bluuebunny/crossref_metadata_2025_split huggingface dataset:
Disclosing Genetic Information to Family Members: The Role of Empirical Ethics
Authors: Dupras Charles , Ravitsky Vardit 
Published: April 2013

Abstract

The familial and predictive nature of genetic information raises ethical issues regarding its disclosure to biological relatives. Arguments in the bioethics literature have centered on the right of the patient to privacy and confidentiality versus the right of family members to receive information that is clinically relevant to them. Empirical research has shown that although the need for disclosure within the family is rarely contested by patients, they are preoccupied by the ethical dimensions of their ‘genetic responsibility’, share a desire to protect relatives from the possible adverse effects of disclosure, and need guidance regarding what, why, to whom, when and how genetic information should be disclosed to mitigate adverse outcomes. Empirical ethics thus contributes to important insights and help reframe the debate to better address the lived experiences of patients, family members and healthcare professionals.

Key Concepts:

Disclosure of genetic information within the family raises particular ethical issues.

The disclosure debate has been framed as a conflict between respect for autonomy (i.e. the duty of the clinician to respect patient confidentiality) and beneficence/‘do no harm’ (i.e. the clinician's duty to warn others).

It is suggested that a patient's relatives have a right to know genetic information when it is clinically relevant to them.

Most patients feel a genetic responsibility to inform family members in order to promote their health and well being.

Empirical studies have shown that disclosure decisions are complex and influenced by numerous factors.

Empirical ethics involves empirical studies which provide information that can frame ethical debates, enhance normative analysis and inform clinical practices.
Limb Development Anomalies: Genetics
Authors: Manouvrier‐Hanu Sylvie , Florence Petit , Holder‐Espinasse Muriel , Escande‐Narducci Fabienne 
Published: April 2013

Abstract

Congenital limb malformations range from reduction defects to subtle digit anomalies (number/length/anatomy). Their prevalence is evaluated from 1.3‰ to 1.9‰ neonates. They can be classified as disruption anomalies and genetic malformations. The later are due to limb development gene function alteration and may be isolated or associated with other malformations.
The genes implicated in the limb bud development are numerous. They work together to trigger limb bud growth (proximodistal axis), polarisation (antero‐posterior and dorsoventral) and patterning. They are often pleiotropic, explaining the frequent association of limb anomalies with other malformations.
Furthermore, limb malformations are often genetically heterogeneous and various anomalies of one single gene can cause different diseases (allelic heterogeneity).

Key Concepts:

The limb bud development requires a constant equilibrium between cell mitotic activity and apoptosis.

The limb bud growth, its antero‐posterior and dorsoventral polarisation as well as its patterning are very interlinked and imply precise space and time regulation of the implicated genes’ expression.

Regulators/enhancers
: Alterations of regulatory elements of key developmental genes play an important role in limb bud development. (For example the Zone of polarising activity Regulatory Sequence (ZRS) is a crucial regulator of SHH expression in the limb bud.)
Colour Vision Defects
Authors: Neitz Maureen , Mancuso Katherine , Neitz Jay 
Published: April 2013

Abstract

Normal colour vision refers to the form of trichromatic colour vision shared by most individuals. It is mediated by three types of retinal cone photoreceptors, short‐ (S), medium‐ (M) and long‐ (L) wavelength‐sensitive. Colour vision defects can either be inherited as the consequence of genetic defects that affect the function of one or more cone type, or they can be acquired through exposure to neurotoxins or as secondary effects of systemic or ocular diseases. Among individuals with colour vision deficiency, there is tremendous variation in the capacity for colour vision, ranging from no colour vision to nearly normal. Viral‐mediated gene therapy for ocular diseases has been an area of intense investigation over the last decade. Because genetic mutations underlying colour vision deficiencies have been identified, gene therapy may be a viable option for curing various forms of colour blindness in the future.

Key Concepts:

Normal colour vision requires three classes of cone photoreceptor in the retina: short‐, medium‐ and long‐wavelength sensitive.

The hallmark feature of colour vision defects is a reduction in the number of different colours that can be distinguished from each other.

Colour vision defects can either be inherited or they can be acquired secondary to disease or through exposure to certain drugs or neurotoxins.

Mutations and rearrangements in the genes encoding the short‐, medium‐ and long‐wavelength sensitive photopigments are responsible for inherited colour vision deficiencies.

Gene therapy has been successfully used to treat colour blindness in animal models and these experiments pave the way towards cures for colour blindness in humans.
Drug‐Metabolising Enzymes: Genetic Polymorphisms
Authors: Ingelman‐Sundberg Magnus 
Published: April 2013

Abstract

Polymorphism in drug‐metabolising enzymes is of great importance for interindividual differences in drug therapy. Variant genes causing increased, decreased or abolished drug metabolism influences the drug response and risk for adverse drug reactions. The genetic alterations include single‐nucleotide polymorphisms, ins/del and gene copy number variations. Of particular importance are the cytochrome P450 enzymes responsible for the metabolism of the majority of clinically important drugs. This variability is now emphasised during drug development and of importance for routine drug prescription. Several different drugs contain pharmacogenomic labels where genotyping before prescription is mandatory or recommended. Predictive genotyping of drug‐metabolising genes can thus help to design individualised, safer and more efficient drug therapies.

Key Concepts:

The majority of drug metabolism is carried out by cytochrome P450 enzymes.

The polymorphic cytochrome P450 enzymes account for 40% of the phase I drug metabolism.

The major phenotypes with respect to drug metabolism are poor metabolisers (PMs), intermediate metabolisers (IMs), extensive metabolisers (EMs) and ultrarapid metabolisers (UMs).

There are large interethnic differences in the drug metabolism caused by genetic factors.

The toxicity of some anticancer drugs, and antibiotics can be predicted by the occurrence of particular genes encoding drug‐metabolising enzymes.

The effective dose of clopidogrel, warfarin, tricyclic antidepressants, tamoxifen and some antipsychotics is determined by the P450 polymorphism.

Irenotecan and mercaptopurine toxicity is dependent on UGT1A1 and TPMT polymorphism, respectively.

85% of the pharmacogenomic drug labels refer to genes encoding drug‐metabolising enzymes, in particular cytochrome P450.
Charcot–Marie–Tooth Disease and Associated Peripheral Neuropathies
Authors: Espinós Carmen 
Published: April 2013

Abstract

Charcot–Marie–Tooth (CMT) disease, a hereditary motor and sensory neuropathy, is the most frequent inherited neuromuscular disorder. According to electrophysiological and nerve biopsy criteria, CMT is classified into three categories: demyelinating, axonal and intermediate. Mutations in more than 30 genes/loci result in CMT phenotype. The main demyelinating CMT form is a 1.4‐Mb duplication, which affects the
PMP22
(70%) gene, followed by mutations in the
GJB1
(6%) and
MPZ
(3–5%) genes. Regarding axonal CMT, the commonest form is due to mutations in the
MFN2
(20%) gene. Other neuropathies that share clinical similarities and genetic basis with CMT include Déjérine–Sottas syndrome, congenital hypomyelinating neuropathy and hereditary neuropathy with liability to pressure palsies. During the last decade advances have allowed to get insight of the molecular bases of this group of peripheral neuropathies and in most cases, an accurate genetic diagnosis is possible.

Key Concepts:

The Charcot–Marie–Tooth (CMT) disease, a hereditary motor sensory neuropathy, is the most frequent inherited neurological disease.

According to electrophysiological and histopathological criteria, CMT can be classified into three forms: demyelinating, axonal and intermediate.

Genes involved in Déjérine–Sottas syndrome, congenital hypomyelinating neuropathy and hereditary neuropathy with liability to pressure palsies are also associated with CMT.

CMT is characterised by a wide genetic heterogeneity because more than 30 genes/loci are related to this disease and also because all the Mendelian patterns can be found in this group of diseases.

The duplication of 1.4 Mb which affects the
PMP22
gene (CMT1A duplication) is the most prevalent cause of Charcot–Marie–Tooth disease with a percentage of 43% of the total CMT.

Once the most frequent genes related to CMT (
PMP22
,
MPZ
,
GJB1
,
MFN2
and
GDAP1
) have been ruled out, mutations in the remaining known genes occur in less than 1% of CMT cases.

The complexity of CMT genetics makes difficult to identify the disease‐causing mutation in many cases and therefore, the next‐generation sequencing (NGS) technologies facilitate the genetic diagnosis.
Chemical, Biological, Radiological and Nuclear Weapons: Genotoxicity
Authors: Gosden Christine M , Gardener Derek 
Published: April 2013

Abstract

Many chemical, biological radiological and nuclear weapons (CBRN) including mustard gas, nerve agents, Aflatoxin, nuclear and radiological weapons are genotoxic, neurotoxic and carcinogenic. They damage
deoxyribonucleic acid (DNA)
, cells, tissues and organs. Almost every decade since World War I (WWI) has seen CBRN manufacture or use, killing and injuring many hundreds of thousands. Survivors of CBRN use (WWI victims, WWII manufacture in Germany, Japan, UK, US and of Conflicts involving CBRN use, such as Northern Iraq, Afghanistan) face increased risk of cancers, infertility, medical disorders and reproductive health effects. Each agent has specific effects, for example, Aflatoxin causes liver cancer and is embryotoxic, Mustard gas, Nuclear and Radiological weapons cause haematological malignancies and solid tumours. This indicates each type of weapon causes specific types of genomic damage. Knowledge of the mechanisms of action of CBRN is important in identifying CBRN use, developing therapies to aid victims and counteracting the threats from these weapons.

Key Concepts:

Despite the Geneva Convention of 1925 prohibiting their use, CBRN have been widely used over the past 100 years in wars and conflicts to subjugate populations, kill and injure.

CBRN are genotoxic and neurotoxic leading to long‐term genomic damage and major risks for survivors of exposures.

There are currently few methods of identifying genomic damage in victims of CBRN; new methods such as next generation genome and transcriptome sequencing will allow the identification of damage and predict methods for screening, protection and treatment.

CBRN may be used by rogue governments or terrorist groups to kill, maim and cause long‐term medical damage.

CBRN have been used in ethnic cleansing campaigns, against guerrilla forces in mountainous regions as well as conventional wars and conflicts resulting in lethality and premature deaths through cancers, medical disorders, embryonic, fetal and infant deaths, birth defects and infertility, leading to ‘silent attrition’ of targeted populations.

There are no known treatments for CBRN damage as these agents cause long‐term irreversible genotoxic and neurotoxic damage; key elements for protection are to identify CBRN use, develop screening methods to identify those exposed, reduce ongoing contamination of food, water and environment, treat victims and develop therapies risks.
Genetics of the Autosomal Dominant Spinocerebellar Ataxias
Authors: Corral‐Juan Marc , Corral Jordi , San Nicolás Héctor , Volpini Victor , Matilla‐Dueñas Antoni 
Published: April 2013

AbstractThe spinocerebellar ataxias (SCAs) are a clinically, genetically and neuropathologically heterogeneous group of neurological disorders defined by variable degrees of cerebellar ataxia often accompanied by additional cerebellar and noncerebellar symptoms that, in many cases, defy differentiation based on clinical characterisation alone. The clinical symptoms are triggered by neurodegeneration of the cerebellum and its rely connections. Currently, there are 43 different genes associated with the autosomal dominant SCAs identified. Genetic studies refine the clinical diagnosis, provide molecular testing of at risk, a/presymptomatic, prenatal or preimplantation and facilitate genetic counselling in 27 SCA subtypes. Recent scientific advances are shedding light into the altered molecular pathways involved and the mechanisms by which the mutant gene products underlie neurodegeneration. This knowledge should be translated into effectively developing selective therapeutic strategies. The scope of this chapter is to provide an updated summary of the genetic aspects of the autosomal dominant SCAs.Key Concepts:Ataxia, a term that derives from the Greek, is a neurological disorder characterised by loss of control of voluntary body movements.Spinocerebellar ataxias, also known as SCAs, are a highly heterogeneous group of neurodegenerative diseases caused by cerebellar atrophy triggered by predominant loss of Purkinje cells in the cerebellum.The term ‘spinocerebellar ataxias’ is commonly used for those inherited progressive, congenital or episodic ataxias presenting an autosomal dominant inheritance.Mutations presenting incomplete penetrance in at least 43 genes are responsible for ataxia in the autosomal dominant SCAs.CAG repeat expansions encoding for polyglutamines in the gene products currently underlie neurodegeneration in seven spinocerebellar ataxia subtypes.Anticipation is a genetic phenomenon whereby the clinical symptoms become apparent at an earlier age as it is passed on to the next generation. This is associated with the germline transmission of an unstable expanded CAG‐triplet repeat.
Albinism: Genetics
Authors: Oetting William S 
Published: April 2013

Abstract

Albinism has classically been described as the complete absence of melanin pigment in the skin, hair and eyes throughout the life of the affected individual. Modern molecular analysis has shown that albinism is a much more complex genetic disorder than previously thought, involving many genes with an array of functions, as well as great variation in the phenotype of affected individuals. There are currently 15 genes that have been associated with albinism, including four nonsyndromic forms of oculocutaneous albinism (reduced pigment affects skin, hair and eyes), one nonsyndromic form of ocular albinism (reduced pigment affects eyes only) and ten syndromic disorders that include albinism as part of the phenotype. The gene functions of the nonsyndromic forms are thought to be involved in melanin biosynthesis and many of the genes associated with the syndromic forms are involved in protein trafficking. Common genetic variants within some of these genes are also associated with normal variation in eye, hair and skin colouration.

Key Concepts:

All animals make melanin as the chief form of colouration.

Melanin is made in specific cells called melanocytes.

Albinism is caused by an absence of melanin biosynthesis resulting in several clinical features.

There are many different types of albinism.

There are several genes associated with albinism.

The molecular pathology of albinism is complex and involves different types of mutations.

Variation in skin pigmentation involves common polymorphisms in some albinism‐related genes.

Albinism can affect interactions between individuals and society.
Human Disease and the Desmosome
Authors: Chidgey Martyn 
Published: April 2013

Abstract

Desmosomes are intercellular junctions of epithelia and cardiac muscle. They are located at the cell membrane where they act as anchors for intermediate filaments. Desmosomes maintain the structural integrity of tissues and disruption of desmosomal adhesion can have devastating consequences for human health. Arrhythmogenic right ventricular dysplasia, a heart muscle disease that is characterised by life‐threatening arrhythmias and increased risk of sudden heart failure, is caused by mutations in genes encoding desmosomal proteins. Other mutations can result in severe skin blistering, catastrophic fluid loss and early death. Cardiocutaneous syndromes that affect the heart, skin and hair are also caused by mutations in desmosomal genes. Pathogenic autoantibodies against desmogleins, membrane‐spanning proteins of desmosomes, cause the skin blistering diseases pemphigus and staphylococcal scalded skin syndrome. Desmosomes and their constituents could contribute to the progression of cancer.

Key Concepts:

Desmosomes are intercellular junctions of epithelia and cardiac muscle.

Desmosomes maintain the structural integrity of tissues.

Mutations in genes encoding desmosomal proteins can result in heart disease and disorders of the skin and hair.

Pemphigus is an autoimmune skin blistering disease that is caused by autoantibodies against desmogleins, membrane‐spanning proteins of desmosomes.

Desmosomes may be important in cancer.
Lesch–Nyhan Disease
Authors: Visser JE , Jinnah HA 
Published: April 2013

Abstract

Lesch–Nyhan disease (LND) is an X‐linked, inherited neurodevelopmental disease caused by a mutation in the gene encoding the purine salvage enzyme
hypoxanthine guanine phosphoribosyltransferase
(HPRT). Virtual absence of
HPRT
is associated with hyperuricemia and specific neurobehavioural features: a hyperkinetic movement disorder dominated by dystonia, cognitive impairment with attentional and executive deficits, and behavioural disturbances including self‐injurious behaviour. Partial
HPRT
deficiencies result in incomplete phenotypes characterised by hyperuricemia with or without neurological dysfunction, but without self‐injury.
HPRT
deficiency leads to a deficiency of the neurotransmitter dopamine, and the subsequent dysfunction of the basal ganglia is thought to play an important role in the pathogenesis of the neurobehavioural phenotype. Administering allopurinol reduces the risk of hyperuricemia‐associated urological and articular complications, but there is currently no effective treatment for the neurobehavioural features of LND. Self‐injurious behaviour is managed by restraints and soft padding of the environment, and sometimes neuroleptics, anxiolytics or sedatives.

Key Concepts:

Lesch–Nyhan disease (LND) is caused by deficiency of the purine salvage enzyme
hypoxanthine guanine phosphoribosyltransferase
(HPRT).

LND is characterised by developmental delay, hyperuricemia, dystonia, attentional and executive deficits and behavioural disturbances including self‐injurious behaviour.

The severity of the clinical phenotype in LND depends on the amount of residual
HPRT
enzyme activity.

Dysfunction of the basal ganglia dopamine systems are thought to play an important role in the pathogenesis of the neurobehavioural phenotype.

LND patients are not globally retarded, but rather have impairments in specific cognitive domains, including attentiveness and mental flexibility.

Compulsive self‐injurious behaviour is considered a hallmark of the disease, and emerges usually within the first few years of life.

HPRT
enzyme activity testing or
HPRT
gene mutation analysis confirms the diagnosis.

As effective treatment for LND is currently lacking, prevention through carrier testing, genetic counselling and prenatal diagnosis is of utmost importance.
Peroxisome Biogenesis Disorders
Authors: Fujiki Yukio 
Published: April 2013

Abstract

Peroxisome biogenesis disorders (PBDs) are autosomal recessive, progressive disorders characterised by loss of multiple peroxisomal metabolic functions and defects in peroxisome assembly, consisting of 13 complementation groups (CGs). Two mutually distinct but complementary approaches, forward genetic approach using more than a dozen CGs of peroxisome‐deficient Chinese hamster ovary (CHO) cell mutants and the homology search by screening the human expressed sequence tag (EST) database using yeast peroxin (

PEX

) genes, have been taken in order to isolate mammalian

PEX

genes. Search for pathogenic genes responsible for PBDs of all 13 CGs is now accomplished. Prenatal DNA diagnosis using

PEX

genes is now possible for PBDs of all 13 CGs. Moreover, molecular mechanisms underlying peroxisome biogenesis involving membrane assembly and matrix protein import are currently investigated by making use of

PEX

genes and

pex

cell mutants.

Key Concepts:

A single cell comprises more than a dozen different organelles that have unique protein compositions. Mechanisms underlying when and how these proteins are transported should be defined.

The ways how the diverse sequences of proteins are recognised for translocation by the transport systems/machineries need to be delineated.

The proteins and the lipid environment catalysing the protein transport must be addressed.

Furthermore, during the cell cycle, each organelle must double in size, divide, and be delivered to its proper location in the daughter cells. How such events are accomplished and regulated should be defined.

In tackling such issues, genetic phenotype complementation screening using mammalian somatic cell mutants and by taking advantage of highly sensitive and rapid detection may lead to cloning of genes essential for protein trafficking and organelle assembly.

Mutations in genes are permanent alterations that may lead to changes in phenotype. Cell mutants are a highly useful tool in genetic, biochemical, as well as cell biological research.

Several methods including the most recent lipofection have been developed for transfecting DNA into animal cells.

Peroxisome biogenesis disorders (PBDs) are autosomal recessive, progressive disorders characterised by loss of multiple peroxisomal metabolic functions and defects in peroxisome assembly, consisting of more than a dozen complementation groups.

Genetic phenotype‐complementation of peroxisome assembly‐defective mutants of mammalian somatic cells such as Chinese hamster ovary (CHO) cells and of several yeast species including

Saccharomyces cerevisiae

and

Pichia pastoris

would lead to identification and characterisation of numerous genes that are essential for peroxisome biogenesis.