Society has historically not taken a benign view of genetic disease. The laws permitting sterilization of the mentally re tarded~ and those proscribing consanguineous marriages are but two examples. Indeed as far back as the 5th-10th centuries, B.C.E., consanguineous unions were outlawed (Leviticus XVIII, 6). Case law has traditionally tended toward the conservative. It is reactive rather than directive, exerting its influence only after an individual or group has sustained injury and brought suit. In contrast, state legislatures have not (...) been inhibited in enacting statutes. Many of their products can be characterized as hasty, unnecessary, ill-conceived, and based on the heart rather than the head. Moreover the lack of expert consultation sought has also been remarkable. One state legislature, for example, has advocated immunization for sickle cell anemia! Many others have enacted laws for the screening of inborn errors of metabolism, e.g., phenylketon uria, but have poorly defined the lines of responsibility to secure compliance. A spate of specific disease-related bills has emerged in the u.S. Congress, each seeking recognition and appropriations. Sickle cell anemia, hemophilia, Cooley's anemia and Tay-Sachs disease have been among the front-runners for support. Finally, in 1975, Congress has begun to examine an omnibus bill concerning all forms of genetic disease. The bill, termed the National Genetic Diseases Act is, however, still far from being enacted. (shrink)

Progressive supranuclear palsy is a movement disorder with prominent tau neuropathology. Brain diseases with abnormal tau deposits are called tauopathies, the most common of which is Alzheimer's disease. Environmental causes of tauopathies include repetitive head trauma associated with some sports. To identify common genetic variation contributing to risk for tauopathies, we carried out a genome-wide association study of 1,114 individuals with PSP and 3,247 controls followed by a second stage in which we genotyped 1,051 cases and 3,560 controls (...) for the stage 1 SNPs that yielded P ≤ 10-3. We found significant previously unidentified signals associated with PSP risk at STX6, EIF2AK3 and MOBP. We confirmed two independent variants in MAPT affecting risk for PSP, one of which influences MAPT brain expression. The genes implicated encode proteins for vesicle-membrane fusion at the Golgi-endosomal interface, for the endoplasmic reticulum unfolded protein response and for a myelin structural component. © 2011 Nature America, Inc. All rights reserved. (shrink)

Modern medicine emphasizes treatment of the sick. It is often said that the widespread genetic testing soon to follow the completion of the Human Genome Project will usher in a new era of preventive medicine. Such changes require new ways of thinking, however. For example, there may be nothing clinically wrong with a healthy patient who requests genetic testing, even if the tests reveal disease genes. Since all individuals have genetic skeletons in their closets, it is important (...) to be careful not to confuse having disease genes with having the diseases that they cause. Unfortunately, many in the public have adopted a kind of genetic determinism that sees genes as destiny: for example, having the gene associated with colon cancer means they will develop colon cancer. Physicians tend to be more careful, yet even they are not immune to subtle versions of genetic determinism. One example of this is the uncritical categorization of certain diseases as “genetic”. In fact, an adequate concept of genetic disease is extremely difficult to come by. The simplest notion would require a 1:1 correspondence between a disease and its genes, but this is the exception rather than the rule. For example, cystic fibrosis (CF) is often put forward as a good example of a genetic disease, since it seems to result from mutations in a single gene, CFTR. Even in this case, however, the exact relationship between CFTR mutations and disease is not clear, as virtually every possible combination of sweat chloride test results, genetic test results, and symptoms has been observed.[1] If a patient presents with the classic symptoms of CF and is found to have a mutation in the CFTR gene, the physician might understandably infer that the mutation caused the disease. But if an asymptomatic patient is tested and it is discovered that he or she has a CFTR mutation, it is unclear what this means. The doctor might tell the patient the gene is abnormal and that he or she is likely to develop pulmonary problems, etc., but it’s not really known whether even this qualified prognosis is true.. (shrink)

There has always been great interest in animal models of human genetic disease, and mice provide the largest number of examples. A mutation in the homologous gene in mice does not always lead to the same phenotype as is found in man, however. Recent studies made it apparent that one mutation can have markedly different phenotypes when placed on different genetic backgrounds. This variation is due to different alleles at modifying loci in various inbred strains. Thus, if one (...) wishes to obtain the optimal mouse model for a human disease, one needs to choose the correct genetic background as well as the correct mutation. (shrink)

Since the human mitochondrial genome was characterised and sequenced in 1981(1), it has been viewed as the likely site of genetic diseases showing a maternal inheritance pattern and associated with defects of the respiratory chain, such as the mitochondrial myopathies (MMs)†(2). The properties that make it a candidate for the source of such conditions are that it encodes polypeptides involved in electron transport(3,4) and that it is maternally inherited(5). However, several of the mtDNA diseases only fulfill one (...) or other of these criteria: the first group of mtDNA diseases showed Only sporadic deletions(6,7), and the first point mutation in Leber's Hereditary Optic Neuropathy(8) (LHON) is not associated with a clear biochemical defect. Furthermore, it is now clear that both autosomal dominant(9) and probably recessive(10) nuclear genes can cause abnormalities of mtDNA. Each of these major groups will be considered in turn. (shrink)

With the reduction in diseases due to nutritional deficiencies and infection, disorders which are wholly or partly genetic are becoming relatively more important in all branches of modern medicine. Genetic counselling has developed in recent years from just explaining to an individual or a couple the risk of them producing a handicapped child, to the possibility in many cases of better diagnosis and active intervention to reduce the risks. At the same time antenatal screening programmes have been (...) introduced to detect women who may be carrying a fetus with a severe handicapping anomaly. The ethical aspects of these advances are considered in this article. A practical approach to the resolution of any dilemmas is proposed which concentrates on the duties incumbent on doctors and other health care workers involved with patients who have or may carry genetic disorders. (shrink)

What exactly is a genetic disease? For a phrase one hears on a daily basis, there has been surprisingly little analysis of the underlying concept. Medical doctors seem perfectly willing to admit that the etiology of disease is typically complex, with a great many factors interacting to bring about a given condition. On such a view, descriptions of diseases like cancer as geneticseem at best highly simplistic, and at worst philosophically indefensible. On the other hand, there is clearly (...) some practical value to be had by classifying diseases according to theirpredominant cause when this can be accomplished in a theoretically satisfactory manner. The question therefore becomes exactly how one should go about selecting a single causal factor among many to explain the presence of disease. When an attempt to defend such causal selection is made at all, the standard accounts offered (Koch's postulates, Hill's epidemiological criteria, manipulability) are all clearly inadequate. I propose, however, an epidemiological account of disease causation which walks the fine line between practical applicability and theoretical considerations of causal complexity and attempts to compromise between patient-centered and population-centered concepts of disease. The epidemiological account is the most basic framework consistent with our strongly held intuitions about the causal classification of disease, yet it avoids the difficulties encountered by its competitors. (shrink)

Trinucleotide repeat expansions are now a well‐established mutational mechanism in human genetic disease. An unstable CAG repeat is known to be responsible for three neurodegenerative disorders: Huntington's disease, spinal and bulbar musclar atrophy and spinocerebellar ataxia type 1. Similarities in the genetics of these diseases, the size of the repeat expansions and the position of the unstable repeat within the gene (when known) suggest a common basis to the observed phenotypes. The cloning of two regions at which chromosome (...) breakage can be induced (FRAXA and FRAXE) has in each case uncovered an unstable CG‐rich triplet repeat which becomes methylated when fully expanded. In addition to these two classes of mutation, the presence of an expanded CTG repeat in the 3′ untranslated region of a protein kinase causes myotonic dystrophy. The size of the respective expansions, repeat stability, mutational origins and possible mechanisms of action are discussed. (shrink)

Common monogenic genetic diseases, ones that have unexpectedly high frequencies in certain populations, have attracted a great number of conflicting evolutionary explanations. This paper will attempt to explain the mystery of why two particularly extensively studied common genetic diseases, Tay Sachs disease and cystic fibrosis, remain evolutionary mysteries despite decades of research. I review the most commonly cited evolutionary processes used to explain common genetic diseases: reproductive compensation, random genetic drift (in the context (...) of founder effect), and especially heterozygote advantage. The latter process has drawn a particularly large amount of attention, having so successfully explained the elevated frequency of sickle cell anemia in malaria-endemic areas. However, the empirical evidence for heterozygote advantage in other common genetic diseases is quite weak. I introduce and illustrate the significance of a hierarchy of genetic disease phenomena found within the genetic disease explanations, which include the phenomena: single mutation variants of a common genetic disease, single genetic diseases, and classes of diseases with related phenotypic effects. I demonstrate that some of the confusion over the explanations of common genetic diseases can be traced back to confusions over which phenomena are being explained. I proceed to briefly evaluate the existing evidence for two common human genetic diseases: Tay Sachs disease and cystic fibrosis. The above considerations will ultimately shed light on why these diseases’ evolutionary explanations remain so deeply unresolved after so such a great volume of research. (shrink)

A new analysis of the Best Interests Standard is given and applied to the controversy about testing children for untreatable, severe late-onset genetic diseases, such as Huntington's disease or Alzheimer's disease. A professional consensus recommends against such predictive testing, because it is not in children's best interest. Critics disagree. The Best Interests Standard can be a powerful way to resolve such disputes. This paper begins by analyzing its meaning into three necessary and jointly sufficient conditions showing it: is (...) an "umbrella" standard, used differently in different contexts, has objective and subjective features, is more than people's intuitions about how to rank potential benefits and risks in deciding for others but also includes evidence, established rights, duties and thresholds of acceptable care, and can have different professional, medical, moral and legal uses, as in this dispute. Using this standard, support is given for the professional consensus based on concerns about discrimination, analogies to adult choices, consistency with clinical judgments for adults, and desires to preserve of an open future for children. Support is also given for parents' legal authority to decide what genetic tests to do. (shrink)

Prior to the genomic sequencing era, the bible for those working in clinical genetics was McKusick’s Mendelian Inheritance in Man, which appeared in multiple editions between the 1960s and the late 1990s. This catalogue was organized according to general patterns of inheritance and focused on phenotypes. Beginning in the mid-1980s, it was replaced by Online Mendelian Inheritance in Man, a continuously updated catalogue documenting molecular relationships between genetic variation and phenotypic expression. This paper explores this resource’s evolution with attention (...) to how disease is distinguished from clinically irrelevant variation and how phenotypic similarities are captured in cases where there is no obvious genotypic association. It is argued that hybrid compromises are encoded into OMIM®; in addition to serving its key original purpose of being a diagnostic catalogue, it also began to record detectable variations in the genome even if they were not known to be associated with phenotypically visible disorders or even phenotypic variations. Although the impacts of geneticization have been well recognized, particularly in popular media, this example allows exploration of some of the historic, epistemic, and methodological causes that underlie tendencies toward disease geneticization in contemporary medicine, while highlighting that such gene-focused strategies may in fact be warranted in some contexts. (shrink)

In the contemporary biomedical literature, every disease is considered genetic. This extension of the concept of genetic disease is usually interpreted either in a trivial or genocentrist sense, but it is never taken seriously as the expression of a genetic theory of disease. However, a group of French researchers defend the idea of a genetic theory of infectious diseases. By identifying four common genetic mechanisms (Mendelian predisposition to multiple infections, Mendelian predisposition to one infection, (...) and major gene and polygenic predispositions), they attempt to unify infectious diseases from a genetic point of view. In this article, I analyze this explicit example of a genetic theory, which relies on mechanisms and is applied only to a specific category of diseases, what we call “a regional genetic theory.” I have three aims: to prove that a genetic theory of disease can be devoid of genocentrism, to consider the possibility of a genetic theory applied to every disease, and to introduce two hypotheses about the form that such a genetic theory could take by distinguishing between a genetic theory of diseases and a genetic theory of Disease. Finally, I suggest that network medicine could be an interesting framework for a genetic theory of Disease. (shrink)

In this paper I will discuss three areas in which advances in human reproductive technology could occur, their uses and abuses, and their effects on society. First is the potential to drastically increase the success rate and availability of in vitro fertilization and embryo freezing. Second is the ability to perform biopsies on embryos prior to the onset of pregnancy. Finally, I will consider the adding or altering of genes in embryos, commonly referred to as genetic engineering.As new reproductive (...) technologies pass from experimental models into the potential for medical utilization, I believe that it will be important for lawmakers everywhere to avoid the impulse to outlaw procedures that a society believes to be unnatural at a first glance. Rather, I would hope that they can respond thoughtfully with legislation that serves two purposes — to protect the rights of couples to overcome infertility or to reduce the risk of genetic disease in their children-to-be, and more importantly, to protect children-to-be from the abuses that could result from some of the practices that I will discuss. (shrink)

In recent years, preimplantation genetic testing (PGT) of IVF embryos have gained much traction in clinical assisted reproduction for preventing various genetic defects, including Down syndrome. However, such genetic tests inevitably reveal the sex of IVF embryos by identifying the sex (X and Y) chromosomes. In many countries with less stringent IVF regulations, information on the sex of embryos that are tested to be genetically normal is readily shared with patients. This would thus present Muslim patients with (...) unintended opportunities for sex selection based on personal or social biases without any pressing need or valid medical reason. Additionally, there are other patients who claim using PGT for preventing genetic defects as a pretext or “convenient excuse,” with a secret intention to do sex selection when it is banned in their home country. Currently, non-medical sex selection is a highly-controversial and hotly debated issue in Islam, because there is generally a strong preference for having sons over daughters due to widespread cultural norms of elderly parents depending on their sons for financial support, as well as the need for male heirs to continue the family lineage within the backdrop of local patriarchal cultures. There is a risk of gender imbalance and social disequilibrium occurring in Islamic societies due to prevalent sex selection. Hence, the question is whether opportunistic sex selection with PGT would contravene Islamic ethics and principles, which will thus be discussed here. (shrink)

The ubiquitous nature of mitochondria, the dual genetic foundation of the respiratory chain in mitochondrial and nuclear genome, and the peculiar rules of mitochondrial genetics all contribute to the extraordinary heterogeneity of clinical disorders associated with defects of oxidative phosphorylation (mitochondrial encephalomyopathies). Here, we review recent findings about nuclear gene defects in isolated OXPHOS enzyme complex deficiency. This information should help in identifying patients with mitochondrial disease and defining a biochemical and molecular basis of the disorder found in each (...) patient. This knowledge is indispensable for accurate genetic counseling and prenatal diagnosis, and is a prerequisite for the development of rational therapies, which are still, at present, woefully inadequate. BioEssays 23:518–525, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Post-Dobbs abortion restrictions impact access and choice in the context of reproductive genetic medicine, raising serious reproductive justice concerns. The consequences of these restrictions are particularly acute and far-reaching for individuals with genetic conditions and their families.

Research and clinical trial development for rare diseases pose unique bioethical challenges. Much of the literature on rare diseases focuses on patient advocacy and drug development to manage or cu...

Technological advances force redefinition of action-mandating concepts and language through complex social, political and economic tendencies that collectively determine what has been dubbed “the technological imperative.” The reverse is also true: redefinition of concepts shapes and guides the direction of technological development through shaping public beliefs and expectations. A powerful and far-reaching example of such occurred with the redefinition of “death” and the concept’s transformed relationship to transplantation technology.

Complex diseases involve both a genetic component and a response to environmental factors or lifestyle changes. Recently, genome-wide association studies (GWAS) have succeeded in identifying hundreds of polymorphisms that are statistically associated with complex diseases. However, the association is usually weak and none of the associated allelic forms is either necessary or sufficient for the disease occurrence. We argue that this promotes a network view, centred on functional redundancy. We adapted reliability theory to the concerned sub-network, modelled (...) as a parallel array of functional modules. In our model, as long as one module remains active, the function correlated with the respective disease is ensured and disease does not occur. Genetic factors reduce the initial number of available modules while environment, contingent surroundings, personal history, epigenetics, and some intrinsic stochasticity influence their persistence time. This model reproduces age-specific incidence curves and explains the influence of environmental changes. It offers a new paradigm, according to which disease occurs due to a lack of functional elements, depending on many idiosyncratic factors. Genetic risk assessed from GWAS is only a statistical notion with no direct interpretation at the individual level. However, genomic profiling could be useful at population level in devising models to guide decisions in health care policy. (shrink)

The New Testament, while rejecting any superficial connection between illness and sin, does not reject a possible connection between illness and a person's relationship with God. An example can be seen in the story of the young blind man who was healed. His blindness does not result from any fault he or his parents had committed but apparently from God's wish to reveal his own healing power. The inner blindness of the Pharisees is a different type of blindness far more (...) difficult to heal. The blind young man was actually healed, not only in body but also in soul. Such miraculous healings are rare nowadays. However, if one takes a closer look at modern genetics and psycho-neuro-immunological findings, one may come to a better understanding of how miracle healings are linked to man's inner life and therefore also to his religiousness. Many diseases have genetic backgrounds. Defective genes, however, do not necessarily lead to subsequent illness. Genes have to be switched on or off. Only activated genes trigger pathological change. The human brain and all of man's thinking and feeling are intimately connected with such activations. We may thus conclude that both inner life and religious outlook on life are relevant to the origin and development of diseases. (shrink)

This paper focuses on the causation of diseases, particularly on the idea of a “genetic cause” taking Alzheimer’s Disease (AD) as an example. We (1) provide some historical information and a synopsis of the current knowledge on the etiology and pathogenesis of AD, (2) analyse some conceptual problems related to the notion of “genetic disease” (3) elaborate on the alleged (genetic) cause of AD, and (4) place the discussion on the cause of AD in a broader (...) philosophical context, paying attention to a constructivist perspective, the notions of causal connection and causal selection, and to some practical and normative consequences of our analysis. We conclude (a) that AD is not a specific disease entity with one specific cause, (b) that the idea of a single (sufficient) cause can still function as a heuristic tool in AD research and practice, and (c) that a “belief” in causation can go together with the notions of multicausality and probability. (shrink)

This paper considers whether existing law could potentially be used to criminalize the transmission of genetic disease. The paper argues that even if an offence could be made out, the criminal law should not be involved in this context for many reasons, including the need to protect reproductive liberty and pregnant women’s rights. The paper also examines whether there might be scope for civil claims between reproductive partners for a ‘failure to warn’ of potential genetic harm and argues (...) there are strong policy grounds for resisting such claims. If such a duty were to exist, there might, in the future, be scope for a child to bring a claim under the Congenital Disabilities 1976. Such a claim could be for the failure by the child’s father to warn her mother, which in turn led to the loss of opportunity to have treatment in utero which could have prevented the disability. It is suggested that the same arguments which supported granting maternal immunity under the Act would also support paternal immunity and that, therefore the issue of the lack of paternal immunity under the Act should be revisited. (shrink)

The study of mental illness by the methods of molecular genetics is still in its infancy, but the use of genetic markers in psychiatry may potentially lead to a Virchowian revolution in the conception of mental illness. Genetic markers may define novel clusters of patients having diverse clinical presentations but sharing a common genetic and mechanistic basis. Such clusters may differ radically from the conventional classification schemes of psychiatric illness. However, the reduction of even relatively simple Mendelian (...) phenomena to molecular genetics has been shown to be a surprisingly complex and problematic enterprise. Mental illnesses exist at many levels of including social, environmental, and developmental interactions. Reductionistic shifts in the classification of such a disease entity will have to address the interlevel dynamics that take place within the structure of theories of mental illness. The question of how molecular analysis of psychiatric disease will impact on the structure of existing theories and classification systems is the central topic of this paper. (shrink)

Alzheimer disease is a huge and growing societal problem with upwards of 35% of the population over the age of 80 developing the disease. AD results in a loss of memory, the ability to make reasoned and sound decisions, and ultimately the inability to take care of oneself. AD has an impact not only on the sufferer, but their caretakers and loved ones, who must take on a costly and time-consuming burden of care. AD is found in virtually all racial (...) and ethnic groups. Genetic influences on AD are substantial, and there has been a 30 year history of both success and failure. Mutations for rare early onset forms of the disease have been identified, but this information has not yet led to an effective treatment. Multiple common genetic variations have also been identified, and have led to new insights into the potential role of microglia cells in addition to neuronal cells in the brain. Despite intensive efforts, a significant portion of the genetic etiology of AD remains unknown and must be identified. (shrink)