Phonetic spelling of accenture Ac-cen-ture. These example sentences are selected automatically from various online news sources to reflect current usage of the word 'accentuate. Comments regarding accenture Post. Ensure that a microphone is installed and that microphone settings are configured correctly. Which is vs cognizant right way to say the number quinhentos in Portuguese? Need even more definitions? Its headquarters is located in Dublin, Ireland.
Genetic tests include: Carrier testing. This looks for gene changes that a person might pass along to their child. Prenatal screening and testing. This checks if a fetus is at risk for or has a condition like Down syndrome. Predictive testing. This is done to see if a person has a genetic change that increases their risk for developing a disease such as Huntington disease.
Forensic testing. This is used to identify family members, crime suspects, and victims of crime, war, or disasters. Diagnostic testing. This may be used to confirm a specific genetic illness when a person has symptoms of a disease. Pharmacogenomic testing.
This is done to see if a person has gene changes that might affect how their body reacts to a specific medicine. At-home genetic testing. This may offer information on ancestry, personal traits, lifestyle factors, and disease risks. How can genetic counseling help? Genetic counseling may involve: Discussing what problems an inherited disease may cause. Teaching you and your partner about how a specific disease is inherited or passed from you to your child.
Discussing whether and how to test for an inherited disease before you become pregnant or before your child is born. Discussing the likelihood that you and your partner will have a child with an inherited disease, based on test results.
Find out if your fetus is at risk for a genetic condition such as Down syndrome. Find out if you carry a gene that increases your risk for a disease later in life, such as breast cancer.
Find out if you have an inherited heart disease called hypertrophic cardiomyopathy. Check for genetic changes that may affect your treatment for an existing disease. Find out if you have inherited gene changes that affect your response to medicines.
Identify family members, crime suspects, or victims of war or disasters for legal purposes. How To Prepare You do not need to do anything special to prepare for most of these tests.
How It Is Done Genetic testing for inherited gene changes can be done using almost any cell or tissue from the body. Samples used in tests include: A blood sample from a vein. A health professional uses a needle to take a blood sample, usually from the arm. A cell sample from the cheek. A swab is used to scrape some tissue from the inside of the cheek.
A saliva sample. The person being tested spits into a tube. A sample of amniotic fluid. This is collected using amniocentesis or chorionic villus sampling. How It Feels Depending on the test, a sample of blood, saliva, amniotic fluid, or other tissue may be used. A blood sample from a vein may involve a quick sting or pinch from the needle.
A saliva sample can be collected by having you spit into a tube. It isn't painful. A cheek swab collects cells from the inside lining of your cheek. A sample of amniotic fluid is removed from your uterus amniocentesis. You may feel a sharp sting for a few seconds when the needle is put in. As the fluid is taken out, you may feel some pulling or pressure in your belly. After the test, the area may be tender or sore for a few days. Risks Risks from gathering a sample There is a very low risk of problems from taking samples of blood, saliva, or cells from a cheek swab.
Other risks The information from a genetic test for inherited gene changes can affect you and your family in many ways. For example, it may affect: Your emotions and relationships. It may be difficult to learn that you are likely to have a serious disease or have a child who has a disease.
This news may also affect your relationship with your partner or other family members. Your treatment choices. If you test positive for a disease-specific gene change, you may have preventive or treatment options to reduce the impact or severity of the disease.
Your pregnancy decisions. Genetic testing can help you make decisions about your pregnancy or plan for the future. If you find out that your fetus has a genetic disease, you may decide to end the pregnancy.
Or you may change your delivery plans. If your baby is likely to need special care after birth, you may need to deliver in a hospital that can provide this care. Your privacy. Many people worry that their genetic information might affect their job options or their ability to get insurance. Review Cigna's list of participating genetic counselors and refer the patient to an independent board-certified genetic counselor or clinical geneticist.
Please fax the completed form and required copies to Cigna at. At that time, the physician may withdraw the request, or ask for a coverage determination to be made. We review the precertification request. We understand that many tests, especially the BRCA test, may be urgent.
If the precertification request is approved, we will inform the ordering physician. If the precertification request is denied, standard appeal rights will be offered.
The genetics professional can facilitate the blood or specimen collection, genetic testing, and result interpretation. The genetics professional will refer the patient back to the ordering physician for ongoing management, providing them with a consultation report.
All rights reserved. All insurance policies and group benefit plans contain exclusions and limitations. For availability, costs and complete details of coverage, contact a licensed agent or Cigna sales representative. This website is not intended for residents of New Mexico. Selecting these links will take you away from Cigna. Cigna may not control the content or links of non-Cigna websites. Article July Genetic Testing and Counseling Resources Genetic counseling provides individuals with the opportunity to become fully informed about complex genetic tests.
Who It's For The Genetic Testing and Counseling Program [PDF] includes a precertification requirement and medical necessity review for certain Tier 1 and all Tier 2 genetic testing codes, including those outlined below, that require genetic counseling. Program Objective Under Cigna-administered plans, prior to undergoing certain genetic tests, customers are required to get counseling from an independent genetics professional on our list of participating genetic counselors in order for precertification to be approved.
The program is designed to protect your patients and our customers: Genetic counseling provides individuals with the opportunity to become fully informed about complex genetic tests and make an informed decision about testing. Meeting with an independent genetics professional who is not employed by any clinical or genetic laboratory prevents conflict of interest between the counselor and the facility that performs the tests.
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|Katie baxter||Current as of: November 22, How To Prepare You do not need to do anything special to prepare for most of these tests. A genetic test checks the DNA of your cells. Prenatal screening and testing. Article July Genetic Testing and Counseling Resources Genetic counseling provides individuals with the opportunity to become fully informed about complex genetic tests. This checks if a fetus is at risk for or has a condition like Down syndrome.|
|Cigna genetic testing coverage policy||Cigna may not control the content or links of non-Cigna websites. You do not need to do anything special to prepare for most of these tests. The testting can look for read article single change in a gene or check the entire gene or chromosome for changes. Shop for Medicare plans. Samples used in tests include: A blood sample from a vein.|
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|Cigna genetic testing coverage policy||It may be difficult to learn that you are testig to have a serious disease or have a child who has a disease. A cell sample from the cheek. For voverage, the results may show if you have a genetic condition, how likely it is that you will authorization amerigroup a genetic condition in the future, or if you are a carrier for a condition. So before you have the test, you may want to talk to a genetic counselor or a doctor who specializes in genetics geneticist. It can find read article in your genes or chromosomes that may cause a genetic illness. Genetic testing and follow-up The genetics professional can facilitate the blood or specimen collection, genetic testing, and result interpretation.|
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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.
ACOG guidelines state that "[c]ystic fibrosis carrier screening should be offered to all women who are considering pregnancy or are currently pregnant.
Farrell and colleagues noted that CF, caused by mutations in the CF transmembrane conductance regulator CFTR gene, continues to present diagnostic challenges. Newborn screening and an evolving understanding of CF genetics have prompted a reconsideration of the diagnosis criteria. To improve diagnosis and achieve standardized definitions worldwide, the CF Foundation convened a committee of 32 experts in CF diagnosis from 9 countries to develop clear and actionable consensus guidelines on the diagnosis of CF and to clarify diagnostic criteria and terminology for other disorders associated with CFTR mutations.
After reviewing relevant literature, the committee convened to review evidence and cases. Following the conference, consensus statements were developed by an executive subcommittee. The entire consensus committee voted and approved 27 of 28 statements, 7 of which needed revisions and a 2nd round of voting. It was recommended that diagnoses associated with CFTR mutations in all individuals, from newborn to adult, be established by evaluation of CFTR function with a sweat chloride test.
The latest mutation classifications annotated in the Clinical and Functional Translation of CFTR project should be used to aid in diagnosis. Unless 2 gene mutations are identified during newborn screening NBS , the babies are discharged from follow-up. These investigators wished to check that none had subsequently developed symptoms suggestive of CF. They retrospectively reviewed patient notes and contacted general practitioners of all babies with a negative sweat test, conducted in 1 of the 4 pediatric specialist CF centers in London, over the first 6 years of screening in South East England.
These results were reassuring in that within the limitations of those lost to follow-up, CF symptoms have not emerged in the discharged children. Clinicians need to be aware that a child can have CF despite a normal sweat test following NBS, and if symptoms suggest the diagnosis, further testing, including extended genome sequencing, is needed. The mutations included in the panel vary among states, depending on the ethnic diversity of their populations. Most states screen for at least 23 of the most common mutations, using a panel developed for population screening by the American College of Medical Genetics ACMG.
However, the panel may be less sensitive for other ethnic groups that have genetic diversity and a wider range of CF-causing mutations; in one study, it detected only Several state screening programs have therefore expanded or modified the ACMG panel to suit multiethnic populations. 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, Long QT Syndrome LQTS is a disorder of the heart's electrical system that predisposes individuals to irregular heartbeats, fainting spells and sudden death. 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.
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 may also be indicated in individuals with a prolonged QT interval on resting electrocardiogram a corrected QT interval QTc of msec or more in males and msec or more in females without an identifiable external cause for QTc prolongation.
Common external causes of QTc prolongation are listed below. 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. Population studies have demonstrated that some patients are compound heterozygotes inheriting 2 different mutations within a single HCM gene , double heterozygotes inheriting mutations in 2 HCM genes , or homozygotes inheriting the same mutation from both parents.
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. Bos and colleagues stated that over the past 20 years, the pathogenic basis for HCM, the most common heritable cardiovascular disease, has been studied extensively.
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. Currently, the objective of intensive clinical research is to access the contribution of molecular genetic methods in HCM diagnostics as well as in risk stratification of SCD.
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.
The role of genetic testing, both in living affected individuals as well as in the setting of a "molecular autopsy", is emerging as a key factor in early diagnosis of an underlying cardiovascular genetic disorder.
The Heart Failure Society of America's practice guideline on "Genetic evaluation of cardiomyopathy" Hershberger et al, stated that genetic testing is primarily indicated for risk assessment in at-risk relatives who have little or no clinical evidence of cardiovascular disease. Genetic testing for HCM should be considered for the one most clearly affected person in a family to facilitate family screening and management. In order to inform and direct genetic testing for at-risk individuals, genetic testing should be initially performed in at least 1 close relative with definite HCM index case if possible.
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. The TEC assessment also concluded that genetic testing for inherited HCM does not meet the TEC criteria for predisposition testing in individuals who are at-risk for development of HCM, defined as having a close relative with established HCM, when there is no known pathogenic gene mutation present in an affected relative.
This includes: i patients with a family history of HCM, with unknown genetic status of affected relatives; and ii patients with a family history of HCM, when a pathogenic mutation has not been identified in affected relatives.
Familial occurrence with an autosomal dominant pattern of inheritance and variable penetrance has been demonstrated. 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, Hereditary hemochromatosis HHC is characterized by inappropriately increased iron absorption from the duodenum and upper intestine, with consequent deposition in various parenchymal organs, notably the liver, pancreas, joints, heart, pituitary gland and skin, with resultant end-organ damage Limdi and Crampton, 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: "Research addressing genetic screening for hereditary hemochromatosis remains insufficient to confidently project the impact of, or estimate the benefit from, widespread or high-risk genetic screening for hereditary hemochromatosis" Whitlock et al, Familial forms of nephrotic syndrome are steroid resistant Niaudet, Mutations in the gene for podocin, called NPHS2, also known as familial focal glomerulosclerosis, are observed in patients with both familial and sporadic steroid-resistant nephrotic syndrome SRNS.
Identifying children with nephrotic syndrome due to NPHS2 mutations can avoid unnecessary exposure to immunosuppressive therapy, because immunosuppressive therapy has not been shown to be effective in treating these children Niaudet, Thus, authorities have recommended testing for such mutations in those with a familial history of steroid resistant nephrotic syndrome and children with steroid-resistant disease. 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.
Severe nephrotic syndrome with marked ascites is always present by 3 months. End-stage renal failure usually occurs between 3 and 8 years of 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.
In some cases, the apparent familial inheritance pattern may be due to clustering of sporadic cases in families with common heavy sun exposure and susceptible skin type. 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. Persons at increased risk of melanoma are managed with close clinical surveillance and education in risk-reduction behavior e. 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.
Charcot-Marie-Tooth CMT hereditary neuropathy refers to a group of disorders characterized by a chronic motor and sensory polyneuropathy, also known as hereditary motor and sensory neuropathy HMSN. It is the most common inherited disorder that involves the peripheral nerves, affecting an estimated , people in the United States.
It occurs in populations worldwide with a prevalence of about 1 in 3, individuals. 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. Charcot-Marie-Tooth disease is usually diagnosed by an extensive physical examination. Symptoms include foot drop or clubfoot, paresthesia in legs, sloping gait, later weakness and atrophy of hands, then arms, absence or reduction of deep tendon reflexes, and occasionally mild sensory loss.
The clinical diagnosis is then confirmed by electromyogram and nerve conduction velocity tests, and sometimes by biopsy of muscle and of sural cutaneous nerve. Genetic testing can aid in confirming the diagnosis after EMG.
Since CMT is a hereditary disease, family history can also help to confirm the diagnosis and it may be appropriate to skip EMG and go directly to genetic testing in a patient with a strong family history of confirmed CMT, especially when a relative has a known mutation. Prenatal testing for pregnancies at increased risk is possible for some types of CMT if the disease-causing mutation in the family is already known. CMT is genetically and clinically heterogeneous.
It is usually inherited in an autosomal dominant manner, and occasionally in an autosomal recessive manner. 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 majority of cases fall within type 1 autosomal dominant inheritance, demyelinating physiology and type 2 autosomal dominant inheritance, axonal physiology , with an estimated prevalence of 40 per , Charcot Marie Tooth Type I disease is a demyelinating neuropathy with hypertrophic changes in peripheral nerves, and has its onset usually during late childhood.
On the other hand, CMT Type II is an axonal non-demyelinating neuronal disorder without hypertrophic changes, and has its onset generally during adolescence. Both CMT Types I and II are characterized by a slow degeneration of peripheral nerves and roots, resulting in distal muscle atrophy commencing in the lower extremities, and affecting the upper extremities several years later.
This gene 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 Charcot Marie Tooth disease is not a fatal disorder. It does not shorten the normal life expectancy of patients, and it does not affect them mentally. As stated earlier, there is a wide range of variation in the clinical manifestations of CMT — the degree of severity can vary considerably from patient to patient, even among affected family members within the same generation.
The condition can range from having no problems to having major difficulties in ambulation in early adult life, however, the latter is unusual. Most patients are able to ambulate and have gainful employment until old age. Currently, there is no specific disease-modifying treatment for this disease. Management of the majority of patients with CMT disease consists of supportive care with emphasis on proper bracing, foot care, physical therapy and occupational counseling.
For example, the legs and shoes can be fitted with light braces and springs, respectively, to overcome foot drop. If foot drop is severe and the disease has become stationary, the ankle can be stabilized by arthrodeses.
In summary, the conventional means of diagnosis of CMT is through physical examination, family history, electromyography EMG and nerve conduction velocity studies. Thus, the value of genetic testing for CMT is to confirm 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, 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.
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.
Improvements in expected numbers of life-threatening events were only 0. For deciding whether to recommend screening mammograms to women aged 50 to 54 years, the reduction in expected losses was 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.
Phosphatase and tensin homolog PTEN hamartoma tumor syndrome is an autosomal dominant group of disorders with significant clinical overlap, most notably predisposition to hamartomatous polyposis of the gastro-intestinal tract. 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 They stated that more studies in clinical trial cohorts are needed to confirm the clinical utility of these markers. 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. Thirteen of the 86 M-D index patients carried a SGCE mutation: 7 nonsense mutations, 2 splice site mutations, 3 missense mutations 2 within 1 patient and 1 multi-exonic deletion.
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: 23andMe, deCode Genetics, Navigenics, and Pathway Genomics. Five saliva donors each sent 2 DNA samples to each company. 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. None of the genetic tests currently offered to consumers has undergone FDA pre-market review.
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. Genetic testing detects approximately 95 percent of mutant alleles". Furthermore, the Endocrine Society's clinical practice guideline on congenital adrenal hyperplasia Speiser et al, suggested genotyping only when results of the adrenocortical profile following cosyntropin stimulation test are equivocal or for purposes of genetic counseling.
The Task Force recommends that genetic counseling be given to parents at birth of a CAH child, and to adolescents at the transition to adult care. Wappler stated that malignant hyperthermia MH -susceptible patients have an increased risk during anesthesia.
The aim of this review was to present current knowledge about pathophysiology and triggers of MH as well as concepts for safe anesthesiological management of these patients. Trigger substances and mechanisms have been well-defined to date. Anesthesia can be safely performed with i. Attention must be directed to the preparation of the anesthetic machine because modern work-stations need longer cleansing times than their predecessors. Alternatively, activated charcoal might be beneficial for elimination of volatile anesthetics.
Day case surgery can be performed in MH-susceptible patients, if all safety aspects are regarded. Whether there is an association between MH susceptibility and other disorders is still a matter of debate. The authors concluded that the incidence of MH is low, but the prevalence can be estimated as up to 1: 3, Because MH is potentially lethal, it is relevant to establish management concepts for peri-operative care in susceptible patients. This includes pre-operative genetic and in-vitro muscle contracture test IVCT , preparation of the anesthetic work-station, use of non-triggering anesthetics, adequate monitoring, availability of sufficient quantities of dantrolene and appropriate post-operative care.
Taking these items into account, anesthesia can be safely performed in susceptible patients. Licis et al stated that sleep-walking is a common and highly heritable sleep disorder.
However, inheritance patterns of sleep-walking are poorly understood and there have been no prior reports of genes or chromosomal localization of genes responsible for this disorder.
These researchers described the inheritance pattern of sleep-walking in a 4-generation family and identified the chromosomal location of a gene responsible for sleep-walking in this family. A total of 9 affected and 13 unaffected family members of a single large family were interviewed and DNA samples collected. Parametric linkage analysis was performed.
Sleep-walking was inherited as an autosomal dominant disorder with reduced penetrance in this family. Genome-wide multi-point parametric linkage analysis for sleep-walking revealed a maximum logarithm of the odds score of 3. The authors described the first genetic locus for sleep-walking at chromosome 20qq In an editorial that accompanied the afore-metnioned study, Dogu and Pressman noted that "[a]ccording to currently accepted evidence-based theories, the occurrence of sleepwalking requires genetic predisposition, priming factors such as severe sleep deprivation or stress, and, in addition, a proximal trigger factor such as noise or touch.
Hereditary factors likely play an important role, with recessive and multifactorial inheritance patterns having been reported. Another study attempted to find a causal relationship between sleepwalking and sleep-disordered breathing in cosegregated families of both disorders. However, this study was limited by the absence of molecular data The current diagnosis of sleepwalking is based almost entirely on clinical history.
There are no objective, independent means of confirming the diagnosis. Additionally, treatment of sleepwalking is symptomatic, aimed at suppressing arousal or reducing deep sleep.
Identification of causative genes may eventually permit development of an independent test and treatments aimed at the underlying causes of this disorder". RetnaGene AMD Sequenom Center for Molecular Medicine is a laboratory developed genetic test to assess the risk of developing choroidal neovascularization CNV , the wet form of age-related macular degeneration AMD , a common eye disorder of the elderly that can lead to blindness.
The test identifies at-risk Caucasians, age 60 and older. A report of the American Academy of Ophthalmology Stone, et al. The report recommends that, in the meantime, genotyping of such patients should be confined to research studies.