Genetic Testing

For individuals with symptoms and a family history of genetic disorders.

Diagnostic testing is used to confirm or rule out a known or suspected genetic disorder in a symptomatic individual.

Points to consider:

• DNA testing may yield diagnostic information at a lower cost and with less risk than other procedures (Clinical Example).
• Diagnostic testing is appropriate in symptomatic individuals of any age (Clinical Example).
• Confirming a diagnosis may alter medical management for the individual (Clinical Example).
• Diagnostic testing of an individual may have reproductive or psychosocial implications for other family members as well (Clinical Example).
• Establishing a diagnosis may require more than one type of genetic test (Clinical Example).
• DNA testing may not always be the best way to establish a clinical diagnosis (Clinical Example).

For individuals with no symptoms but with a family history of genetic disorders.

Predictive testing is offered to asymptomatic individuals with a family history of a genetic disorder. Predictive testing is of two types: presymptomatic (eventual development of symptoms is certain when the gene mutation is present, e.g., Huntington disease) and predispositional (eventual development of symptoms is likely but not certain when the gene mutation is present, e.g., breast cancer).

Points to consider:

• Predictive testing is MEDICALLY INDICATED if early diagnosis allows interventions which reduce morbidity or mortality (Clinical Example).
• Even in the absence of medical indications, predictive testing can influence life planning decisions (Clinical Example).
• Because predictive testing can have psychological ramifications, careful patient assessment, counseling, and follow-up are important (Clinical Example).
• Many laboratories will not proceed with predictive testing without proof of informed consent and genetic counseling.
• Identification of the specific gene mutation in an affected relative or establishment of linkage within the family should precede predictive testing (Clinical Example).
• Predictive testing of asymptomatic children at risk for adult onset disorders is strongly discouraged when no medical intervention is available.

Prenatal testing is performed during a pregnancy to assess the health status of a fetus. Prenatal diagnostic tests are offered when there is an increased risk of having a child with a genetic condition due to maternal age, family history, ethnicity, or suggestive multiple marker screen or fetal ultrasound examination. Routine prenatal diagnostic test procedures are amniocentesis and chorionic villus sampling (CVS). More specialized procedures include placental biopsy, periumbilical blood sampling (PUBS), and fetoscopy with fetal skin biopsy.

Points to consider:

• A laboratory that performs the disease-specific test of interest must be identified before any prenatal diagnostic test procedure is offered (Clinical Example).
• All prenatal diagnostic test procedures have an associated risk to the fetus and the pregnancy; therefore, informed consent is required, most often in conjunction with genetic counseling.
• In most cases, before prenatal diagnosis using molecular genetic testing can be offered, specific gene mutation(s) must be identified in an affected relative or carrier parent(s) (Clinical Example).
• Prenatal testing for adult-onset conditions is controversial. Individuals seeking prenatal diagnosis for these conditions should be referred to a professional trained in genetic counseling for a complete discussion of the issues.

Genetic testing for embryos resulting from in vitro fertilization.

Preimplantation testing is performed on early embryos resulting from in vitro fertilization in order to decrease the chance of a particular genetic condition occurring in the fetus. It is generally offered to couples with a high chance of having a child with a serious disorder. Preimplantation testing provides an alternative to prenatal diagnosis and termination of affected pregnancies.

Points to consider:

• Preimplantation testing is only performed at a few centers and is only available for a limited number of disorders.
• Preimplantation testing is not possible in some cases due to difficulty in obtaining eggs or early embryos and problems with DNA analysis procedures.
• Due to possible errors in preimplantation diagnosis, traditional prenatal diagnostic methods are recommended to monitor these pregnancies.
• The cost of preimplantation testing is very high and is usually not covered by insurance.

GeneTests was created to simplify the search for genetic testing laboratories, which may be difficult to locate. For many diseases, there may be only one laboratory providing genetic testing. U.S. patents have been issued covering diagnostic testing for some genetic disorders. A given laboratory may or may not be the exclusive licensee to such a patent. If there is a choice of laboratories, the following factors should be considered:

Laboratory Personnel

Genetics laboratory personnel have two major roles: processing patient samples (technologists), and interfacing with referring clinicians regarding their patients (clinical consultants). Lab personnel, who are usually certified in their specialty, may include lab directors, supervisors, technologists, and genetic counselors.

Compatibility: The test offered by the laboratory must match the specific clinical need

• Clinical testing gives a result which can be used in patient care; research testing usually does not. If only research testing is available, the patient or family may choose to defer testing until a clinical test is available.
• The test methodology must be suited to the testing purpose (e.g., Prader-Willi syndrome can be diagnosed with methylation testing, but other tests are required for recurrence risk counseling).
• Some diseases are caused by mutations in more than one gene. It is important to be sure that the lab selected is testing the appropriate gene(s).
• Different kinds of DNA tests are available. The laboratory selected should offer what is most appropriate for a specific clinical situation. For instance:
  • A specific gene mutation (e.g., if the familial mutation has been identified)
  • A panel of mutations (e.g., the Ashkenazi Jewish BRCA1 panel of 3 mutations)
  • The complete gene sequence

Reliability: Direct contact with the laboratory is needed to assess the laboratory's experience and qualifications

• Does the laboratory have any other certification? (Laboratories with clinical listings in GeneTests have CLIA certification.)
• Is the laboratory associated with a reputable company or university?
• Is the laboratory director board-certified?
• Is the laboratory's work published in the medical literature?
• What is the laboratory's experience with the specific test being ordered?

Ease of Communication

• What professionals are on staff to help assess the appropriateness of testing, determine the best testing paradigm for the family, and interpret test results?
• Does the laboratory have information on tests offered and logistics of sample collection and shipping easily available by phone, fax, or Internet?
• What information is contained in the test result report (e.g., raw data, interpretation, references, sensitivity and specificity information)?

Geographical Location

• Some states have restrictions on insurance coverage or, as is the case in New York , additional regulatory restrictions.
• Samples shipped outside of the U.S. must go through Customs, which requires that hazard identification and a statement of value accompany the sample. Language barriers and time zones can also be an issue.

Turn-Around Time: Time from sample receipt to test result report may vary

• Clinical laboratories generally have similar turn-around times for tests performed using the same methodology.
• A shorter turn-around time is advantageous only when it can be determined that quality control and thoroughness are not compromised.
• Test results for pregnancy management (prenatal diagnosis) are considered urgent due to restrictions on options late in pregnancy. Pregnancy dating should be included with all prenatal samples.
• The laboratory should be notified in advance of any sample that is "stat" (rush), as the sample processing may be different.

Cost: May vary from less than $100 to more than $2000 based on several factors

• Test methodology. Low complexity tests (e.g., single gene mutation) are less expensive than high complexity tests (e.g., full gene sequencing)
• Laboratory testing strategy. Some labs test for a large number of mutations all at once; other labs test in stepwise fashion, beginning with the most common mutations.
• Number of individuals tested. Several family members may need to be tested to obtain a meaningful test result.
• Contractural agreements. Hospitals, insurers, and laboratories negotiate contracts to set the price of testing and amount of reimbursement.
• Specimen handling. Some cell types require culturing or other special handling before testing.
• Additional services. Genetic consultation or counseling is usually recommended and sometimes required before genetic testing is performed. These fees should be considered in the total cost.

If genetic testing is clinically available and useful for a particular patient, the patient needs to understand why it is being offered and its implications for medical management and psychosocial well-being. If a competent patient (or parent/guardian) agrees to the proposed genetic test after full disclosure, this constitutes informed consent. Informed consent may be verbal or written. Some laboratories require written documentation of informed consent. (See sample informed consent form from CompGene.)

Pretest counseling includes:

• Assessing the patient's risk perception, expectations and support systems.
• Explaining the implications of testing vs. not testing for medical management and reproductive options.
• Describing the methods used to obtain specimens and associated risks.
• Reviewing test accuracy (sensitivity and specificity).
• Estimating the chance that the test will be positive based on available information (e.g., family history, clinical symptoms).
• Discussing any out-of-pocket costs to the patient.
• Establishing a plan for conveying test results. Depending on the circumstances, results may be given:
  • in person
  • by phone, with or without a follow-up appointment
  • by mail (negative results only)
  • only when positive (e.g., newborn screening)

Results should be revealed only to the individual tested, or his/her parent or guardian, unless explicit permission has been granted to share results.

Additional issues relevant in some testing situations:

• Need to clarify biological relationships (parentage, zygosity) for linkage studies.
• Potential discrimination in employment, insurability or educational opportunities, especially in predictive testing. (Some states have State Genetics Laws in place prohibiting genetic discrimination).
• Results from research testing are not generally available for patient care.

Contact the lab directly to ask the following questions:

What are the sample requirements?

• Are samples from other family members needed?
• What specimen type is needed?
• Does the specimen need to be cultured before shipping?
• What is the requested amount of specimen? Will less be accepted in hard-to-draw situations?
• What information should be included on the label?

What supporting documentation is needed?

• Does the lab have a speciSample Logistics and Supporting Documentation specific requisition form?
• What clinical history should be included?
• Are medical records or test results on family members needed?
• Is family history needed for test interpretation? A pedigree is an efficient way to show family relationships. See Sample Pedigree for Laboratory Documentation (pdf).
• Is ethnicity relevant to test interpretation?
• If crossing international borders, are hazard labels and customs paperwork included?

How should the sample be transported?

• What is the correct delivery address?
• When is delivery accepted?
• Should the sample be frozen, refrigerated or at room temperature during shipping?
• Is there a courier to the lab, or is taxicab, mail or overnight shipping required?

Test results are provided in writing by the laboratory to the referring clinician. The details of the lab report vary by lab, but may include:

• Raw data
• Clinical interpretation of test result
• Sensitivity and specificity information
• References

See Sample Lab Report.

The clinician explains the meaning of the test result to the patient and to other family members as needed. Test results and follow-up should be documented in the medical record and a copy made available to the patient. For many conditions, educational materials may be available from patient support organizations.

Parent support & information:

• The Genetic Alliance
• Family Village
• Family Voices
• Kansas University Medical Center
• March of Dimes