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Promoting Safe and Effective Genetic Testing in the United States

Chapter 5

Genetic Testing for Rare Inherited Disorders

The vast majority of single-gene (Mendelian) disorders are rare, occurring less often than 1 in 10,000 live births. Exceptions are sickle cell anemia, cystic fibrosis, thalassemia, and Tay-Sachs disease in some populations, and heterozygous familial hypercholesterolemia, Duchenne muscular dystrophy, and the hemophilias more generally. Phenylketonuria, for which newborns are routinely screened, occurs in slightly less than 1 in 10,000 births. Most of the several thousand other known inherited diseases occur much less frequently, but their combined incidence is by no means rare. Between 10 and 20 million Americans may suffer from one of the several thousand known rare diseases over their lifetimes.1(p. xiii) With the discovery of the role of inherited mutations in common diseases, such as breast and colon cancer and Alzheimer disease (albeit in a small proportion of affected people), the Task Force is concerned that research might shift away from the multitude of rare diseases. Commercial genetic test developers, for instance, expend a greater effort on the common, complex disorders than on rare ones (see table 3, Appendix 3). The development and maintenance of tests for rare genetic diseases must continue to be encouraged.

Congress recognized the need to provide incentives for the development of drugs for rare diseases when it passed the Orphan Disease Act in 1983.2 To stimulate research and development, it granted a 7-year period of market exclusivity for unpatented drugs, a tax credit to offset the cost of drug development (the tax credit expired in 1994), and government grants and contracts to help defray costs of clinical studies. Over 300 grants have been awarded, primarily to support the development of drugs and biologics. (Personal communication, Dr. John V. Kelsey, Office of Orphan Products Development, FDA, February 22, 1996) In 1988, Congress added medical devices, authorizing government grants and contracts for "defraying the costs of developing medical devices for rare diseases or conditions."3 Devices now account for about 10 percent of all orphan products receiving assistance under the Act.

As part of the Safe Medical Devices Act of 1990, Congress enacted the Humanitarian Device Exemption "to encourage the discovery and use of devices intended to benefit patients in the treatment and diagnosis of diseases or conditions that affect fewer than 4,000 individuals in the United States."4 The incentive to device manufacturers is temporary authorization to market the device without meeting the effectiveness requirements of FDA. The exemption lasts for 18 months, although it can be renewed for up to five years. During the period of the exemption, the manufacturer cannot obtain a profit on device sales; the device must receive pre-market approval before a profit mark-up can be included in the price. In addition to the special incentives under these Acts, approximately 20 percent of the National Institutes of Health (NIH) budget funds research that is related to rare diseases, of which about 90-95 percent are inherited. (Personal communication, Steven Groft, Director Office of Rare Diseases, NIH, October-November 1996)

There is no uniform definition of a rare disease. The Orphan Drug Act (ODA) defines orphan disease as one affecting less than 200,000 persons in the U.S., or approximately 1 in 1,250 Americans. For devices (which include genetic tests), the 1988 ODA Amendments define rare disease as "any disease or condition that occurs so infrequently in the United States that there is no reasonable expectation that a medical device...will be developed without [financial] assistance."a As already noted, the Humanitarian Device Exemption of the Safe Medical Devices Act of 1990 applies to diseases or conditions that affect fewer than 4,000 persons in the United States (1 in 62,500 Americans). It is silent on what constitutes a disease or condition (e.g., whether rare variants of a common genetic disease constitute a separate disease, or whether carriers are excluded). The carrier (heterozygote) frequency for autosomal recessive disorders with an incidence of 1 in 10,000 is 1 in 50.

Of great concern to the Task Force is the dissemination of information related to the diagnosis and management of rare diseases, the continuing availability of tests for their diagnosis and for predicting risk of future disease, and, finally, the quality of laboratories performing genetic tests for rare diseases. We consider these topics in turn in the remainder of this chapter.


Research Activity

The NIH Office of Rare Diseases (ORD), founded in 1994, maintains a database of clinical studies involving rare diseases that are funded by NIH. At the end of 1996, approximately 300 studies were contained in the database. ORD plans to expand the database to include clinical research supported by private organizations, including the biotechnology and pharmaceutical industries. When fully operational, the database will contain abstracts of studies, enrollment criteria, and the names of principal investigators and how to contact them. The database is available to patients, providers, and other researchers on the World Wide Web as part of the National Institutes of Health's clinicaltrials.gov site. In the future, people may be able to contact principal investigators of clinical studies through the databases. ORD would also like to coordinate rare disease research by the establishment of an information center, which would also respond to inquiries about rare genetic disorders. Funds have been authorized but not appropriated.

The Metabolic Information Network (MIN) (Dallas, Texas) is a registry containing medical information on approximately 10,000 living and deceased patients with any one of 86 metabolic disorders. Funded originally by the National Institute of Child Health and Human Development, MIN currently receives most of its support from pharmaceutical companies. Through MIN, an investigator doing research on a particular disease can locate other investigators doing related research. Names of patients are not included in the registry and requests for investigator-to-investigator contact are reviewed by a scientific advisory board.

A major concern of the Task Force is that as tests to diagnose and, in many cases, to predict, rare diseases are developed, data will not be systematically compiled on their clinical, as well as analytical validity. A comprehensive system to collect data on rare diseases must be established. As discussed in Chapter 2, the Center for Disease Control and Prevention (CDC) can and should play a role in coordinating data collection from multiple sources to facilitate the review of new genetic tests, particularly for rare diseases. Multiple sources will almost always be needed to validate tests for rare diseases. CDC and ORD should work closely to develop the appropriate data-gathering and monitoring systems to assess the validity of genetic tests for rare diseases.

Finding Information on the Interpretation of Clinical Findings

Some rare genetic diseases present with unusual symptoms or signs, making diagnosis relatively easy for knowledgeable physicians. Many rare inherited metabolic disorders present with commonly encountered problems for which the usual explanation is not a rare disease.5 When the clinical problem persists or recurs despite treatment, health care providers must be aware that a rare disease could be the explanation. Prompt recognition can often save the patient's life by leading to initiation of effective therapy before irreversible damage occurs. Many of these metabolic disorders appear in infants and children; early diagnosis can alert the parents to their risk of having another affected child. Several tests can be used predictively for prenatal diagnosis. Carrier testing in collateral relatives is often possible.

Unfortunately, the diagnosis of rare diseases is often delayed. One reason for the delay is inaccessibility of information. Physicians who encounter patients with symptoms and signs of rare genetic diseases should have access to accurate information that will enable them to include such diseases in their differential diagnosis, to know where to turn for assistance in clinical and laboratory diagnosis, and to locate laboratories that test for rare diseases. The commonly encountered symptoms and signs with which rare diseases present and the process of evaluating them should be taught to medical students and residents. It would be too much to expect health care providers to retain information on all the unusual presentations, but they should be taught where to seek information. Although textbooks and medical journals are the classical starting points, and referrals to specialists may help, computerized databases in which a user could search by the patient's presenting finding would be more expeditious and effective. Most available information is organized by disease, not by presenting findings. The National Organization of Rare Diseases, Inc. (NORD) publishes The Physician's Guide to Rare Diseases, which includes an atlas of visual diagnostic signs. NORD also maintains the rare disease database [rarediseases.org] containing entries on over 1,100 rare diseases. The database is logically organized by a description of the disorder, symptoms, causes, affected population, related disorders, diagnostic procedures, status of treatment (investigational or standard of care), resource referral for further information and support, and references from peer-reviewed medical literature.

Although primarily providing information to researchers, the Metabolic Information Network can provide information to physicians on over 200 metabolic disorders.

Once diagnoses are made, patients and/or their families often want written information about the diseases. In a survey of 270 physicians conducted about 10 years ago, 42 percent were unable to find printed information to distribute to their patients with rare diseases.1 NORD's database on rare diseases has since been made available to consumers. NORD also maintains a Patient Services Department, one of whose functions is to help affected individuals and families in need of accessing services. The Department also maintains a confidential patient registry.

Information about individual disorders, particularly for consumers, is also available through individual genetic support organizations, which can be located through NORD (Washington, DC) or the Alliance of Genetic Support Groups (Chevy Chase, Maryland).

Finding Clinical Diagnostic Laboratories

Because of the rarity of many diseases, only one or a few laboratories in the United States, or the world, accurately perform tests for them. This raises the problem of how physicians caring for patients will be able to identify these laboratories in time to benefit patients who present with acute illness.

The Helix Directory of Medical Genetics Laboratories, supported by the National Library of Medicine, lists approximately 300 laboratories that perform tests on over 480 genetic diseases. Helix began by listing laboratories performing DNA-based tests including fluorescent in situ hybridization (FISH), but will extend to biochemical tests in the future. As of July 1997, Helix has 4,500 registered users and receives 150 requests per day. (Personal communication, Maxine L. Covington, Helix Directory Manager, July 23, 1997) Helix provides information by phone and fax, but it is encouraging inquiries via the World Wide Web (note: Helix is now part of Geneclinics) [geneclinics.org]. As many of the laboratories entered in the database do not want to be contacted directly by patients, passwords for entry to the database are available only to health care providers. Consequently, Helix is not listed in NORD's databases.

Through ORD's database on clinical research studies, physicians can get help in the diagnosis of patients in whom they suspect particular rare diseases. To maintain and expand its database, ORD should identify laboratories worldwide that perform tests for rare genetic diseases, the methodology employed, and whether the tests they provide are in the investigational stage, or are being used for clinical diagnosis and decision making.

Need for Coordination

The Task Force is concerned that there might be some unnecessary duplication of effort in compiling databases while, at the same time, some diseases or laboratories offering tests will not be included. In addition to the databases mentioned so far, several other organizations, including the Alliance of Genetic Support Groups, some of its member organizations, and other independent genetic disease interest groups maintain databases and, in some cases, patient registries. The American Academy of Pediatrics provides information periodically on newborn screening and other disorders. The Society for Inherited Metabolic Disorders is compiling information for providers about diagnostic evaluations of rare disorders, and ACMG is developing databases on tests that should be used to diagnose specific disorders. In order to avoid redundancy and to use the expertise of these organizations more efficiently, NIH should assign its Office of Rare Diseases (ORD) the task of coordinating these efforts and provide ORD with sufficient funds to fulfill the Task Force's recommendations on rare diseases. ORD should periodically report to the proposed Secretary's Advisory Committee on the status of these activities. With CDC playing a greater role in genetics, it should be closely involved in activities in this area.


The clinical diagnostic tests for some rare diseases are available only from laboratories that are primarily engaged in research. Some of these laboratories perform clinical tests at no cost to the patient and with the primary purpose of furthering their own research. This raises two questions: First, what happens to the availability of the test for clinical diagnostic purposes when the laboratory (or laboratories) performing the assay ceases to do so because it switches to other research projects or for other reasons? Second, as discussed in the concluding section, how can the quality of clinical test performance be assured in laboratories engaged primarily in research?

Research laboratories that were offering genetic tests for rare diseases will cease performing them as they complete their investigations and move on to other areas of interest. This is particularly a problem for the continued availability of clinical tests when only one research laboratory performed the test. It is not unlikely, however, that as progress on a given rare diseases is made, all of the research laboratories offering tests will move on to solve other problems.

The Task Force considered the transitioning problem at great length. It rejected the possibility of creating central or regional laboratories that could perform a wide range of tests for rare diseases because assembling the necessary expertise for performing and interpreting all of the tests under one roof would be difficult or impossible. For the same reason, it rejected transfer of these tests to large mega-test commercial laboratories that might be willing to add on tests for rare diseases if they could cover costs. The Task Force also considered whether agencies funding research that included the development and offering of tests for rare diseases should be asked to allocate a small part of the grant or contract they awarded to enable the investigator to transfer the test to a service laboratory just before funding for the research terminated. This might discourage investigators from applying for grants if they were reluctant to take on this responsibility. Agencies funding research might also be reluctant to use funds to establish service activities. They might also have concerns about the quality of the tests being offered as a service.

The Task Force is not convinced that the transitioning problem is insurmountable. One possibility is that a laboratory that was offering genetic tests as part of its research, but on which clinical decisions were being made, procure CLIA certification (see below) and serve as a service laboratory, recovering its costs for the test by instituting charges for it. Another possibility is for the research laboratory to transfer the testing capabilities to the clinical diagnostic laboratory in its institution. The proximity of the expert investigator could facilitate a smooth transition and ensure the test would be performed and interpreted properly. A third possibility is that the test be transferred to a research laboratory elsewhere that is willing to perform the test as a service. In this case, mechanisms are needed to ensure that providers know where to obtain the test. Whichever alternative is adopted, the test should undergo some form of external review before transition to a service.

The NIH Office of Rare Diseases should have the lead responsibility in ensuring the continued availability of safe and effective tests for rare diseases when it learns that a test will cease being offered. Funds to enable it to accomplish this task should be available. Laboratories should notify ORD about impending cessation of their testing so that provisions for a transition to other laboratories can be made. ORD should, in turn, notify other laboratories when a demonstrably safe and effective genetic test ceases to be available and make every effort to get another laboratory to perform it. If this fails, ORD should notify the other organizations with whom it coordinates, as well as the proposed Secretary's Advisory Committee.


Neither the clinical nor the laboratory diagnosis of rare inherited diseases is easy. If clinicians do not mention the possibility of a rare disorder when they order clinical laboratory tests, the laboratory might not test for them. Clinical laboratories, too, might misinterpret abnormal findings, often neglecting rare disorders in favor of more common situations, such as poisoning. Some clinical laboratories do not have the equipment or expertise to diagnose a rare disorder, but clinicians might not realize it. (That is one reason why directories of qualified laboratories, as will be discussed further, are so important.) Many rare disorders will be diagnosed only by special laboratories accustomed to looking for rare diseases and having the equipment and expertise to do so.

Some genetic tests for rare diseases have been developed in research laboratories under grants. In accordance with current law, the Task Force recommends that any laboratory performing any genetic test on which clinical diagnostic and/or management decisions are made should be certified under CLIA. Research laboratories that are not currently providing genetic test results to providers or patients but that plan to do so in the future must register under CLIA. Once a laboratory registers, it does not have to wait for a survey (see Chapter 3) before performing clinical tests.

Some research laboratories have complained of the difficulty and expense of obtaining CLIA approval for tests that constitute a small part of their activity and will only be performed occasionally. A laboratory performing 2,000 or fewer tests a year can register for $100 and obtain certification for $300 (including onsite inspection for its first two years.)b

The Task Force recognizes the important contribution that research laboratories make to clinical testing, particularly for rare diseases. The type of skills that are needed for research, including a willingness to modify experimental conditions, are not necessarily the skills for maintaining the quality of a service laboratory, in which consistency of performance ensures reliability. Research laboratories that provide physicians with results of genetic tests, which may be used for clinical decision making, must validate their tests and be subject to the same internal and external review as other clinical laboratories. Nevertheless, the proposed genetics subcommittee of CLIAC should consider developing regulatory language under the proposed genetics specialty that is less stringent, but does not sacrifice quality for laboratories that only occasionally and in small volume perform tests whose results are made available to health care providers or patients.c

Of great concern to the Task Force, discussed at length in Chapter 3, is whether certification under CLIA will ensure the quality of genetic tests, particularly those for rare genetic diseases. The creation of a subspecialty of genetics under CLIA will greatly improve the situation. Many tests for rare disorders are biochemical. The quality of performance of these tests would be ensured if they were included under a genetics specialty.

Directories of laboratories that perform tests for rare genetic diseases should indicate whether or not the laboratory is CLIA-certified and whether it has satisfied other quality assessment and proficiency assessments, such as those provided by CAP and ACMG. Directors of these laboratories are encouraged to participate in these programs or other programs of at least comparable quality that may be established.

The Task Force is concerned that third-party payers, including managed care organizations will not recognize that tests for rare diseases can only be performed in certain highly-specialized laboratories. Patients will be misdiagnosed and harmed unless these laboratories are used. The Society of Inherited Metabolic Diseases is preparing a list of laboratories qualified to perform tests for several rare diseases. The Helix database should also indicate whether the laboratories listed in it are CLIA-registered and/or certified. When the proposed genetics specialty is established, the directories should indicate whether the laboratory performing genetic tests is certified in that specialty or the appropriate subspecialty.


  1. National Commission on Orphan Diseases: Report of the National Commission on Orphan Diseases. 1989;(Abstract)
  2. Public Law 97-414: 1995;U.S.C. Sec 360aa et:(Abstract)
  3. Public Law 100-290: Orphan Drug Amendments of 1988. 1995;U.S.C. Sec 360cc(a):(Abstract)
  4. Public Law: Safe Medical Devices Act of 1990. 1995;U.S.C. Sec 360j(m):(Abstract)
  5. Holtzman NA: Rare diseases, common problems: Recognition and management. Pediatrics 1978;62:1056-1060.
  6. Shoemaker JD, Lynch RE, Hoffmann JW, Sly WS: Misidentification of propionic acid as ethylene glycol in a patient with methylmalonic acidemia. Journal of Pediatrics 1992;120:417-421.
  7. Woolf AD, Wynshaw-Boris A, Rinaldo P, Levy HL: Intentional infantile ethylene glycol poisoning presenting as an inherited metabolic disorder. Journal of Pediatrics 1992;120:421-424.

Last updated: January 20, 2010