Genes and inheritance

The information gained from the Human Genome Project and related genetic research will undoubtedly create significant changes in healthcare practice. It is becoming increasingly clear that nurses in all areas of clinical practice will require a fundamental understanding of basic genetics. This article provides the oncology nurse with an overview of basic genetic concepts, including inheritance patterns of single gene conditions, pedigree construction, chromosome aberrations, and the multifactorial basis underlying the common diseases of adulthood. Normal gene structure and function are introduced and the biochemistry of genetic errors is described.     

Primer on medical genomics. Part VIII: Essentials of medical genetics for the practicing physician

After the mapping and sequencing of the human genome, medical professionals from essentially all specialties turned their attention to investigating the role genes play in health and disease. Until recently, medical genetics was considered a specialty of minor practical relevance. This view has changed with the development of new diagnostic and therapeutic possibilities. It is now realized that genetic disease represents an important part of medical practice. Achievements in cancer genetics, in the field of prenatal diagnostics (including carrier testing for common recessive disorders), and in newborn screening for treatable metabolic disorders reinforce the rapidly expanding role of genetics in medicine. Diagnosing a genetic disorder not only allows for disease-specific management options but also has implications for the affected individual's entire family. A working understanding of the underlying concepts of genetic disease with regard to chromosome, single gene, mitochondrial, and multifactorial disorders is necessary for today's practicing physician. Routine clinical practice in virtually all medical specialties will soon require integration of these fundamental concepts for use in accurate diagnosis and ensuring appropriate referrals for patients with genetic disease and their families.     

Genetics of dementia

Many neurodegenerative diseases are exceedingly complex disorders (Fig. 6). In the past decade, we have made tremendous advances in our understanding [figure: see text] of the genetic basis of these disorders. One common characteristic of these disorders is the existence of rare families in which a given disease is inherited as a Mendelian trait. In this article, we have reviewed the genetics of several common neurodegenerative disorders that are associated with cognitive disturbances and for which causative genes have been identified. Further genetic analysis should clarify the roles of known genes in the pathogenesis of common sporadic forms of these various diseases. Investigation of the normal and aberrant functions of these genes should provide insight into the underlying mechanisms of these disorders. Such research should facilitate new strategies for therapeutic interventions. Although molecular genetics has helped to clarify the etiology of these disorders, clinicians have played a critical role in the careful identification and classification of many families who were involved in the eventual mapping and cloning of causative mutations. The role of the clinician should not be underestimated. Future clinical and molecular genetics findings hold many clinical implications. It is likely that new diagnostic and therapeutic strategies for dementing disorders are just on the horizon.     

The genetics of nephrolithiasis

Renal stone formation (nephrolithiasis) is a worldwide problem causing substantial morbidity and economic burden. The heritability of stone formation has long been recognized, and with the advent of the genomic era, we have the potential to define the underlying genetic defects. Renal stone formation is multifactorial, with environmental factors interacting with underlying genetic factors. Isolated genetic defects and single gene disorders which lead to stone formation have been valuable in defining renal pathophysiology, but these remain rare diseases. In this review, we examine the genetics of nephrolithiasis by considering the genetic components of defined metabolic risk factors. Hypercalciuria is the most important risk factor for calcium stone formation, although hyperoxaluria, cystinuria and other rarer defects are discussed. It is important to consider the complexity of this condition, and realize that the understanding of the genetic basis of nephrolithiasis is within our grasp.     

Chromosome 21 abnormalities a review and report of a case of erondu-cymet syndrome

Original Article The co-existence of rare clinical findings in a patient with a genetic abnormality has often led to the characterization of new syndromes. Although these genetic syndromes are generally rare, the pathophysiology of these disorders has broadened our understanding of common medical conditions. The variety of disorders that map to chromosome 21 provide insight into the effects of lifelong low pO2 and poor perfusion on various organs. In discovering the different disorders that map specifically to chromosome 21, we can characterized, treat and even prevent some medical conditions. We present the case of a man whose incidental finding of hypoxemia lead to the discovery of many unusual disorders that appear to be related to abnormalities in chromosome 21.     

Clinical and biochemical landmarks in systemic autoinflammatory diseases

Abstract

Systemic autoinflammatory diseases are a group of inherited disorders of the innate immune system characterized by seemingly unprovoked inflammation recurring at variable intervals and involving skin, serosal membranes, joints, and gastrointestinal apparatus, with reactive amyloidosis as a possible severe long-term complication. Recent advances in genetics and molecular biology have improved our understanding of the pathogenesis of these diseases, including familial Mediterranean fever, mevalonate kinase deficiency syndrome, tumor necrosis factor receptor-associated periodic syndrome, cryopyrin-associated periodic syndromes, and hereditary pyogenic and granulomatous disorders: the vast majority of these conditions are related to the activation of the interleukin-1 pathway, which results in (or from?) a common unifying pathogenetic mechanism. Their diagnostic identification derives from the combination of clinical data, evaluation of acute phase reactants, clinical efficacy in response to specific drugs, and recognition of specific mutations in the relevant genes, although genetic tests may be unconstructive in some cases. This review will discuss clinical and laboratory clues useful for a diagnostic approach to systemic autoinflammatory diseases.     

Clinical and biochemical landmarks in systemic autoinflammatory diseases

Abstract Systemic autoinflammatory diseases are a group of inherited disorders of the innate immune system characterized by seemingly unprovoked inflammation recurring at variable intervals and involving skin, serosal membranes, joints, and gastrointestinal apparatus, with reactive amyloidosis as a possible severe long-term complication. Recent advances in genetics and molecular biology have improved our understanding of the pathogenesis of these diseases, including familial Mediterranean fever, mevalonate kinase deficiency syndrome, tumor necrosis factor receptor-associated periodic syndrome, cryopyrin-associated periodic syndromes, and hereditary pyogenic and granulomatous disorders: the vast majority of these conditions are related to the activation of the interleukin-1 pathway, which results in (or from?) a common unifying pathogenetic mechanism. Their diagnostic identification derives from the combination of clinical data, evaluation of acute phase reactants, clinical efficacy in response to specific drugs, and recognition of specific mutations in the relevant genes, although genetic tests may be unconstructive in some cases. This review will discuss clinical and laboratory clues useful for a diagnostic approach to systemic autoinflammatory diseases.     

Genetic testing for Alzheimer''s disease: Impact on health behaviors

Cardiovascular disease is the leading cause of illness and death in the USA, as well as other countries. Advances in genetics have led researchers to identified associations between a number of cardiac syndromes and diagnostic molecular findings. Therefore, a more precise understanding of the molecular pathways involved in cardiovascular diseases is clinically significant. Current literature suggests that while etiologies remain complex, a number of cardiovascular diseases can be linked to specific metabolic inheritable factors. A broad multifactorial model is gradually being replaced with disease specific models where independent genetic and/or teratogenic pathways may lead to a particular outcome. These genetic pathways include chromosome deletions, disruptions (translocations), duplications of particular genetic regions, point mutations involving single genes, or alteration in the ability for a gene to be transcribed into a functional protein. In this review the molecular mechanisms underlying cardiovascular diseases and their clinical manifestations will be explained.     

Lessons learned: next-generation sequencing applied to undiagnosed genetic diseases

Rare genetic disorders, when considered together, are relatively common. Despite advancements in genetics and genomics technologies as well as increased understanding of genomic function and dysfunction, many genetic diseases continue to be difficult to diagnose. The goal of this Review is to increase the familiarity of genetic testing strategies for non-genetics providers. As genetic testing is increasingly used in primary care, many subspecialty clinics, and various inpatient settings, it is important that non-genetics providers have a fundamental understanding of the strengths and weaknesses of various genetic testing strategies as well as develop an ability to interpret genetic testing results. We provide background on commonly used genetic testing approaches, give examples of phenotypes in which the various genetic testing approaches are used, describe types of genetic and genomic variations, cover challenges in variant identification, provide examples in which next-generation sequencing (NGS) failed to uncover the variant responsible for a disease, and discuss opportunities for continued improvement in the application of NGS clinically. As genetic testing becomes increasingly a part of all areas of medicine, familiarity with genetic testing approaches and result interpretation is vital to decrease the burden of undiagnosed disease.     

Neuroinflammation and ageing: current theories and an overview of the data

The increase in the average lifespan and the consequent proportional growth of the elderly segment of society has furthered the interest in studying ageing processes. Ageing may be considered a multifactorial process derived from the interaction between genetic and environmental factors including lifestyle. There is ample evidence in many species that the maximum age attainable (maximum lifespan potential, MLSP) is genetically determined and several mitochondrial DNA polymorphisms are associated with longevity. This review will address the current understanding of the relationship between ageing and several factors both genetics and life style related. Firstly we focused on the most reliable and commonly shared theories which attempt to explain the phenomenon of ageing as the genetic, cellular, neuroendocrine, immunological and free-radicals related theories. Many studies have shown that most of the phenotypic characteristics observed in the aging process are the result of the occurrence, with age, of a low grade chronic pro-inflammatory status called "inflammaging", partially under genetic control. The term indicate that aging is accompanied by a low degree of chronic inflammatory, an up-regulation of inflammatory response and that inflammatory changes are common to many age-related diseases. In this review special attention was dedicated to diseases related to age as atherosclerosis, cancer and Alzheimer disease. Despite the fact that in recent years many theories about ageing have been developed, we are still far from a full understanding of the mechanisms underlying the ageing process.     

The muscular dystrophies: from genes to therapies

The genetic basis of many muscular disorders, including many of the more common muscular dystrophies, is now known. Clinically, the recent genetic advances have improved diagnostic capabilities, but they have not yet provided clues about treatment or management. Thanks to better management strategies and therapeutic interventions, however, many patients with a muscular dystrophy are more active and are living longer. Physical therapists, therefore, are more likely to see a patient with a muscular dystrophy, so understanding these muscle disorders and their management is essential. Physical therapy offers the most promise in caring for the majority of patients with these conditions, because it is unlikely that advances in gene therapy will significantly alter their clinical treatment in the near future. This perspective covers some of the basic molecular biological advances together with the clinical manifestations of the muscular dystrophies and the latest approaches to their management.     

Neurological channelopathies: diagnosis and therapy in the new millennium

Rapid progress in the complementary fields of molecular genetics and cellular electrophysiology has led to a better understanding of many disorders which are caused by ion channel dysfunction. These channelopathies may manifest in a multitude of ways depending on the tissue specificity of the channel that is affected. Several important general medical conditions are now known to be channelopathies but the neurological members of this family are amongst the best characterized. Over recent years, ion channel dysfunction in skeletal muscle in particular has emerged as a paradigm for understanding neurological ion channel disorders. This review concentrates mainly on the diseases caused by dysfunction of the voltage-gated ion channels. We initially focus on the skeletal muscle channelopathies (the periodic paralyses, malignant hyperthermia, paramyotonia congenita and myotonia congenita). The central nervous system channelopathies are then explored, with particular reference to the advances which have implications for understanding the mechanisms of common neurological disorders such as epilepsy and migraine. Looking towards the new millennium, DNA-based diagnosis will become a realistic proposition for most neurological channelopathies. Furthermore, it seems likely that new therapies will be designed based on genotype and mode of ion channel dysfunction.     

Hereditary cancer syndromes of the gastrointestinal system

Gastrointestinal (GI) malignancies account for a large percentage of the cancer burden in the United States. Although the majority of cancer cases are sporadic, approximately 5% to 10% of cancer results from inherited genetic mutations. There are several hereditary cancer syndromes of the GI tract that have been identified. To date, the genetics of colorectal cancer and its associated hereditary cancer syndromes have been characterized in detail, and effective screening modalities and recommendations have been incorporated into standards of care. Today, scientists are beginning to understand the genetic basis of pancreatic and gastric cancer, and in some cases have identified a number of their associated inherited cancer syndromes. Information about cancer genetics and hereditary cancer syndromes not only will provide advanced practice nurses with knowledge of these diseases but also, more importantly, will provide opportunities to improve patient care by providing patients with treatment options and opportunities for the early detection and prevention of cancer.     

Genomics, Nutrition, Obesity, and Diabetes

PURPOSE: To present evidence of genetic and environmental interactions as they relate to nutrition, diabetes, and obesity. METHODS: A review of seminal literature related to genetics, obesity, and diabetes. FINDINGS: Multifactorial interactions are important in the development of nutrition-related disorders, but the challenge remains to explain how these interactions are expressed. Treating subpopulations of people might be important and useful to some extent at present, but in the future treating people of given genetic predispositions and other personal and environmental factors will have greater effects on quality-of-life indicators and life expectancies. CONCLUSIONS: Individualization coupled with multifactorial interactions will lead to new and more effective preventive and treatment modalities of nutrition-related disorders. With obesity and diabetes, genomics will bridge the traditional use of diet, exercise, and weight reduction with other environmental factors, ultimately leading to healthier lives.     

Neurological channelopathies: diagnosis and therapy in the new millennium

Rapid progress in the complementary fields of molecular genetics and cellular electrophysiology has led to a better understanding of many disorders which are caused by ion channel dysfunction. These channelopathies may manifest in a multitude of ways depending on the tissue specificity of the channel that is affected. Several important general medical conditions are now known to be channelopathies but the neurological members of this family are amongst the best characterized. Over recent years, ion channel dysfunction in skeletal muscle in particular has emerged as a paradigm for understanding neurological ion channel disorders. This review concentrates mainly on the diseases caused by dysfunction of the voltage-gated ion channels. We initially focus on the skeletal muscle channelopathies (the periodic paralyses, malignant hyperthermia, paramyotonia congenita and myotonia congenita). The central nervous system channelopathies are then explored, with particular reference to the advances which have implications for understanding the mechanisms of common neurological disorders such as epilepsy and migraine. Looking towards the new millennium, DNA-based diagnosis will become a realistic proposition for most neurological channelopathies. Furthermore, it seems likely that new therapies will be designed based on genotype and mode of ion channel dysfunction.     

Inflammatory bowel disease: Crohn's disease and the success of NODern genetics

The inflammatory bowel diseases (IBDs), Crohn's disease and ulcerative colitis, are multifactorial in etiology, but a major causative role for genetic factors has long been recognized. Recent advances in genetic technologies have made dissection of the genes underlying common diseases possible; consequently, there is an emerging understanding of the inherited factors that predispose to IBD. In this review, we summarize current information on the genetics of IBD, emphasizing the discovery of CARD15 variants as susceptibility alleles for Crohn's disease and the impact of this discovery on patient care and in delineating pathogenesis of this complex disease.     

Genetics of dilated cardiomyopathy

Dilated cardiomyopathy (DCM) is a myocardial disease characterized by dilatation and impaired systolic function of the left or both ventricles. The etiology of DCM is multifactorial, and many different clinical conditions can lead to the phenotype of DCM. During recent years it has become evident that genetic factors play an important role in the etiology and pathogenesis of idiopathic DCM. The genetics of DCM have been under intensive investigation lately, and thereby the knowledge on the genetic basis of DCM has increased rapidly. The genetic background of the disease seems to be relatively heterogeneous, and the disease-associated mutations concern mostly single families and only few affected patients. Disease-associated mutations have been detected e.g. in genes encoding sarcomere, cytoskeletal, and nuclear proteins, as well as proteins involved with regulation of Ca(2+) metabolism. The mechanisms, by which mutations eventually result in clinical heart failure, are complex and not yet totally resolved. DCM causes considerable morbidity and mortality. Better knowledge of the genetic background and disease-causing mechanisms would probably help us in focusing early treatment on right subjects and potentially also developing new treatment modalities and improving cardiac outcome in the affected patients. This review deals with DCM of genetic origin.     

Neurological potassium channelopathies

Potassium channel dysfunction has been implicated in a variety of genetic and acquired neurological disorders that are collectively referred to as the potassium channelopathies. These include acquired neuromyotonia, episodic ataxia type-1, hereditary deafness syndromes, benign familial neonatal convulsions and hypokalaemic periodic paralysis. Insight into potassium channel structure and function is crucial to understanding the pathophysiology of these conditions. This article describes potassium channel structure and function and then outlines what is known about the immunology and genetics of the neurological potassium channelopathies.     

Molecular genetic pathways in Parkinson's disease: a review

Major progress has been made in the last decade in understanding the genetic basis of PD (Parkinson's disease) with five genes unequivocally associated with disease. As a result, multiple pathways have been implicated in the pathogenesis of PD, including proteasome impairment and mitochondrial dysfunction. Although Mendelian genetics has been successful in establishing a genetic predisposition for familial PD, this has not been reiterated in the sporadic form. In fact no genetic factors have been unequivocally associated with increased risk for sporadic PD. The difficulty in identifying susceptibility factors in PD has not only been because of numerous underpowered studies, but we have been unable to dissect out the genetic component in a multifactorial disease. This review aims to summarize the genetic findings within PD.     

From Mendel to the Human Genome Project: the implications for nurse education

The Human Genome Project has heralded a whole new era in our understanding of the molecular basis of disease. New opportunities now arise to predict disease by genetic testing, and in some cases to prevent disease through surveillance or other specific interventions. Increasingly it will be possible to test for predisposition to disease, to develop new treatments or to tailor available treatments more specifically to an individual's genetic make-up. Midwives and paediatric nurses are at the forefront of these developments with new national antenatal and neonatal genetic screening programmes due to be implemented by 2004. However, in the near future it is likely that nurses in most clinical areas will encounter genetic aspects of their practice. If they are to capitalise on opportunities offered by the new genetics, health professionals will need to become knowledgeable and skilled in genetics. They will need to understand something of the basic science and also develop an awareness of many ethical, legal and social aspects. In the light of a recent review of education in genetics for health professionals, the Department of Health and The Wellcome Trust have commissioned a process to develop a programme of education for the United Kingdom.