Valley Health Magazine

Basically, without variation, the world would be a very bland and colorless place. However, some of this DNA code variation is harmful. Mutations change the way the gene and its product (usually a protein) function and are the cause of hereditary disease. Some mutations have been inherited from a parent, while others have occurred de novo (in the egg or sperm from which an individual was conceived).

Mutations: Genetic "Spelling Errors"

Mutations we are born with are called constitutional, and can be transmitted to our children. Other mutations happen sometime after conception, in the fetus, the infant or the adult, and are thus present only in a limited group of cells or a particular organ. These are called somatic (acquired) mutations. Somatic mutations may also affect our health. In fact, most cancers start with mutations in a single cell, giving it some growth or survival advantage. However, such somatic mutations are not inherited and are only rarely passed down. This said, most somatic mutations will not affect our health directly because those genetic spelling errors will either be repaired by our DNA repair genes, be lethal to the cell in which they occur, or be recognized by the immune system which will destroy the abnormal cell. The deciphering of the genetic code has allowed us to be able to "read" the whole Book of Life, using DNA (molecular) technology. We do not yet understand, however, the relationship of health and disease to many of the variations that lie within. And most of the key information about how the 25,000 chapters in our book of life interact with each other has yet to be deciphered.

Genetic testing: When and How
Genetic testing involves choosing one or more of these chapters—based on medical and/or family history—and "reading" it, page by page, letter by letter, one gene at a time, to determine whether a harmful mutation is present. The most informative type of test is the one where a mutation has been identified by first studying a family member who is affected with the condition. At-risk family members (parents, infants, even unborn children) can then have predictive testing to determine whether or not they carry the abnormal gene. Knowledge is indeed power: knowing that someone has inherited an abnormal gene(s) can allow for enlightened medical management, and in some cases treatment or prevention of the disease. This approach is particularly useful in hereditary predisposition to cancer (see A Working Model)

As more is learned about human/medical genetics, healthcare providers, media, and consumers of genetic services are increasingly seeking information about the availability of genetic testing for specific disorders, and about how genetic testing may be used. Specific gene or chromosome tests are not yet available for all conditions, but the field of genetics is growing rapidly and testing not available this year may be offered next year. Individuals and families who are concerned about a genetic condition will often benefit from a genetic consultation whether or not testing is available for that condition. Many people are seeking information and coping strategies as much as test results.
Because the results of genetic testing may have a huge impact on the individual or family involved, consultation and counseling is a necessary predecessor of any actual test.

#1: Genetic Consultation
In some families and for some conditions (see below), the specific genetic diagnosis or indication for testing is clear, and may have been known to the family for several generations. In such cases, a referral may be made directly to a genetic counselor. Other individuals, however, will be the first in their family with a particular problem or group of problems, and a diagnosis must first be established, or confirmed. In the latter case, your health care provider should refer you for a genetics consultation. The consultation seeks to establish a specific diagnosis, which is necessary before genetic counseling can be offered. Steps in identifying an individual or a family's diagnosis include a review of medical and family histories, a physical examination, laboratory testing and/or other procedures such as X-rays. Genetic consultation is usually provided by a physician trained and Board-Certified in Medical Genetics; the clinical geneticist is usually aided in this process by a genetic counselor.

Who might request a genetics consultation? Anyone who has questions about birth defects or medical conditions in their family such as:

Individuals who are affected by, have a child with, or a family history of: physical birth defects; abnormal growth or mental retardation; a chromosomal abnormality (such as Down or Turner syndrome); an inherited condition such as hemophilia or muscular dystrophy.

Pregnant women who: will be 35 years or older at delivery; have had a positive serum screening result (blood test during pregnancy that reveals the likelihood of certain conditions) or an abnormal ultrasound; are concerned that their medical condition, family history or lifestyle may increase risk to their pregnancy.

Couples who: experience infertility or pregnancy loss; are carriers of autosomal recessive disorders such as sickle cell anemia, cystic fibrosis,Tay Sachs disease, or thalassemia.
Individuals with: a late-onset condition such as a clotting disorder (thrombophilia), a neurological disease, or cancer at a young age (e.g. breast or colon cancer before age 50).

#2: Genetic Counseling
Genetic testing should be preceded and often followed by genetic counseling. What then, is genetic counseling? After a genetic consultation, when a specific diagnosis or risk for a certain disease is established or suspected, a patient(s) will speak with a genetic counselor who can help prepare them for the outcome of their gene analysis. Genetic counseling can be defined as the process of helping people understand and adapt to the medical, psychological and familial implications of genetic contributions to disease. Genetic counseling is a process which includes:

Interpretation of family and medical histories to assess the chance of disease occurrence or recurrence. Education about inheritance, testing, management, prevention, resources and research. Counseling to promote informed choices and adaptation to the risk or condition.

For the more common genetic disorders, a primary care physician may explain the reasons for and implications of a gene test, and will order it directly. However, most genetic disorders are individually rare, so that diagnosis, testing and clinical management require the help of a specialist, such as a clinical geneticist and/or a genetic counselor.

#3: Genetic Testing/Gene Analysis
The type of genetic testing to be ordered depends on the goal/reasons for testing. These reasons include:

Diagnostic testing is used to confirm or rule out a known or suspected genetic disorder in a symptomatic individual. Such may alter medical treatment and may have reproductive or psychosocial implications for other family members as well. Diagnostic testing is appropriate in symptomatic individuals of any age, and is sometimes ordered by a clinical specialist other than a geneticist (e.g. neurologist, endocrinologist). It is important, however, to realize that DNA testing is not always the best way to establish a clinical diagnosis.

Predictive Testing is offered to asymptomatic individuals with a family history of a genetic disorder, and serves to identify those at high risk of genetic disease. This type of testing is medically indicated if early diagnosis will allow interventions that reduce sickness or death. Even in the absence of medical indications, predictive testing can influence life-planning decisions. As predictive testing has psychological ramifications, careful assessment, counseling, and follow-up are important. Many laboratories will not perform predictive testing without proof of informed consent and prior genetic counseling. Predictive testing is strongly discouraged in asymptomatic children at risk for adult-onset disorders unless treatment is available.

Carrier Testing is performed to identify individuals who have a gene mutation for a disorder inherited in an autosomal recessive or X-linked recessive manner. Carriers usually do not themselves have symptoms related to the gene mutation, but may want to know their status in order to make reproductive choices. Carrier testing is offered to those who have family members with a genetic condition, family members of an identified carrier, and individuals in ethnic or racial groups known to have a higher carrier rate for a particular condition.

Finding genetic services
Clinical genetic services may be located in a hospital, medical center or in a private office. They are usually provided through a perinatology or genetics clinic, which may be specialized by age group (e.g., prenatal, pediatric, adult), or by medical condition (e.g., cancer genetics). Sometimes these services are offered as part of a multidisciplinary evaluation in a specialty clinic. Genetic services can be located through the websites of the American College of Medical Genetics and the National Society of Genetic Counselors.

A Working Model: Genetic Testing for Hereditary Predisposition to Cancer
Approximately 7-10% of individuals with breast and/or ovarian cancer, and a similar proportion of those with colon cancer, carry a gene mutation that confers an extremely high (70-80% or more) lifetime risk of malignancy. The proportion of hereditary cases appears to be lower for cancers in the prostate, thyroid, pancreas, kidney and skin, but any type of cancer can be linked to an inherited predisposition in rare families. When an inherited (constitutional) gene mutation is present, cancer develops at a young age (generally under age 50), and individuals are at risk for developing more than one cancer in their lifetime. "Hereditary" cancers are NOT more aggressive, but they do develop at earlier ages and/or more than once, so that screening for these cancers must start at younger ages and be done regularly. The benefit of such medical surveillance has been clearly proven.

Most cancer predisposition syndromes are inherited as autosomal dominant conditions, which means that each child of an affected individual has a 1 in 2 (50%) risk of inheriting the gene (mutation). The opposite is also true: half of the children of an affected person, on the average, will NOT inherit the gene mutation; these individuals see their cancer risk decrease to that of the general population, and cannot pass down to their children a gene mutation which they do not have.

The first step for the health care provider is to refer the person with a suggestive personal and/or family history of cancer for a genetics consultation. The consultation includes an assessment of genetic risk, followed by genetic education/counseling. The counselor will explain the probability of a hereditary cancer predisposition syndrome, diagnostic or predictive testing which may be available, benefits and limitations of genetic testing, and the implications for managing the patient and his/her family if a gene mutation is identified. The genetics specialist will then coordinate any genetic analysis the patient/family opts for, including practical aspects such as insurance authorization, obtaining blood or tissue samples for testing and forwarding these to the cancer genetics laboratory. When test results are available, the patient and/or family are scheduled for follow-up genetic counseling.

An Example: Genetic Testing for Lynch Syndrome
Making the Diagnosis
Lynch syndrome (LS), also known as Hereditary Nonpolyposis Colorectal Cancer (HNPCC), affects about 5% of individuals with colon or rectal cancer, and a similar percentage of women with uterine (endometrial) cancer. These individuals have developed these specific malignancies because they have Lynch syndrome. LS is an inherited form of cancer predisposition, transmitted as an autosomal dominant condition. Each child of a person with LS has a 50% risk of inheriting the condition. The person with LS is likely someone who had their first cancer diagnosed before the age of 50, who may have had more than one cancer, and who has close relatives diagnosed with digestive system (intestine and stomach), reproductive system (uterus and ovary), or urinary tract (prostate and bladder) cancer at a young age. When Lynch syndrome is suspected by an oncologist or other health care provider, the patient or family should be referred for a genetic consultation and counseling. When a specific mutation in one the of DNA repair genes is identified, family members at risk can have predictive or pre-symptomatic gene testing to learn whether or not they carry the abnormal gene.

Putting Life-Saving Information to Use
These cancers can be detected early or even prevented when we know that the patient and family has Lynch syndrome. These malignancies are not worse, but they do develop at a much younger age in the affected persons. Because we know that the lifetime risk of colon or rectal cancer is 70-80% and the risk of uterine cancer is 40-60% in individuals with LS, cancer screenings should start at age 25 (much younger than the normal recommendations). Colonoscopy should be done every 12-18 months and women should have ultrasound and endometrial biopsy performed every year. The reason for this high risk of cancer is that Lynch syndrome individuals carry a mutation in the DNA repair gene that restores the DNA cells in these body systems. Criteria have been established by multidisciplinary medical teams to help recognize individuals/families with Lynch syndrome. However, LS is still under-recognized and too many people in LS families do not know they have the condition and are not getting the early surveillance they need.

About the Author: Dawn DeLozier, Ph.D. is Director of Clinical Services at Genetic Medicine Central California and is a UCSF Associate Professor of Pediatrics. Her specialty is Cancer Genetics