Organizations With PRS Accounts

National Institutes of Health (NIH)


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Nutrition Research Database Provides Nutrition Reports for Foods and Supplements


Regions of the brain have differing amounts and reliance on these types of neurons, and are affected accordingly. The remaining variation is attributed to environment and other genes that modify the mechanism of HD.

In some cases the onset may be so late that symptoms are never noticed. Huntington's disease has autosomal dominant inheritance, meaning that an affected individual typically inherits one copy of the gene with an expanded trinucleotide repeat the mutant allele from an affected parent. This probability is sex-independent. Trinucleotide CAG repeats over 28 are unstable during replication , and this instability increases with the number of repeats present.

Individuals with both genes affected are rare. For some time HD was thought to be the only disease for which possession of a second mutated gene did not affect symptoms and progression, [32] but it has since been found that it can affect the phenotype and the rate of progression. The huntingtin protein interacts with over other proteins, and appears to have multiple biological functions. Early damage is most evident in the striatum , but as the disease progresses, other areas of the brain are also more conspicuously affected.

Early symptoms are attributable to functions of the striatum and its cortical connections—namely control over movement, mood and higher cognitive function. HTT is expressed in all cells. The highest concentrations are found in the brain and testes , with moderate amounts in the liver , heart , and lungs.

It interacts with proteins which are involved in transcription, cell signaling , and intracellular transporting. Caspase , an enzyme which plays a role in catalyzing apoptosis, is thought to be activated by the mutated gene through damaging the ubiquitin-protease system.

It also acts as an anti-apoptotic agent preventing programmed cell death and controls the production of brain-derived neurotrophic factor , a protein which protects neurons and regulates their creation during neurogenesis.

HTT also facilitates vesicular transport and synaptic transmission and controls neuronal gene transcription. There are multiple cellular changes through which the toxic function of mHTT may manifest and produce the HD pathology.

Over time, the aggregates accumulate to form inclusion bodies within cells, ultimately interfering with neuron function. Inclusion bodies have been found in both the cell nucleus and cytoplasm. Several pathways by which mHTT may cause cell death have been identified.

An additional theory that explains another way cell function may be disrupted by HD proposes that damage to mitochondria in striatal cells is of central importance numerous accounts of mitochondrial metabolism deficiency have been found. Mutant Huntingtin protein has been found to play a key role in mitochondrial dysfunction. The interactions of the altered huntingtin protein with numerous proteins in neurons leads to an increased vulnerability of glutamine, which, in large amounts, has been found to be an excitotoxin.

Excitotoxins may cause damage to numerous cellular structures. Although glutamine is not found in excessively high amounts, it has been postulated that because of the increased vulnerability, even normal amounts glutamine can cause excitotoxins to be expressed. HD affects the whole brain, but certain areas are more vulnerable than others.

The most prominent early effects are in a part of the basal ganglia called the neostriatum , which is composed of the caudate nucleus and putamen. The basal ganglia—the part of the brain most prominently affected in early HD—play a key role in movement and behavior control.

Their functions are not fully understood, but current theories propose that they are part of the cognitive executive system [18] and the motor circuit. To initiate a particular movement, the cerebral cortex sends a signal to the basal ganglia that causes the inhibition to be released. Damage to the basal ganglia can cause the release or reinstatement of the inhibitions to be erratic and uncontrolled, which results in an awkward start to motion or motions to be unintentionally initiated, or a motion to be halted before, or beyond, its intended completion.

The accumulating damage to this area causes the characteristic erratic movements associated with HD. Because of the basal ganglia's inability to inhibit movements, individuals affected by it will inevitably experience a reduced ability to produce speech and swallow foods and liquids dysphagia. CREB-binding protein CBP , a transcriptional coregulator, is essential for cell function because as a coactivator at a significant number of promoters, it activates the transcription of genes for survival pathways.

Thus, the glutamines on CBP interact directly with the increased numbers of glutamine on the HTT chain and CBP gets pulled away from its typical location next to the nucleus.

Medical diagnosis of the onset of HD can be made following the appearance of physical symptoms specific to the disease. Even before the onset of symptoms, genetic testing can confirm if an individual or embryo carries an expanded copy of the trinucleotide repeat in the HTT gene that causes the disease. Genetic counseling is available to provide advice and guidance throughout the testing procedure, and on the implications of a confirmed diagnosis.

These implications include the impact on an individual's psychology, career, family planning decisions, relatives and relationships. A physical examination , sometimes combined with a psychological examination , can determine whether the onset of the disease has begun.

If these are abrupt and have random timing and distribution, they suggest a diagnosis of HD. Cognitive or behavioral symptoms are rarely the first symptoms diagnosed; they are usually only recognized in hindsight or when they develop further. How far the disease has progressed can be measured using the unified Huntington's disease rating scale , which provides an overall rating system based on motor, behavioral, cognitive, and functional assessments. Cerebral atrophy can be seen in the advanced stages of the disease.

Functional neuroimaging techniques, such as functional magnetic resonance imaging fMRI and positron emission tomography PET , can show changes in brain activity before the onset of physical symptoms, but they are experimental tools, and are not used clinically. Because HD follows an autosomal dominant pattern of inheritance, there is a strong motivation for individuals who are at risk of inheriting it to seek a diagnosis. Testing before the onset of symptoms is a life-changing event and a very personal decision.

It occurred at higher rates within personal relationships than health insurance or employment relations. Counseling and guidelines on the use of genetic testing for HD have become models for other genetic disorders, such as autosomal dominant cerebellar ataxias. Embryos produced using in vitro fertilization may be genetically tested for HD using preimplantation genetic diagnosis PGD. This technique, where one or two cells are extracted from a typically 4- to 8-cell embryo and then tested for the genetic abnormality, can then be used to ensure embryos affected with HD genes are not implanted, and therefore any offspring will not inherit the disease.

Some forms of preimplantation genetic diagnosis—non-disclosure or exclusion testing—allow at-risk people to have HD-free offspring without revealing their own parental genotype, giving no information about whether they themselves are destined to develop HD.

In exclusion testing, the embryos' DNA is compared with that of the parents and grandparents to avoid inheritance of the chromosomal region containing the HD gene from the affected grandparent. In non-disclosure testing, only disease-free embryos are replaced in the uterus while the parental genotype and hence parental risk for HD are never disclosed.

It is also possible to obtain a prenatal diagnosis for an embryo or fetus in the womb, using fetal genetic material acquired through chorionic villus sampling. An amniocentesis can be performed if the pregnancy is further along, within 14—18 weeks. This procedure looks at the amniotic fluid surrounding the baby for indicators of the HD mutation.

The parents can be counseled on their options, which include termination of pregnancy , and on the difficulties of a child with the identified gene. In addition, in at-risk pregnancies due to an affected male partner, non-invasive prenatal diagnosis can be performed by analyzing cell-free fetal DNA in a blood sample taken from the mother via venipuncture between six and twelve weeks of pregnancy.

Other autosomal dominant diseases that can be misdiagnosed as HD are dentatorubral-pallidoluysian atrophy and neuroferritinopathy. There are also autosomal recessive disorders that resemble sporadic cases of HD. These include chorea acanthocytosis and pantothenate kinase-associated neurodegeneration.

One X-linked disorder of this type is McLeod syndrome. There is no cure for HD, but there are treatments available to reduce the severity of some of its symptoms. Weight loss and eating difficulties due to dysphagia and other muscle discoordination are common, making nutrition management increasingly important as the disease advances. This is a feeding tube, permanently attached through the abdomen into the stomach, which reduces the risk of aspirating food and provides better nutritional management.

People with Huntington's disease may see a physical therapist for non-invasive and non-medication-based ways of managing the physical symptoms.

Physical therapists may implement fall risk assessment and prevention, as well as strengthening, stretching, and cardiovascular exercises. Walking aids may be prescribed as appropriate. Physical therapists also prescribe breathing exercises and airway clearance techniques with the development of respiratory problems.

Participation in rehabilitation programs during early to middle stage of the disease may be beneficial as it translates into long term maintenance of motor and functional performance. Rehabilitation during the late stage aims to compensate for motor and functional losses. Tetrabenazine was approved in for treatment of chorea in Huntington's disease in the EU, and in in the US.

Psychiatric symptoms can be treated with medications similar to those used in the general population. The families of individuals who have inherited or are at risk of inheriting HD have generations of experience of HD, but may be unaware of recent breakthroughs in understanding the disease, and of the availability of genetic testing. Genetic counseling benefits these individuals by updating their knowledge, seeking to dispel any unfounded beliefs that they may have, and helping them consider their future options and plans.

Also covered is information concerning family planning choices, care management, and other considerations. A longer repeat results in an earlier age of onset and a faster progression of symptoms. The largest risk is pneumonia , which causes death in one third of those with HD. As the ability to synchronize movements deteriorates, difficulty clearing the lungs and an increased risk of aspirating food or drink both increase the risk of contracting pneumonia.

The second greatest risk is heart disease , which causes almost a quarter of fatalities of those with HD. It is unclear to what extent suicidal thoughts are influenced by behavioral symptoms, as they signify sufferers' desires to avoid the later stages of the disease. The late onset of Huntington's disease means it does not usually affect reproduction.

The rate of occurrence is highest in peoples of Western European descent, averaging around 7 per , people, and is lower in the rest of the world; e. A epidemiological study of the prevalence of Huntington's disease in the UK between and found that the average prevalence for the UK was Until the discovery of a genetic test , statistics could only include clinical diagnosis based on physical symptoms and a family history of HD, excluding those who died of other causes before diagnosis.

These cases can now be included in statistics; and, as the test becomes more widely available, estimates of the prevalence and incidence of the disorder are likely to increase. Although Huntington's has been recognized as a disorder since at least the Middle Ages , the cause has been unknown until fairly recently. Huntington's was given different names throughout this history as understanding of the disease changed. Originally called simply 'chorea' for the jerky dancelike movements associated with the disease, HD has also been called "hereditary chorea" and "chronic progressive chorea".

Waters described "a form of chorea, vulgarly called magrums", including accurate descriptions of the chorea, its progression, and the strong heredity of the disease. The first thorough description of the disease was by George Huntington in Examining the combined medical history of several generations of a family exhibiting similar symptoms, he realized their conditions must be linked; he presented his detailed and accurate definition of the disease as his first paper.

Huntington described the exact pattern of inheritance of autosomal dominant disease years before the rediscovery by scientists of Mendelian inheritance. When either or both the parents have shown manifestations of the disease But if by any chance these children go through life without it, the thread is broken and the grandchildren and great-grandchildren of the original shakers may rest assured that they are free from the disease.

Sir William Osler was interested in the disorder and chorea in general, and was impressed with Huntington's paper, stating that "In the history of medicine, there are few instances in which a disease has been more accurately, more graphically or more briefly described. During the rediscovery of Mendelian inheritance at the turn of the 20th century, HD was used tentatively as an example of autosomal dominant inheritance. Researchers have found contrary evidence; for instance, the community of the family studied by George Huntington openly accommodated those who exhibited symptoms of HD.

The search for the cause of this condition was enhanced considerably in , when the Hereditary Disease Foundation HDF was created by Milton Wexler , a psychoanalyst based in Los Angeles , California , whose wife Leonore Sabin had been diagnosed earlier that year with Huntington's disease.

The foundation was involved in the recruitment of over scientists in the Huntington's Disease Collaborative Research Project who over a year period worked to locate the responsible gene. Thanks to the HDF, the ongoing US-Venezuela Huntington's Disease Collaborative Research Project was started in , and reported a major breakthrough in with the discovery of the approximate location of a causal gene. It involved over 18, people—mostly from a single extended family.

Among other innovations, the project developed DNA -marking methods which were an important step in making the Human Genome Project possible. In the same time frame, key discoveries concerning the mechanisms of the disorder were being made, including the findings by Anita Harding 's research group on the effects of the gene's length.

Modelling the disease in various types of animals, such as the transgenic mouse developed in , enabled larger scale experiments. As these animals have faster metabolisms and much shorter lifespans than humans, results from experiments are received sooner, speeding research.

The discovery that mHTT fragments misfold led to the discovery of the nuclear inclusions they cause. These advances have led to increasingly extensive research into the proteins involved with the disease, potential drug treatments, care methods, and the gene itself.

The condition was formerly called 'Huntington's chorea' but this term has been replaced by 'Huntington's disease' because not all patients develop chorea and due to the importance of cognitive and behavioral problems. Huntington's disease, particularly the application of the genetic test for the disease, has raised several ethical issues.

The issues for genetic testing include defining how mature an individual should be before being considered eligible for testing, ensuring the confidentiality of results, and whether companies should be allowed to use test results for decisions on employment, life insurance or other financial matters.

There was controversy when Charles Davenport proposed in that compulsory sterilization and immigration control be used for people with certain diseases, including HD, as part of the eugenics movement. Some HD research has ethical issues due to its use of animal testing and embryonic stem cells. The development of an accurate diagnostic test for Huntington's disease has caused social, legal, and ethical concerns over access to and use of a person's results.

There is consensus for testing only individuals who are considered cognitively mature, although there is a counter-argument that parents have a right to make the decision on their child's behalf. With the lack of an effective treatment, testing a person under legal age who is not judged to be competent is considered unethical in most cases.

There are ethical concerns related to prenatal genetic testing or preimplantation genetic diagnosis to ensure a child is not born with a given disease. This would require parts of the process to be kept secret from the parent. In , after experiencing HD in his wife's family, Dr. Milton Wexler was inspired to start the Hereditary Disease Foundation HDF , with the aim of curing genetic illnesses by coordinating and supporting research. Since then, support and research organizations have formed in many countries around the world and have helped to increase public awareness of HD.

A number of these collaborate in umbrella organizations, like the International Huntington Association and the European HD network. The largest funder of Huntington's disease research globally, in terms of financial expenditure, [] is the CHDI Foundation , a US non-profit biomedical foundation that aims to "rapidly discover and develop drugs that delay or slow Huntington's disease". Research into the mechanism of HD has focused on identifying the functioning of HTT, how mHTT differs or interferes with it, and the brain pathology that the disease produces.

Research is conducted using in vitro methods, animal models and human volunteers. Animal models are critical for understanding the fundamental mechanisms causing the disease and for supporting the early stages of drug development.

Research is being conducted on many different approaches to prevent Huntington's disease or slow its progression. Disease-modifying strategies can be broadly grouped into three categories: In addition, novel therapies to improve brain functioning are under development; these seek to produce symptomatic rather than disease-modifying therapies, and include phosphodiesterase inhibitors.

Gene silencing aims to reduce the production of the mutant protein, since HD is caused by a single dominant gene encoding a toxic protein. Gene silencing experiments in mouse models have shown that when the expression of mHTT is reduced, symptoms improve. One way of accomplishing this is to identify polymorphisms present on only one allele and produce gene silencing drugs that target polymorphisms in only the mutant allele.

Among the approaches aimed at improving cell survival in the presence of mutant huntingtin are correction of transcriptional regulation using histone deacetylase inhibitors , modulating aggregation of huntingtin, improving metabolism and mitochondrial function and restoring function of synapses.

Stem cell therapy is the replacement of damaged neurons by transplantation of stem cells into affected regions of the brain. Experiments have yielded mixed results using this technique in animal models and preliminary human clinical trials. Several clinical trials of new experimental treatments are underway and planned in Huntington's disease.

Compounds that have failed to prevent or slow progression of Huntington's disease in human trials include remacemide , coenzyme Q10 , riluzole , creatine , minocycline , ethyl-EPA , phenylbutyrate and dimebon.

From Wikipedia, the free encyclopedia. List of Huntington's disease media depictions. Archived from the original on 27 July Retrieved 19 July A Journey through History". Tremor and other hyperkinetic movements New York, N. Archived from the original on 4 July Archived from the original on 19 November Retrieved 18 November Huntington's Disease Society of America. Archived from the original on 9 April Retrieved 17 March J Neuropsychiatry Clin Neurosci.

Archived from the original on 10 February Retrieved 12 March Huntington's Outreach Project for Education, at Stanford. Archived from the original on 8 August Retrieved 4 August Huntington's Disease — Third Edition. Aetna considers genetic testing for SHOX-related short stature medically necessary for children and adolescents with any of the following features:. Aetna considers genetic testing for SHOX-related short stature experimental and investigational for all other indications because its effectiveness for indications other than the ones listed above has not been established.

Aetna considers genetic testing for HCM medically necessary for individuals who meet the following criteria:. Individual to be tested has been evaluated eg, electrocardiogram [ECG], echocardiography and exhibits no clinical evidence of HCM; and. Individual has a 1st degree relative i. Test for known familial mutation. Aetna considers genetic testing for HCM experimental and investigational for all other indications because its effectiveness for indications other than the one listed above has not been established.

Genetic testing for thoracic aortic aneurysms and dissections TAAD is considered experimental and investigational for any other indication, including but not limited to patients clinically diagnosed with TAAD, with a positive family history of the disorder, and for whom a genetic syndrome has been excluded.

Asymptomatic individual who has an affected first-degree blood relative ie, parent, full-sibling, child with a known deleterious or suspected deleterious mutation Testing strategy: Test for known familial mutation ; or. Genetic testing for neurofibromatosis is considered experimental and investigational for all other indications.

Testing of an asymptomatic individual who has an affected first-degree blood relative i. In the presence of family history of Marfan syndrome, the presence of one of any of the following is diagnostic for Marfan syndrome: Symptomatic individuals to confirm a diagnosis of EDS vascular type when the following criteria are met:.

Testing begins with sequence analysis of COL3A1 gene. Biochemical protein-based testing may be considered for individuals with a negative sequencing result or when a sequence variant of unknown significance VUS is found.

Genetic testing for EDS is considered experimental and investigational for all other indications, including the following: Aetna considers genetic testing medically necessary to confirm a diagnosis of AS when the following criteria are met:. Presence of unique behavior with inappropriate happy demeanor that includes frequent laughing, smiling and excitability. Aetna considers genetic testing medically necessary to confirm a diagnosis of PWS when the following criteria are met:. Testing begins with a targeted mutation panel.

If negative, sequence analysis may be considered. Genetic testing for Huntington disease is considered experimental and investigational for indications other than those listed above. Individual to be tested exhibits signs and symptoms of SCA such as progressive gait and limb incoordination, imbalance, dysarthria and disturbances of eye movements; and.

Non-genetic causes of ataxia have been excluded eg, alcoholism, multiple sclerosis, primary or metastatic tumors or paraneoplastic diseases associated with occult carcinoma of the ovary, breast or lung, vascular disease, vitamin deficiencies. Carrier screening when the individual to be tested is an asymptomatic female and has an affected blood relative in whom a disease-causing DMD or BMD mutation has been identified.

Test for known mutation ; or. Normal value ranges may vary slightly among different labs. Some labs use different measurements or test different samples. Individual to be tested exhibits characteristic features of DM1 or DM2 eg, muscle weakness, muscle pain, myotonia.

Has an affected first-degree blood relative ie, parent, full-sibling, child in whom a disease-causing DM1 or DM2 mutation has been identified.

Insufficient evidence exists in the literature to include fibrocystic disease of the breast, fibromas, and uterine fibroids as diagnostic criteria. If only one partner is of Ashkenazi Jewish ancestry, then testing of that partner is considered medically necessary. Aetna considers genetic testing for SMAD4 medically necessary for infants with first degree relatives with JPS because of the risk of hereditary hemorrhagic telangiectasia.

Familial Hypercholesterolemia Based upon a consensus statement on familial hypercholesterolemia FH from the European Atherosclerosis Society Nordestgaard, et al. When a causative mutation is found in the index case, a genetic test should be offered to all first-degree relatives. Initial family members to be tested are biological first-degree relatives, namely parents, siblings, and children. Biological second-degree relatives including grandparents, grandchildren, uncles, aunts, nephews, nieces, and half-siblings should also be considered.

Aetna considers genetic testing of SP-C and ABCA3 mutations medically necessary for interstitial lung disease ILD in infants presenting with acute respiratory failure in the absence of other explanations, or in older children with chronic presentation or family history of ILD, especially if the diagnostic imaging radiographic patterns or bronchoscopic findings is consistent with ILD.

Genetic tests are laboratory studies of human deoxyribonucleic acid DNA , chromosomes, genes or gene products to diagnose the presence of a genetic variation associated with a high risk of having or transmitting a specific genetic disorder. The obligation to counsel and obtain consent is inherent in the clinician-patient and investigator-subject relationships. In the case of most genetic tests, the patient or subject should be informed that the test might yield information regarding a carrier or disease state that requires difficult choices regarding their current or future health, insurance coverage, career, marriage, or reproductive options.

The objective of informed consent is to preserve the individual's right to decide whether to have a genetic test. This right includes the right of refusal should the individual decide the potential harm stigmatization or undesired choices outweighs the potential benefits. DNA-based mutation fanalysis is not covered for routine carrier testing for the diagnosis of Tay-Sachs and Sandhoff disease.

Under accepted guidelines, diagnosis is primarily accomplished through biochemical assessment of serum, leukocyte, or platelet hexosaminidase A and B levels. The literature states that mutation analysis is appropriate for individuals with persistently inconclusive enzyme-based results and to exclude pseudo-deficiency non-disease related mutations in carrier couples. Confirmation by molecular analysis of inborn errors of metabolism by traditional screening methodologies e. Rigorous clinical evaluation should precede diagnostic molecular testing.

In many instances, reliable mutation analysis requires accurate determination of specific allelic variations in a proband affected individual in a family before subsequent carrier testing in other at-risk family members can be accurately performed.

Coverage of testing for individuals who are not Aetna members is not provided, except under the limited circumstances outlined in the policy section above. Two genes have been identified as being primary responsible for this syndrome: Unlike other genetic disorders that are easily diagnosed, the diagnosis of HNPCC relies on a very strongly positive family history of colon cancer.

Specifically, several organizations have defined criteria that must be met to make the diagnosis of HNPCC. Although HNPCC lacks strict clinical distinctions that can be used to make the diagnosis, and therefore diagnosis is based on the strong family history, genetic testing is now available to study patient's DNA for mutations to one of the mismatch repair genes.

Identifying individuals with this disease and performing screening colonoscopies on affected persons may help reduce colon cancer mortality. Microsatellite instability MSI is found in the colorectal cancer DNA but not in the adjacent normal colorectal mucosa of most individuals with germline mismatch repair gene mutations. Individuals with MSI-low or microsatellite stable MSS results are unlikely to harbor mismatch repair gene mutations, and further genetic testing is usually not pursued.

HNPCC is a relatively rare disease, which makes screening the entire populace burdensome and ineffective. The incidence of this disease, even among the families of patients with colon cancer, is too small to make screening effective.

According to guidelines from the American Gastroenterological Association AGA, , adenomatous polyposis coli gene testing is indicated to confirm the diagnosis of familial adenomatous polyposis, provide pre-symptomatic testing for at-risk members 1st degree relatives 10 years or older of an affected patient , confirm the diagnosis of attenuated familial adenomatous polyposis in those with more than 20 adenomas, and test those 10 years or older at risk for attenuated FAP.

The AGA guidelines state that germline testing should first be performed on an affected member of the family to establish a detectable mutation in the pedigree. If a mutation is found in an affected family member, then genetic testing of at-risk members will provide true positive or negative results. The AGA guidelines state that, if a pedigree mutation is not identified, further testing of at-risk relatives should be suspended because the gene test will not be conclusive: When an affected family member is not available for evaluation, starting the test process with at-risk family members can provide only positive or inconclusive results.

In this circumstance, a true negative test result for an at-risk individual can only be obtained if another at-risk family member tests positive for a mutation. Mutation of the MYH gene may result in colon cancer. In this regard, the MYH gene has been found to be significantly involved in colon cancer, both in cases where there is a clear family history of the disease, as well as in cases without any sign of a hereditary cause. The National Comprehensive Cancer Network NCCN 's practice guidelines on colorectal cancer screening recommended testing for MYH mutations for individuals with personal history of adenomatous polyposis more than 10 adenomas, or more than 15 cumulative adenomas in 10 years either consistent with recessive inheritance or with adenomatous polyposis with negative adenomatous polyposis coli APC mutation testing.

The guideline noted that when polyposis is present in a single person with negative family history, de novo APC mutation should be tested; if negative, testing for MYH should follow.

When family history is positive only for a sibling, recessive inheritance should be considered and MYH testing should be done first. In a polyposis family with clear autosomal dominant inheritance, and absence of APC mutation, MYH testing is unlikely to be informative.

Members in such family are treated according to the polyposis phenotype, including classical or attenuated FAP. Thrombophilia is a disorder of blood coagulation that increases the risk for blood clots thrombosis in veins or arteries.

Thrombophilia can be acquired or inherited. The most common acquired thrombophilias occur as a result of injury, surgery or a medical condition. The most common hereditary thrombophilias are factor V leiden FVL , due to a mutation in the F5 gene and prothrombin GA, as a result of a mutation in the F2 gene. Factor V Leiden mutation is the most common hereditary blood coagulation disorder in the United States.

Factor V Leiden increases the risk of venous thrombosis 3 to 8 fold for heterozygous individuals and 30 to fold for homozygous individuals.

Factor V Leiden mutation has been associated with the following complications:. Routine testing is also not recommended for patients with a personal or family history of arterial thrombotic disorders e.

According to the ACMG, testing may be worthwhile for young patients less than 50 years of age who develop acute arterial thrombosis in the absence of other risk factors for atherosclerotic arterial occlusive disease. The ACMG does not recommend general screening for factor V Leiden mutation before administration of oral contraceptives. The ACMG recommends targeted testing prior to oral contraceptive use in women with a personal or family history of venous thrombosis.

Factor V Leiden screening of asymptomatic individuals with other recognized environmental risk factors, such as surgery, trauma, paralysis, and malignancy is not necessary or recommended by the ACMG, since all such individuals should receive appropriate medical prophylaxis for thrombosis regardless of carrier status.

Patients who test positive by a functional assay should then be further studied with the DNA test for confirmation and to distinguish heterozygotes from homozygotes. According to the ACMG, patients testing positive for factor V Leiden or APC resistance should be considered for molecular genetic testing for prothrombin A, the most common thrombophilia with overlapping phenotype for which testing is easily and readily available. It is only a mild risk factor for thrombosis, but may potentiate other risk factors such as Factor V Leiden, oral contraceptives, surgery, trauma, etc.

In one study, co-inheritance of the HR2 haplotype increased the risk of venous thromboembolism associated with factor V Leiden by approximately 3-fold Faioni et al, However, double heterozygosity for factor V Leiden and the R2 polymorphism was not associated with a significantly higher risk of early or late pregnancy loss than a heterozygous factor V Leiden mutation alone Zammiti et al, Whether the HR2 haplotype alone is an independent thrombotic risk factor is still unclear.

In contrast, other studies de Visser ; Luddington et al, ; Dindagur et al, found no significant increase in thrombotic risk GeneTests, University of Washington, Seattle, Plasminogen activator inhibitor-1 PAI-1 is an inhibitor of fibrinolysis, the clot dissolving portion of the coagulation process. PAI-1 is under investigation as a risk factor for conditions such as cardiovascular disease, thrombophilia and pregnancy-related complications.

The PAI-1 test is an antibody-based enzyme assay. CADASIL cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy is a rare, genetically inherited, congenital vascular disease of the brain that causes strokes, subcortical dementia, migraine-like headaches, and psychiatric disturbances.

DNA testing for CADASIL is appropriate for symptomatic patients who have a family history consistent with an autosomal dominant pattern of inheritance of this condition. DNA testing is also indicated for pre-symptomatic patients where there is a family history consistent with an autosomal dominant pattern of inheritance and there is a known mutation in an affected member of the family.

Cystic fibrosis is the most common potentially fatal autosomal recessive disease in the United States. CF is characterized by the production of abnormally viscous mucous produced by the affected glands and usually causes respiratory infections and impaired pancreatic functions.

CF produces chronic progressive disease of the respiratory system, malabsorption due to pancreatic insufficiency, increased loss of sodium and chloride in sweat, and male infertility as a consequence of atresia of the vas deferens.

Pulmonary disease is the most common cause of mortality and morbidity in individuals with CF. The incidence of this disease ranges from 1: It occurs less frequently in people with other ethnic and racial backgrounds. Because of recent advances in clinical management of CF, babies born today are expected to live well into middle age.

Currently, the most frequently employed test for CF is the quantitative pilocarpine iontophoresis sweat test. However, this test can not detect CF carriers because the electrolyte content of sweat is normal in heterozygotes Wallach, Genetic testing is used to diagnose CF in individuals with signs and symptoms of the disease. It is also used for carrier screening of potential parents to identify genetic mutations for which they are at risk of passing along to their children.

Carriers may be unaffected but are at risk for producing children who are affected. Preferably carrier screening takes place before pregnancy, but can take place during the early stages of pregnancy.

The gene for CF cystic fibrosis trans-membrane conductance regulator, CFTR was cloned, and the principal mutant gene in white people DF was characterized in This mutation is due to a 3-base-pair deletion that results in the loss of a phenylalanine at position from the 1,amino acid coding region Riordan et al, Available evidence indicates that CFTR functions as a chloride channel, although it may also serve other functions.

Since then, more than CF mutations have been described. The genetic screening test for CF is usually based on mouthwash samples collected by agitating sucrose or saline in the mouth. The DNA of these cells are amplified, digested, and subjected to separation techniques that identify 3 to 5 common mutations. A National Institutes of Health consensus panel recommended that genetic testing for CF should be offered to adults with a positive family history of CF, to partners of people with the disease, to couples currently planning a pregnancy, and to couples seeking prenatal testing.

However, the panel did not recommend genetic testing of CF to the general public or to newborn infants. The American College of Obstetricians and Gynecologists has issued similar recommendations on genetic carrier testing for CF. ACOG also recommends that screening should be made available to couples in other racial and ethnic groups.

To date, over mutations in the CF gene have been identified. This mutation panel incorporates all CF-causing mutations with an allele frequency of greater than or equal to 0.

This standard panel of mutations is intended to provide the greatest pan-ethnic detectability that can practically be performed. Fragile X syndrome was originally thought to be transmitted in an X-linked recessive manner; however, the inheritance pattern of fragile X syndrome has been shown to be much more complex. Standard chromosomal analysis does not consistently demonstrate the cytogenetic abnormality in patients with fragile X syndrome, and molecular diagnostic techniques DNA testing have become the diagnostic procedure of choice for fragile X syndrome.

Lactase-phlorizin hydrolase, which hydrolyzes lactose, the major carbohydrate in milk, plays a critical role in the nutrition of the mammalian neonate Montgomery et al, Lactose intolerance in adult humans is common, usually due to low levels of small intestinal lactase.

Low lactase levels result from either intestinal injury or in the majority of the world's adult population alterations in the genetic expression of lactase. Although the mechanism of decreased lactase levels has been the subject of intensive investigation, no consensus has yet emerged. According to the manufacturer, this test provides a more definitive diagnosis and scientific explanation for patients with persistent symptoms.

There is insufficient evidence that the assessment of the genetic etiology of lactose intolerance would affect the management of patients such that clinical outcomes are improved. Current guidelines on the management of lactose intolerance do not indicate that genetic testing is indicated NHS, ; National Public Health Service for Wales, The irregular heartbeats are typically brought on by stress or vigorous activity. Voltage-gated sodium channels are transmembrane proteins that produce the ionic current responsible for the rising phase of the cardiac action potential and play an important role in the initiation, propagation, and maintenance of normal cardiac rhythm.

Inherited mutations in the sodium channel alpha-subunit gene SCN5A , the gene encoding the pore-forming subunit of the cardiac sodium channel, have been associated with distinct cardiac rhythm syndromes such as the congenital long QT3 syndrome LQT3 , Brugada syndrome, isolated conduction disease, sudden unexpected nocturnal death syndrome SUNDS , and sudden infant death syndrome SIDS.

Electrophysiological characterization of heterologously expressed mutant sodium channels have revealed gating defects that, in many cases, can explain the distinct phenotype associated with the rhythm disorder.

The long QT syndrome LQTS is a familial disease characterized by an abnormally prolonged QT interval and, usually, by stress-mediated life-threatening ventricular arrhythmias Priori et al, Characteristically, the first clinical manifestations of LQTS tend to appear during childhood or in teenagers.

Two variants of LQTS have been described: Five genes encoding subunits of cardiac ion channels have been associated to LQTS and genotype-phenotype correlation has been identified.

The principal diagnostic and phenotypic hallmark of LQTS is abnormal prolongation of ventricular repolarization, measured as lengthening of the QT interval on the lead ECG Maron et al, This is usually most easily identified in lead II or V1, V3, or V5, but all 12 leads should be examined and the longest QT interval used; care should also be taken to exclude the U wave from the QT measurement. LQT3 appears to be the most malignant variant and may be the one less effectively managed by beta blockers.

LQT1 and LQT2 have a higher frequency of syncopal events but their lethality is lower and the protection afforded by beta-blockers, particularly in LQT1, is much higher. The Jervell and Lange-Nielsen recessive variant is associated with very early clinical manifestations and a poorer prognosis than the Romano-Ward autosomal dominant form.

The presence of syndactyly seems to represent a different genetic variant of LQTS also associated with a poor prognosis. Guidelines on sudden cardiac death from the European College of Cardiology Priori et al, state that identification of specific genetic variants of LQTS are useful in risk stratification. The clinical variants presenting association of the cardiac phenotype with syndactyly or with deafness Jervell and Lange-Nielsen syndrome have a more severe prognosis.

Genetic defects on the cardiac sodium channel gene SCN5A are also associated with higher risk of sudden cardiac death. In addition, identification of specific genetic variants may help in suggesting behavioral changes likely to reduce risk. LQT1 patients are at very high risk during exercise, particularly swimming. LQT2 patients are quite sensitive to loud noises, especially when they are asleep or resting.

Genetic testing for LQTS may be indicated in persons with close relatives that have a defined mutation. Genetic testing for long QT syndrome has not been evaluated in patients who present with a borderline QT interval, suspicious symptoms e. In these patients, the incidence of false positive and false negative results and their implications for management remain unknown.

Genetic testing may also be necessary in person with long QT syndrome in sudden death close relatives. Brugada syndrome is an inherited condition comprising a specific EKG abnormality and an associated risk of ventricular fibrillation and sudden death in the setting of a structurally normal heart.

Brugada syndrome is characterized by ST-segment abnormalities on EKG and a high risk of ventricular arrhythmias and sudden death. Brugada syndrome presents primarily during adulthood but age at diagnosis ranges from 2 days to 85 years. Clinical presentations may also include sudden infant death syndrome and sudden unexpected nocturnal death syndrome, a typical presentation in individuals from Southeast Asia. Brugada et al reported that Brugada syndrome and LQTS are both due to mutations in genes encoding ion channels and that the genetic abnormalities causing Brugada syndrome have been linked to mutations in the ion channel gene SCN5A.

Brugada explained that Brugada syndrome is a clinical diagnosis based on syncopal or sudden death episodes in patients with a structurally normal heart and a characteristic ECG pattern. When ST elevation is the most prominent feature, the pattern is called "coved-type". When the most prominent feature is J point elevation, without ST elevation the pattern is called "saddle-type". Brugada pointed out that it is important to exclude other causes of ST segment elevation before making the diagnosis of Brugada syndrome.

Brugada syndrome is inherited in an autonomic dominant manner with variable penetrance. Most individuals diagnosed with Brugada syndrome have an affected parent. According to Brugada, antiarrhythmic drugs do not prevent sudden death in symptomatic or asymptomatic individuals with Brugada syndrome and that implantation of an automatic cardioverter-defibrillator is the only currently proven effective therapy.

Moreover, a positive genetic test adds little or nothing to the clinical management of such a person HRUK, The identification of an SCN5A mutation does, of course, allow screening of family members but the usefulness of genetic screening may be less than for other familial syndromes, however, given that the routine lead EKG with or without provocative drug testing appears to be a relatively effective method of screening for the condition. Hypertrophic cardiomyopathy HCM is a disease of the myocardium in which a portion of the myocardium is hypertrophied without any obvious cause; it is among the most common genetically transmitted cardiovascular diseases.

In HCM, the heart muscle is so strong that it does not relax enough to fill with the heart with blood and therefore has reduced pumping ability. The genetic abnormalities that cause HCM are heterogeneous.

Hypertrophic cardiomyopathy is most commonly due to a mutation in one of 9 genes that results in a mutated protein in the sarcomere. Some of the genes responsible for HCM have not yet been identified, and among those genes that have been identified, the spectrum of possible disease-causing mutations is incomplete.

As a result, a thorough evaluation of known genes requires extensive DNA sequencing, which is onerous for routine clinical testing. Less rigorous methods such as selective sequencing reduces the likelihood of identifying the responsible mutation. To be certain of detecting such genotypes, sequencing of candidate genes would need to continue in a given patient even after a single mutation was identified. In many persons with HCM mutations, the disease can be mild and the symptoms absent or minimal.

In addition, phenotypic expression of HCM can be influenced by factors other than the basic genetic defect, and the clinical consequences of the genetic defect can vary. There is sufficient heterogeneity in the clinical manifestations of a given gene mutation that, even when a patient's mutation is known, his or her clinical course can not be predicted with any degree of certainty.

In addition, the prognostic impact of a given mutation may relate to a particular family and not to the population at large. Many families have their own "private" mutations and thus knowledge of the gene abnormalities can not be linked to experience from other families.

In general, genetically affected but phenotypically normal family members should not be subjected to the same activity restriction as patients with HCM.

In recent years, genomic medicine has been moving from the bench to the bedside throughout all medical disciplines including cardiology. Now, genomic medicine has entered clinical practice as it pertains to the evaluation and management of patients with HCM.

The continuous research and discoveries of new HCM susceptibility genes, the growing amount of data from genotype-phenotype correlation studies, and the introduction of commercially available genetic tests for HCM make it essential that cardiologists understand the diagnostic, prognostic, and therapeutic implications of HCM genetic testing. Hudecova et al noted that the clinical symptoms of HCM are partly dependent on mutations in affected sarcomere genes.

Different mutations in the same gene can present as malign with a high-risk of SCD, while other mutations can be benign. The clinical symptomatology can also be influenced by other factors such as the presence of polymorphisms in other genes.

It is expected that genetic analyses will have an important consequence in the screening of the relatives of HCM patients and also in the prenatal diagnostics and genetic counseling.

Shephard and Semsarian stated that genetic heart disorders are an important cause of SCD in the young. While pharmacotherapies have made some impact on the prevention of SCD, the introduction of implantable cardioverter-defibrillator ICD therapy has been the single major advance in the prevention of SCD in the young. In addition, the awareness that most causes of SCD in the young are inherited, means family screening of relatives of young SCD victims allows identification of previously unrecognised at-risk individuals, thereby enabling prevention of SCD in relatives.

Genetic testing for HCM should be considered for the one most clearly affected person in a family to facilitate family screening and management.

This testing is intended to document whether a known pathologic mutation is present in the family, and optimize the predictive value of predisposition testing for at-risk relatives.

Recessive variants have been reported. Twelve-lead ECG and echocardiography can be used to identify affected relatives. Most affected individuals live a normal lifestyle.

According to the Heart Failure Society of America's Practice Guideline on the genetic evaluation of cardiomyopathy , the clinical utility for all genetic testing of cardiomyopathies remains to be defined. The guideline stated, "[b]ecause the genetic knowledge base of cardiomyopathy is still emerging, practitioners caring for patients and families with genetic cardiomyopathy are encouraged to consider research participation.

Enrollment in the study was completed in May and the study is currently in the follow-up period. Catecholaminergic polymorphic ventricular tachycardia CPVT is a highly lethal form of inherited arrhythmogenic disease characterized by adrenergically mediated polymorphic ventricular tachycardia Liu et al, The clinical presentation encompasses exercise- or emotion-induced syncopal events and a distinctive pattern of reproducible, stress-related, bi-directional ventricular tachycardia in the absence of both structural heart disease and a prolonged QT interval.

CPVT typically begins in childhood or adolescence. Clinical evaluation by exercise stress testing and Holter monitoring and genetic screening can facilitate early diagnosis. Katz et al noted that CPVT is a primary electrical myocardial disease characterized by exercise- and stress-related ventricular tachycardia manifested as syncope and sudden death.

Both RyR2 and calsequestrin are important participants in the cardiac cellular calcium homeostasis. These researchers reviewed the physiology of the cardiac calcium homeostasis, including the cardiac excitation contraction coupling and myocyte calcium cycling.

Although the clinical presentation of CPVT is similar in many respects to the LQTS, there are important differences that are relevant to genetic testing. CPVT appears to be a more malignant condition, as many people are asymptomatic before the index lethal event and the majority of cardiac events occur before 20 years of age.

Affected people are advised to avoid exercise-related triggers and start prophylactic beta-blockers with dose titration guided by treadmill testing. Clinically the condition is difficult to diagnose in asymptomatic family members as the ECG and echocardiogram are completely normal at rest.

Exercise stress testing has been advised in family members in order to identify exercise-induced ventricular arrhythmias, but the sensitivity of this clinical test is unknown.

The guidelines from the American College of Cardiology on management of patients with ventricular arrhythmias and the prevention of sudden cardiac death Zipes et al, included the following recommendations for patients with CPVT:. Hemochromatosis, a condition involving excess accumulation of iron, can lead to iron overload, which in turn can result in complications such as cirrhosis, diabetes, cardiomyopathy, and arthritis Burke ; Hanson et al, Clinical features may be non-specific and include lethargy and malaise, or reflect target organ damage and present with abnormal liver tests, cirrhosis, diabetes mellitus, arthropathy, cardiomyopathy, skin pigmentation and gonadal failure.

Early recognition and treatment phlebotomy is essential to prevent irreversible complications such as cirrhosis and hepatocellular carcinoma. CY is the more severe mutation, and homozygosity for the CY genotype accounts for the majority of clinically penetrant cases. HHC is a very common genetic defect in the Caucasian population. CY heterozygosity ranges from 9. Accurate data on the penetrance of the different HFE genotypes are not available. But current data suggest that clinical disease does not develop in a substantial proportion of people with this genotype.

Thus, DNA-based tests for hemochromatosis identify a genetic risk rather than the disease itself. Environmental factors such as diet and exposure to alcohol or other hepatotoxins may modify the clinical outcome in patients with hemochromatosis, and variations in other genes affecting iron metabolism may also be a factor. As a result, the clinical condition of iron overload is most reliably diagnosed on the basis of biochemical evidence of excess body iron Burke, Whether it is beneficial to screen asymptomatic people for a genetic risk of iron overload is a matter of debate.

To date, population screening for HHC is not recommended because of uncertainties about optimal screening strategies, optimal care for susceptible persons, laboratory standardization, and the potential for stigmatization or discrimination Hanson et al, ; Whitlock et al, A systematic evidence review prepared for the U. Preventive Services Task Force concluded: Some have suggested that, to avoid unnecessary exposure to steroid therapy, all children with a first episode of the nephrotic syndrome should be screened for NPHS2 mutations Niaudet, However, screening a child with a first episode of the nephrotic syndrome with a familial history of steroid-resistant nephrotic syndrome has been recommended because they are at increased risk for having a NPHS2 gene mutation.

CNF is inherited as an autosomal recessive trait, with both sexes being involved equally. There are no manifestations of the disease in heterozygous individuals. Most infants with the CNF are born prematurely 35 to 38 weeks , with a low birth weight for gestational age.

Prolonged survival is possible with aggressive supportive treatment, including dialysis and renal transplantation. The nephrotic syndrome in CNF is always resistant to corticosteroids and immunosuppressive drugs, since this is not an immunologic disease Niaudet, Furthermore these drugs may be harmful due to affected individuals' already high susceptibility to infection.

The CNF becomes manifest during early fetal life, beginning at the gestation age of 15 to 16 weeks. The initial symptom is fetal proteinuria, which leads to a more than fold increase in the amniotic fluid alpha-fetoprotein AFP concentration Niaudet, A parallel, but less important increase in the maternal plasma AFP level is observed.

These changes are not specific, but they may permit the antenatal diagnosis of CNF in high risk families in which termination of the pregnancy might be considered. However, false positive results do occur, often leading to abortion of healthy fetuses. Genetic linkage and haplotype analyses may diminish the risk of false positive results in informative families Niaudet, Authorities do not recommend screening for NPHS1 mutations for all children with the first episode of nephrotic syndrome, for the reasons noted above regarding NPHS2 mutation screening.

However, genetic testing may be indicated for infants with congenital nephrotic syndrome i. The primary purpose of this testing is for pregnancy planning. Detection of an NPHS1 mutation also has therapeutic implications, as such nephrotic syndrome is steroid resistant.

Dystonia consists of repetitive, patterned, twisting, and sustained movements that may be either slow or rapid. Dystonic states are classified as primary, secondary, or psychogenic depending upon the cause Jankovic, By definition, primary dystonia is associated with no other neurologic impairment, such as intellectual, pyramidal, cerebellar, or sensory deficits.

Cerebral palsy is the most common cause of secondary dystonia. Primary dystonia may be sporadic or inherited Jankovic, Cases with onset in childhood usually are inherited in an autosomal dominant pattern. The role of torsinA in the pathogenesis of primary dystonia is unknown. The purpose of such testing is to help rule out secondary or psychogenic causes of dystonia, and for family planning purposes. Approximately 10 percent of melanomas are familial. A subset of CDKN2A mutations carrier families also displays an increased risk of pancreatic cancer; however, at this time, detecting a CDKN2A mutation does not affect the clinical management of an affected patient or at-risk family members.

Regardless of the results of genetic testing, close dermatologic surveillance is recommended for individuals at risk for familial melanoma based due to family history, and the efficacy of screening for pancreatic cancer is uncertain. Thus, no mutations will be identifiable in the majority of families presenting to clinical geneticists. The report notes that the sensitivity and specificity of the commercially available test for CDKN2A mutations are not fully known.

Because of the difficulties with interpretation of the genetic tests, and because test results do not alter patient or family member management, ASCO recommends that CDKN2A testing be performed only in the context of a clinical trial.

The Scottish Intercollegiate Guidelines Network SIGN, protocols on management of cutaneous melanoma reached similar conclusions, stating that "[g]enetic testing in familial or sporadic melanoma is not appropriate in a routine clinical setting and should only be undertaken in the context of appropriate research studies.

The Melanoma Genetics Consortium recommends that genetic testing for melanoma susceptibility should not be offered outside of a research setting Kefford et al, First-degree relatives of individuals at high risk should be engaged in the same programmes of melanoma prevention and surveillance irrespective of the results of any genetic testing.

With an estimated prevalence of at least 1: This hereditary peripheral neuropathy is genetically and clinically heterogeneous. It is usually inherited in an autosomal dominant manner, and occasionally in an autosomal recessive manner.

Sporadic as well as X-linked cases have also been reported. In the X-linked recessive patterns, only males develop the disease, although females who inherit the defective gene can pass the disease onto their sons. In the X-linked dominant pattern, an affected mother can pass on the disorder to both sons and daughters, while an affected father can only pass it onto his daughters.

The clinical manifestations can vary greatly in severity and age of onset. The clinical features may be so mild that they may be undetectable by patients, their families and physicians. A point mutation in the PMP22 gene which encodes a peripheral myelin protein with an apparent molecular weight of 22, or a DNA duplication of a specific region 5 megabases including the PMP22 gene in the proximal short arm of chromosome 17 band 17p The value of this molecular test in family planning is questionable because of its relatively low detection rate and its inability to predict the severity of the disease.

Since CMT is not life-threatening, rarely severely disabling, and has no specific treatment, it is unclear how the results of this CMT Type I DNA test, which can not predict the severity of the disease, would affect family planning. Moreover, because of its low detection rate, the CMT Type I DNA test appears to be inferior to the conventional means of diagnosis through physical examination, family history, electromyography and nerve conduction velocity studies.

Thus, the sole value of genetic testing for CMTIA is to establish the diagnosis and to distinguish this from other causes of neuropathy. UMN signs include hyperreflexia, extensor plantar response, increased muscle tone, and weakness in a topographical representation. LMN signs include weakness, muscle wasting, hyporeflexia, muscle cramps, and fasciculations.

In the early stage of the disease, the clinical aspects of ALS can vary. Affected individuals typically present with asymmetric focal weakness of the extremities stumbling or poor handgrip or bulbar findings dysarthria, dysphagia. Other findings include muscle fasciculations, muscle cramps, and lability of affect but not necessarily mood.

Regardless of initial symptoms, atrophy and weakness eventually affect other muscles. Approximately 5, people in the U. Most people with ALS have a form of the condition that is described as sporadic or non-inherited. The cause of sporadic ALS is largely unknown but probably involves a combination of genetic and environmental factors. The mean age of onset of ALS in individuals with no known family history is 56 years and in familial ALS it is 46 years.

The diagnosis of ALS is based on clinical features, electrodiagnostic testing EMG , and exclusion of other health conditions with related symptoms. At present, genetic testing in ALS has no value in making the diagnosis.

The only genetic test currently available detects the SOD1 mutation. Migrainous vertigo is a term used to describe episodic vertigo in patients with a history of migraines or with other clinical features of migraine.

The underlying cause of migrainous vertigo is not very well understood. There are no confirmatory diagnostic tests or susceptible genes associated with migrainous vertigo. Other conditions, specifically Meniere's disease and structural and vascular brainstem disease, must be excluded Black, At this time, there are no susceptibility genes that have been unequivocally associated with prostate cancer predisposition. Genetic testing for prostate cancer is currently available only within the context of a research study.

The report noted that, while the monitoring of high-risk men may improve outcomes, it is also possible that these could be offset by the harms of identifying and treating additional indolent disease. Available evidence has shown that screening for a panel of gene variants associated with type 2 diabetes does not substantially improve prediction of risk for the disease than an assessment based on traditional risk factors.

Available evidence suggests that both genetic and environmental factors play a role in the development of type 2diabetes. Recent genetic studies have identified 18 gene variants that appear to increase the risk for type 2 diabetes. A study reported in the New England Journal of Medicine evaluated the potential utility of genetic screening in predicting future risk of type 2 diabetes Meigs et al, The investigators analyzed records from the Framingham Offspring Study, which follows a group of adult children of participants of the original Framingham Heart study, to evaluate risk factors for the development of cardiovascular disease, including diabetes.

Full genotype results for the 18 gene variants as well as clinical outcomes were available for 2, participants, of whom developed type 2 diabetes during 28 years of follow-up.

Each participant was assigned a genotype score, based on the number of risk-associated gene copies inherited. The investigators compared the predictive value of the genotype score to that of family history alone or of physiological risk factors. Overall, the genetic score was The investigators found that, while the genetic score did help predict who would develop diabetes, once other known risk factors were taken into consideration, it offered little additional predictive power.

The investigators concluded that: A similar study among Swedish and Finnish patients, published in the same issue of the New England Journal of Medicine, also found only a small improvement in risk estimates when genetic factors were added to traditional risk factors Lyssenko et al, The OncoVue breast cancer risk test Intergenetics, Inc. Cells that are collected from the inside of the cheek are analyzed using thousands of proprietary Intergenetic, Inc.

The genetic information and the data from the medical history are combined to assign a numeric value that tells a woman's lifetime risk of developing breast cancer. Her OncoVue risk test will tell her if she is standard, moderate or high risk for developing breast cancer during each stage of her life. OncoVue is based on an un-published case-controlled associative study that examined common genetic polymorphisms and medical history variables.

Currently, common polymorphisms mostly SNPs located in over 87 genes believed to alter breast cancer risk are examined. Most result in amino acid changes in the proteins encoded by the genes in which they occur. There are no published controlled studies on the OncoVue breast cancer risk test in the peer-reviewed medical literature. Gail evaluated the value of adding SNP genotypes to a breast cancer risk model.

Criteria included number of expected life-threatening events for the decision to take tamoxifen, expected decision losses in units of the loss from giving a mammogram to a woman without detectable breast cancer for the decision to have a mammogram, rates of risk re-classification, and number of lives saved by risk-based allocation of screening mammography.

For all calculations, the following assumptions were made: Improvements in expected numbers of life-threatening events were only 0. Improvements from BCRATplus7 were small for risk-based allocation of mammograms under costs constraints. The author concluded that additional studies are needed to validate a model with SNPs and justify its use. These investigators retrospectively collected tumors from patients with mCRC. All but 1 patient received a cetuximab-based regimen as second-line or greater therapy.

EGFR amplification was assessed by chromogenic in situ hybridization and fluorescent in situ hybridization, and the expression of PTEN was assessed by immunochemistry. PTEN null expression was found in Siena et al noted that the monoclonal antibodies panitumumab and cetuximab that target the EGFR have expanded the range of treatment options for mCRC.

The realization that detection of positive EGFR expression by immunostaining does not reliably predict clinical outcome of EGFR-targeted treatment has led to an intense search for alternative predictive biomarkers. Additional knowledge of the molecular basis for sensitivity or resistance to EGFR-targeted monoclonal antibodies will allow the development of new treatment algorithms to identify patients who are most likely to respond to treatment and could also provide rationale for combining therapies to overcome primary resistance.

Myoclonus-dystonia M-D , an autosomal dominant inherited movement disorder, has been associated with mutations in the epsilon-sarcoglycan gene SCGE on 7q Raymond et al noted that M-D due to SGCE mutations is characterized by early onset myoclonic jerks, often associated with dystonia. Penetrance is influenced by parental sex, but other sex effects have not been established. Moreover, the authors found no association between mutation type and phenotype. The lack of stringent clinical inclusion criteria and limitations of mutation screens by direct sequencing might explain this observation.

Eighty-six M-D index patients from the Dutch national referral center for M-D underwent neurological examination and were classified according to previously published criteria into definite, probable and possible M-D. Sequence analysis of the SGCE gene and screening for copy number variations were performed. In addition, screening was carried out for the 3 bp deletion in exon 5 of the DYT1 gene.

Based on clinical examination, 24 definite, 23 probable and 39 possible M-D patients were detected. The authors concluded that mutation carriers were mainly identified in the definite M-D group. Walker stated that according to an undercover investigation by the Government Accountability Office GAO , home genetic tests often provide incomplete or misleading information to consumers. For the GAO investigation, investigators purchased 10 tests each from 4 different direct-to-consumer genetic tests companies: In one sample, the donor used his or her real personal and medical information, and for the second sample, they developed faux identifying and medical information.

The results, according to the GAO, were far from precise. For example, a donor was told by a company that he had a "below average" risk of developing hypertension, but a second company rated his risk as "average", while a third company, using DNA from the same donor, said the sample revealed an "above average" risk for hypertension.

In some cases, the results conflicted with the donor's real medical condition. It is rare and is estimated as having a prevalence of 1 per million people and mainly affects Americans and Europeans.

Familial cold autoinflammatory syndrome shares symptoms, and should not be confused, with acquired cold urticaria, a more common condition mediated by different mechanisms that usually develop later in life and are rarely inherited. UpToDate reviews on "Cold urticaria" Maurer, and "Cryopyrin-associated periodic syndromes and related disorders" Nigrovic, do not mention the use of genetic testing.

Santome Collazo et al noted that congenital adrenal hyperplasia CAH is not an infrequent genetic disorder for which mutation-based analysis for CYP21A2 gene is a useful tool.

An UpToDate review on "Diagnosis of classic congenital adrenal hyperplasia due to hydroxylase deficiency" Merke, states that "[g]enetic testing also can be used to evaluate borderline cases.