many studies underway which are attempting to determine the roles of genetic factors in the aetiology of these disorders. Beyond the obvious implications for diagnosis, treatment and understanding, success in these efforts promises to shed light on the links between genes and aspects of cognition and behaviour. However, the deceptive simplicity of finding correlations between genetic and phenotypic variation has led to a common misconception that there exist straightforward linear relationships between specific genes and particular behavioural and/or cognitive outputs. The problem is exacerbated by the adoption of an abstract view of the nature of the gene, without consideration of molecular, developmental or ontogenetic frameworks. To illustrate the limitations of this perspective, I select two cases from recent research into the genetic underpinnings of neurodevelopmental disorders. First, I discuss the proposal that dyslexia can be dissected into distinct components specified by different genes. Second, I review the story of the FOXP2 gene and its role in human speech and language. In both cases, adoption of an abstract concept of the gene can lead to erroneous conclusions, which are incompatible with current knowledge of molecular and developmental systems. Genes do not specify behaviours or cognitive processes; they make regulatory factors, signalling molecules, receptors, enzymes, and so on, that interact in highly complex networks, modulated by environmental influences, in order to build and maintain the brain. I propose that it is necessary for us to fully embrace the complexity of biological systems, if we are ever to untangle the webs that link genes to cognition.