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Real Doctors (Life Makers)  |  Basic Science  |  Genetics  |  Genetic Testing - An introduction « previous next »
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Genetic Testing - An introduction
« on: /November/ 07, 2005, 04:11:30 PM »

Genetic Testing? ?

Patients diagnosed with chronic venous disease (CVD) who carry the genetic mutation associated with hemochromatosis (HFE) have an increased risk of developing leg ulcers, according to the results of a study found in the August 2005 issue of Journal of Vascular Surgery. According to background information provided in the article, this investigation was undertaken to determine the association between HFE, a genetic defect in iron metabolism, and CVD, a condition that leads to local iron overload in the affected legs.

Italian researchers conducted a case-controlled study of 238 patients who were diagnosed with severe CVD (clinical efficacy assessment project [CEAP] clinical classes C4 to C6). The patients in the study were drawn from a group of 980 consecutive patients with the same diagnosis and were selected because they did not have comorbidities associated with wound etiology. This cohort was designated as group A and was then subdivided into groups B and C. Persons in group B (n = 137) consisted of patients with ulcers (CEAP classes C5 and C6; 98 had primary and 39 had postthrombotic ulcers). Patients in group C (n = 101) had no skin lesions (CEAP class C4).

The researchers also enrolled persons into group D, which consisted of 280 healthy subjects. These subjects were matched for age, sex, and geographic origin to patients in group A and served as the control group. Members of groups A and D were genotyped for HFE mutations (H63D and C282Y).

It was determined that the presence of a C282Y mutation significantly increased the risk of ulcer in patients with primary CVD by almost 7-fold (odds ratio, 6.69; 95% confidence interval, 1.45-30.8; P = .01). It was also found that the application of the HFE test in patients with primary CVD demonstrated increased specificity and positive predictive values (98% and 86%, respectively), with negligible sensitivity and negative predictive values.

In conclusion, the researchers found that when patients have primary CVD and are positive for the C282Y mutation, they are at an increased risk of developing venous leg ulceration. They also propose that HFE genetic testing could be performed in patients who are placed in CEAP class C2 (characterized by varicose veins), and that the presence of the C282Y mutation could strengthen the decision for surgical correction of superficial venous insufficiency.

In other news, it was found that predictive genetic testing for hereditary nonpolyposis colorectal carcinoma (HNPCC) was associated with appropriate screening behaviors in a majority of patients, especially among carriers of the mutation. Findings of this study were reported in the July 15, 2005, issue of Cancer.

Australian researchers analyzed data obtained from questionnaires completed by study participants attending Australian familial cancer clinics who had undergone genetic testing for HNPCC. Information was gathered on self-reported cancer screening behaviors and prophylactic surgery by comparing questionnaires completed at baseline and at 12 months after receipt of genetic test results. The screening behaviors and prophylactic surgical procedures delineated in the questionnaires included colonoscopy and colectomy for persons of both sexes, and transvaginal ultrasonography, endometrial sampling, hysterectomy, and bilateral oophorectomy for women. The researchers also gathered data on gender, age, perceived risk of cancer, and cancer-specific distress, which were considered predictors of colonoscopic screening.

Baseline questionnaires were received from 114 participants (82 noncarriers and 32 carriers of an HNPCC mutation), and 12-month follow-up questionnaires were received from 98 participants. Of those persons who returned the 12-month questionnaire and were 25 years of age or older, 73% reported having had a colonoscopy before genetic testing was performed. In the group that returned follow-up questionnaires, 15 of 25 of the mutation carriers (71%) and 8 of 65 noncarriers (12%) reported having a colonoscopy during the 12 months after receipt of test results. The reduction in colonoscopies performed among noncarriers was statistically significant (P < .001).

At baseline, high perceived risk was associated with colonoscopy, whereas at follow-up, mutation status was the only variable significantly associated with colonoscopy. Of women who were mutation carriers, 53% reported having endometrial sampling and 47% reported having transvaginal ultrasonography during the follow-up period. Few participants selected the option of prophylactic surgery for colorectal, ovarian, or endometrial cancers.

The researchers concluded that the majority of persons who have predictive genetic testing for HNPCC subsequently report engaging in appropriate screening behaviors. In addition, they speculate that additional counseling might be beneficial to noncarriers who undergo screening after genetic testing is completed.

The following Clinical Topic Tour provides an overview of genetic testing and was adapted from materials published by the U.S. Department of Health and Human Services, the National Human Genome Research Institute, and the Centers for Disease Control and Prevention.


A genetic test is the analysis of human DNA, RNA, chromosomes, proteins, and certain metabolites to detect heritable disease-related genotypes, mutations, phenotypes, or karyotypes for clinical purposes. Such purposes include predicting risk of disease, identifying carriers, and establishing prenatal and clinical diagnosis or prognosis.

In genetic testing, DNA in cells taken from a person's blood, body fluids, or tissues is examined for an abnormality that flags a disease or disorder. The abnormality can be relatively large, such as a piece of a chromosome, or even an entire chromosome, missing or added. The change can also be very small, such as an extra, missing, or altered chemical base within the DNA strand. Genes can also be amplified, over-expressed, inactivated, or lost altogether. Sometimes pieces of chromosomes can become switched, transposed, or discovered in an incorrect location.

A genetic disorder is a disease caused in whole or in part by a genetic variation or mutation. Genetic disorders can be passed to family members who inherit the genetic abnormality. Most disorders involving genetic factors, such as heart disease and most cancers, arise from a complex interplay of multiple genetic changes and environmental influences.

Categories of Genetic Disorders

Geneticists group genetic disorders into 3 categories:
Single gene disorders are caused by a mistake in a single gene. The mutation may be present on one or both chromosomes of a pair. Sickle cell disease, cystic fibrosis, and Tay-Sachs disease are examples of single gene disorders.
Chromosome disorders are caused by an excess or deficiency of genes. For example, Down syndrome is caused by an extra copy of a chromosome, but no individual gene on the chromosome is abnormal.
Multifactorial inheritance disorders are caused by a combination of small variations in genes, often in concert with environmental factors. Heart disease, most cancers, and Alzheimer's disease are examples of these disorders.

Information Provided Through Genetic Testing

Genetic testing can provide information that can predict risk of disease, identify disease carriers, identify persons at risk for passing on genetic disorders to offspring, and identify infants born with genetic abnormalities.

Predictive testing identifies persons who are at risk of developing a disease before any symptoms appear. Predictive tests include those that screen for some inherited predispositions to certain forms of cancer, such as colon and breast cancer. Being predisposed does not mean that a person will acquire the disease, but it does mean that a person has a certain risk of developing the disease.

Carrier testing can allow persons to know whether they are carriers of an inherited disorder that they may pass to their children. A person who has only one abnormal copy of a gene for a recessive condition is known as a carrier. Carriers do not develop disease, but they can pass the defective gene to their children. Cystic fibrosis and Tay-Sachs disease are examples of disorders for which parents can be carriers.

Prenatal testing is available to persons at risk for having children with a chromosomal abnormality or an inherited genetic condition. Two procedures are commonly used in prenatal testing. Amniocentesis involves analyzing a sample of amniotic fluid taken from the uterus. Chorionic villus sampling involves taking a tiny tissue sample from outside the sac where the fetus develops. Prenatal testing is often used to look for disorders such as Down syndrome, spina bifida, cystic fibrosis, and Tay-Sachs disease.

Newborn screening, the most widespread type of genetic testing, tests infant blood samples for abnormal or missing gene products. For example, infants are commonly screened for phenylketonuria, an enzyme deficiency that can lead to severe mental retardation if untreated.

Types of Genetic Tests

About 900 genetic tests are now offered by diagnostic laboratories.

Some genetic tests look at whether the number of chromosomes is correct and whether any evidence of a chromosome rearrangement or other abnormality exists. This kind of test, for instance, would detect Down syndrome. Most genetic problems are more subtle than this, so tests able to detect them must look at the actual DNA sequence of a particular gene. To detect a carrier of Huntington's disease, for instance, the test must discover a particular expanded repeated sequence of a gene on chromosome 4.

Many genes can be mutated in multiple different ways. In such a case, an effective test may need to detect many possible mutations. For example, a standard test for cystic fibrosis looks for 32 different mutations in the CFTR gene but will still miss rare ones.

Other types of genetic tests examine RNA instead of DNA, or they examine the actual protein product of the gene. Carrier detection for Tay-Sachs disease, for instance, measures the enzyme activity of the protein product.

Pharmacogenomics involves tests that predict response to therapy. Some such tests are already available, such as a test for estrogen receptors in breast tumor samples to determine whether the drug Herceptin will be an effective treatment. A much larger array of tests that predict drug responsiveness to cancer, heart disease, asthma, and other disorders is under development.

Making the Decision to Undergo Genetic Testing

The decision to undergo testing is a very personal one. For many persons, a pivotal consideration is whether preventive measures can be taken if a test result is positive. For example, those who test positive for inherited forms of breast or colon cancer can benefit from preventive measures, screening for early detection, and early treatment.

In contrast, no preventive measures or cures exist for Huntington's disease. But a positive result in a test for Huntington's disease might help a person make lifestyle decisions, such as career choice, family planning, or insurance coverage.

Because the decision about whether to be tested for a genetic disease is complex, most persons seek guidance from a genetic counselor trained to help persons and families weigh the scientific, emotional, and ethical considerations that affect this decision.

Genetic Testing in the United States

In recent years, the National Institutes of Health created a task force whose purpose was to review genetic testing in the United States and make recommendations to ensure the development of safe and effective genetic tests, with consideration of social, legal, and ethical implications. The need for recommendations arose after a review of current practices revealed the following:
some genetic tests are introduced before they have been demonstrated to be safe, effective, and useful;
no assurance exists that every laboratory performing genetic tests for clinical purposes meets certain standards;
informational materials distributed by academic and commercial testing laboratories often do not provide sufficient information for full understanding by providers and patients;
providers, who are expected to offer genetic testing with greater frequency, often have little formal training or experience in the field of genetics.
This task force strongly advocated the use of written informed consent from persons receiving genetic testing in the clinical practice arena. The task force also recommended that, before the initiation of predictive testing, health care providers should first describe the features of the genetic test, including potential consequences, to potential test recipients.

With regard to newborn screening where informed consent is waived, the analytical and clinical validity and clinical utility of the test must be established, and the parents must be provided with sufficient information to understand the reasons for screening.

To protect patient confidentiality, the task force recommended that genetic test results should be released only to those persons for whom the test recipient has given consent for information release, and that the means of transmitting information should be chosen to minimize the likelihood that results will become available to unauthorized persons or organizations. It is recommended that, under no circumstances, should results with identifiers be provided to any outside parties, including employers, insurers, or government agencies, without the test recipient's written consent, and that health care providers have an obligation to the person being tested not to inform other family members without the permission of the person tested, except in extreme circumstances. In addition, the task force recommended that no person should be subjected to unfair discrimination by a third party on the basis of having had a genetic test or having received an abnormal genetic test result.

Regarding the use of new genetic tests, the task force recommended the following:
The genotypes to be detected by a genetic test must be shown by scientifically valid methods to be associated with the occurrence of a disease. The observations must be independently replicated and subject to peer review.
Analytical sensitivity and specificity of a genetic test must be determined before it is made available in clinical practice.
Data to establish the clinical validity of genetic tests (clinical sensitivity, specificity, and predictive value) must be collected under investigative protocols. In clinical validation, the study sample must be drawn from a group of subjects representative of the population for whom the test is intended. Formal validation for each intended use of a genetic test is needed.
Before a genetic test can be generally accepted in clinical practice, data must be collected to demonstrate the benefits and risks that accrue from both positive and negative results.
Regarding the role of health care professionals in genetic counseling, the task force recognized that specialists in genetic counseling may not always be available, and that this task could be performed by primary care providers and other non?genetic specialists. However, the task force stipulated that this would be feasible only when these practitioners have adequate knowledge of test validity, disease, and mutation frequencies in the ethnic groups to whom they provide care. These providers should be aware of family history, test specificity, and other considerations in interpreting test results and must be capable of communicating risk information and its implications to those who are tested or their parents or guardians. The task force also encouraged the development of genetics curricula in medical school and residency training to enable all physicians to recognize inherited risk factors in patients and families and to appreciate issues in genetic testing and the use of genetic services.


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