In debates over health privacy proposals, it was often said that video rental records had better privacy protection than medical records.

Unfortunately, now that the final privacy rules have been issued under HIPAA, the Health Insurance Portability and Accountability Act, it is still true that video rental records have better protections from marketing uses and disclosures than medical records.

The act, approved by President Clinton and Congress in 1996, gives the Department of Health and Human Services (HHS) the authority to craft health privacy regulations.

The new HIPAA health privacy rules,  authorize health providers and health plans to use and disclose patient records, including results of genetic testing, for many marketing purposes without patient consent or authorization.

So, how will this affect the public? Marketing permitted under the rule would far exceed current practices. In fact, the Clinton-Shalala marketing rule is the most anti-privacy proposal that I have seen in more than 20 years of work on health privacy policy and is likely to result in more junk mail and telemarketing calls to individuals from marketers who have obtained detailed information about the medical history of the individual.

QUOTE FROM THE PREAMBLE OF THE NEW HIPAA RULES: “However, the final rule permits an alternative arrangement: the covered entity can engage in health-related marketing on behalf of a third party, presumably for a fee. Moreover, the covered entity could retain another party, through a business associate relationship, to conduct the actual health-related marketing, such as mailings or telemarketing, under the covered entity’s name.” This language says expressly that marketing is permissible for a fee, that marketing is permissible on behalf of third parties, and that telemarketing is permissible.

For example, the rule would permit telemarketers and even door-to-door sales people to obtain diagnostic or treatment information from a physician, health plan, pharmacy, laboratory, pharmacy benefit manager or other health care institution and use that information to sell products and services. They may contact individuals and say, “Hi. We understand from your doctor that you have hemorrhoids, and we have a product that will make your life easier.”

Without the marketing language, the health privacy rules would be a mixed bag, with some things to like and others to dislike.

Janlori Goldman of the Health Privacy Project called the rules a “great victory for consumers.” I disagree strongly, as the marketing provision is so anti-consumer and anti-privacy that it outweighs any other positive features of the rest of the rules.

(Interestingly, the marketing rule was not in the draft rule published for comment.)

Here are some highlights of the rules:

• The rule expressly authorizes disclosures for marketing without patient consent.
  For example, information about a woman’s pregnancy can be used by health providers or plans for marketing and disclosed to others for marketing. A woman can only object after the fact.
• All medical information held by providers and payers can be used by them for marketing without affirmative patient consent or with no opportunity to opt-out in advance.
• All protected health information can be disclosed for marketing.
  The rule does not protect information about diagnoses, prescriptions, pregnancy, sexually transmitted diseases, mental health treatments, or confidential communications.
• Patients have the right to opt-out of marketing only after receiving a marketing communication.
  If a family of four has a dozen doctors, clinics, health plans, hospitals, laboratories, pharmacies or pharmacy benefit managers, the family may have to write 48 separate letters to opt-out of each organization’s marketing activities.

  VIDEO PRIVACY ACT HIPAA Does not allow video operators to disclose the names of movies that an individual rented without affirmative consent. Allows use and disclosure of any protected health information for many marketing purposes without the affirmative consent of the individual. Allows video operators to disclose the categories of movies rented (not actual titles) only if an individual was given an opportunity in advance to opt-out. Allows disclosure of any protected health information for many marketing purposes without mandating an advance opt-out.

• Patients do not have to be offered toll-free numbers to opt-out, the ability to opt-out online, or postpaid opt-out letters. A covered entity could require an individual to send a separate “snail mail” letter to each marketing organization in order to opt out.

Nothing in the rule says that a covered entity cannot charge patients who want to opt-out.

HHS has defended the marketing rule by saying that it allows physicians to make recommendations to patients. However, the definition of marketing expressly excludes these recommendations. A rule allowing broad uses and disclosures for marketing is certainly not necessary to permit physicians to make treatment recommendations.

Robert Gellman is a Washington, DC-based Privacy and Information Policy Consultant.

Editor’s Note:

Privacy and confidentiality are essential components of the provider/patient relationship and can be part of policies to enhance the benefits of genetic information while limiting adverse discrimination. Robert Gellman, a nationally recognized expert on privacy policy, comments here on the new medical privacy policies enacted as part of the Health Insurance Portability and Accountability Act (HIPAA; Kennedy/Kassebaum Bill).

The appearance in 1998 of a new medicine for an intractable and especially savage form of breast cancer was a medical milestone for two reasons.

For one, the drug, called Herceptin, shrank tumors and prolonged lives.

What received much less attention, however, was the unique way in which Herceptin is prescribed.

Herceptin is one of the first drugs for which tests are performed to predict whether it will work in a particular patient prior to drug prescription.

How do physicians know if Herceptin will work in a particular patient?

The drug is specially designed to treat metastatic breast cancer patients whose tumors are shown to express abnormally high amounts of a protein called HER2.

For those patients – up to 30 percent of women with breast cancer – Herceptin can bind to HER2, slowing tumor growth.

The flip side: for those with normal HER2 levels, the drug is as useless a weapon as a hilt without its blade.

That Herceptin and other drugs help some individuals but not others is not exceptional – in fact, it is the rule for drugs. This principle was established around 40 years ago by researchers studying pharmacogenetics, the science of how genes influence response to medicine.

Pharmacogenetics revealed instances of genes influencing drug responses in enormous numbers of people.

Millions, for instance, get less pain relief from codeine because their particular variant of a gene called CYP2D6 is unable to convert codeine into its active form, morphine.

The codeine/CYP2D6 story is not alone.

If they take aspirin or one of dozens of other drugs, more than 400 million inhabitants of equatorial Africa, Asia and South America are at risk for hemolytic anemia, a potentially fatal reduction in the blood’s capacity to carry oxygen, due to differences in another gene, called G6PD.

Despite these cases, insights were few and difficulties of routine medical testing for gene variants were great. So, pharmacogenetics remained for quite some time a minor field of research.

Now the human genome project, the international effort to catalog all human genes, has brought the idea of personalized medicine into the limelight.

Renamed “pharmacogenomics” to reflect a more global genome survey and revamped to supply actual medical applications, the field has a simple goal: to develop genetic tests that will help doctors prescribe drugs that work, not ones that don’t.

Major drug companies, joined by a young band of pharmacogenomics companies, are hunting assiduously for variants of human genes that explain why drugs work well for some but not others.

Consider how better-suited prescriptions might improve treatment of high blood pressure, says Bill Campbell, a specialist in clinical laboratory tests and Director of Genomics at Princeton, NJ-based Covance, a drug development services company.

“Today,” Campbell explains, “if a patient has high blood pressure, a doctor will say, ‘This is a pretty good drug. Why don’t you try it at this dose.’ When the patient is tested a few weeks later, if the drug doesn’t work, the doctor may try increasing the dose. Then the patient has to return later to see if that works. If it still doesn’t, the doctor will have to try something else. It may take six or seven visits before the right combination of drugs is found.”

The point of pharmacogenomics is to avoid all that by getting the prescription right the first time.

Trial and error exacts an even higher price with immediately life-threatening diseases like certain cancers, where using the wrong drugs means patients may not survive to try something new.

“You can’t afford to let someone suffer six months of irreversible decline because they didn’t get the right therapy,” says Colin Dykes, chief scientist of Variagenics, a Cambridge, Massachusetts based pharmacogenomics company.

But delay and suffering is precisely our situation today when, according to Taylor Crouch, the company’s CEO, most cancer drugs help less than half of patients, exposing them to toxic side effects without hope of improving their health.

Herceptin leads a parade of at least four drugs in various developmental stages that attack tumors with overactive cancer genes. Intended for a variety of cancers – brain, melanoma, prostate, breast, and lung- they will be prescribed only after first verifying cancer gene overactivity.

As knowledge increases about how tumor-causing genes influence drug responses, pharmacogenomics may also help doctors use drugs to prevent cancer.

Limited clinical studies show that Tamoxifen reduces risk of breast cancer in women with BRCA1 and BRCA2 gene variants that heighten risk of the disease. This has spurred scientists to ask if similar measures might lower risk of bladder and prostate cancers.

Cancers, of course, won’t be the only diseases affected by pharmacogenomics. Discoveries of gene variants affecting how Tacrin works with Alzheimer’s patients, how Pravochol lowers cholesterol, and how Albuterol helps asthma point to just a few of the diseases in which pharmacogenomics will have a big impact.

Personalized medicines have also been introduced into the treatment of HIV.

In treating AIDS, doctors prescribe combinations of three or four drugs at a time to hold the HIV virus at bay. Although there are now 17 drugs from which to choose combinations, there are also at least 120 HIV gene variants that render one or more drugs ineffective.

To learn which medicines it would be useless to prescribe, doctors have increasingly been getting their patients’ viruses analyzed for drug-resistance gene variants. Ineffective treatment with the wrong drug – and the associated cost and suffering – can be thus avoided.

They challenge the notion of race, so deeply imbedded in our culture. They will change the nature of the fight against disease. They have dramatically changed agriculture, have raised the prospect of increased longevity and of feeding the poor with more nutritious food.

Just as with Darwin’s publication of Origin of Species in 1859 and the dropping of the atom bomb on Hiroshima and Nagasaki in 1945, the genetic revolution has and will change our view of ourselves and the world.

As always, however, with revolutionary advances come significant and legitimate social, ethical, and political concerns. All of these concerns are real, and deeply felt by a segment of the population.

This feature is based on a presentation to the Second Annual National Conference on the Future of Genomics, Biotechnology and Pharmaceuticals in Medical Care.

At its heart, however, I think that the concern and the fuss are over some fundamental issues:

• What does it mean to be human?
• What is nature?
• What is our place in the world?
• Is globalization good for us?
• Is science moving too fast, without adequate controls?
• Who are the winners, and who are the losers?

It sometimes seems to those of us in the biotechnology business – either in the production of the science or its utilization – that everyone must know everything about it. It has been headlined everywhere, it has been on television, and numerous books have been written.

It turns out that the group that defines itself as ignorant or poorly informed about the issue is a large one. The Los Angeles Times, for example, tells us that a scant 14 percent of the population pays close attention to these fundamental social, ethical and political issues in genetics.

Generally, the public is supportive of genetic science, as it is supportive of science in general. Science Indicators, the comprehensive survey published every other year by the National Science Foundation, for example, finds that, “in 1999, 44 percent of those interviewed agreed that the benefits [of genetic engineering] outweigh the harms,” compared to 38 percent who felt the reverse. A Harris Poll, however, reported that “a clear, but not huge, 48 to 38 percent plurality believes that the risks of GM crops and foods outweigh the benefits.”

We face a very interesting dilemma. On the one hand, Americans, along with others in the developed world, continue to have faith in science and technology to improve their lives.

On the other hand, “the number of people who feel either well informed or moderately well informed about science and technology is fairly low.” Seventeen percent felt themselves well informed, while 30 percent felt they were poorly informed. And perhaps most important: “About three quarters of Americans lack a clear understanding of the nature of scientific inquiry.”

It adds up to a troubling picture. While Americans generally have a positive view of science and technology, it may be no more than skin deep.

Let us now turn to the future. What does this mean? Are we content with this relatively low level of public understanding, either of science in general or genomics in particular? If not, what should we do about it?

Anytime one is on an exponential growth curve, the terrain behind you looks flat and that in front of you seems a steep hill. As Nobel Laureate Harold Varmus said recently, the “race” to complete the human genome is really a race to the starting line.

If the science has gotten a little ahead of the politics thus far, in the future it is going to be racing ahead of the politics and of public understanding, unless we do something about it. A public that does not understand something is apt to reject it.

We must, therefore, do something about the relatively low understanding of the public of the genetic revolution. .

Cornelia Dean, science editor of the New York Times, recently said about reporting in the sciences: “Science journalism has a problem, and it is a problem that must be solved by scientists.”

According to Dean, the science writer often has to write many stories on very different subjects, each one of which has complications which must be dealt with. There is no way the writers can get it right all the time, without significant effort on the part of the scientific community itself.

The public, while generally supportive of science in general and genomics in particular, is nervous about it and does not know enough to allay those fears. It is also clear that whatever issues are there today, there will be ten times more tomorrow, ten times that the day after tomorrow, and so forth.

It is essential, therefore, that there be a marriage between the science and media communities to bring this deeper understanding about. Perhaps marriage is too strong a word. I wish to convey the notion of a strong bond and working relationship, one that emphasizes the skill of both parties – the scientist as the producer of new knowledge, and the journalist as the translator to the public whom they study – to bring about another revolution, the revolution in the understanding of this science.

The author is President of the Gene Media Forum, S.I. Newhouse School of Public Communications, Syracuse University

References:

• Avins, Mimi. “Genome Map Success: Much Yet to Discover.” Los Angeles Times, August 7, 2000, page E-1.
• Kanigel, Robert. “The Perils of Popularizing Science. Science Writer, Summer 2000.

Although there is a growing literature on ethics and genetics, surprisingly little of it deals directly with how ordinary people have fit this new knowledge and ethics into their lives. How culture influences the use of genetic services is only rarely taken into account.

An anthropologist might ask: How much do people understand about genetics? How do they confront risk? How do they plan? How influential is the impact of genetics on previous patterns of life? The literature dealing with these topics outside of the US and Europe, in particular, is almost non-existent.

The work of a young German anthropologist, Stefan Beck (of Berlin’s Humboldt University and currently a visiting assistant professor at the University of California at Berkeley), provides a rich addition to our understanding of these issues.

Beck has carried out detailed ethnographic fieldwork on the changing cultural and social context of beta thalassemia, an inherited blood disorder that results in anemia, in Cyprus – a nation in which one in seven individuals harbors a genetic mutation for the disease and in which institutions such as the Orthodox Church play a strong cultural role.

(While carrying a single mutation usually does not result in a significant health impact, carrying two can end up in severe, often lethal, health effects. In Cyprus, one in 158 newborns runs the risk of carrying two mutations associated with beta thalassemia mutations.)

The lives of Cypriots with beta thalassemia have changed over the years. Improved health care during the last several decades has dramatically increased life expectancy for those with two mutations associated with beta thalassemia from three or four years to almost thirty.

These extended life expectations, however, have come with a hefty cost to this small Mediterranean nation. They have placed enormous demands on care-giving institutions, for example, resulting in crisis proportions in terms of shortage of blood for transfusions. And they have contributed to an astronomical rise in medical costs, threatening the very existence of the entire health care system of Cyprus.

In an effort to reduce the incidence of newborns with two mutations associated with beta thalassemia, acting on a recommendation from the World Health Organization in 1973, the Cypriot government established a policy of compulsory carrier screening and counseling which was actively supported by the Orthodox Church of Cyprus.

(The role of the Church was crucial because engagement and marriage of Cypriot couples requires blessing and a certificate from the Church.)

Although two carriers are free to marry, Beck’s research suggests they are unlikely to do so anymore. Today, the number of children born with thalassemia in Cyprus is virtually zero. This shift has had dramatic effects in Britain, as well, where young Cypriot immigrants follow the same pattern.

As Beck writes in a forthcoming text, “The obligatory screening and counseling for Thalassemia in Cyprus is one of the most successful public health programs – but it violates all existing ethical norms. It is obvious that this program is successful because it violates the bioethical rules formulated by international agencies and associations of geneticists.”

Among the Cypriots, the testing is basically compulsory, not voluntary. It is driven by an epidemiological approach to the population, not the individual as the fundamental unit. Counseling is directive, not non-directive. The result is eugenic.

In this instance, an adaptive culture has ignored international bioethical norms – in the name of health and prosperity.

For additional information on thalassemia screening in Cyprus, see Beck’s chapter in the forthcoming text:

Putting genetics to use. Inquiring into the interface between scientific knowledge and vernacular culture. In: Floya Anthias (ed.): Cyprus into the New Millennium, forthcoming.

The “war against cancer” is, in actuality, a battle against a large group of sometimes very different conditions caused by differing agents.

Generally, cancer results from an altered balance between cell proliferation – growth and division – and cell death. A number of factors, including certain genes, viruses, chemicals or exposure to radiation, have been blamed for these normal activities gone awry.

Mutations in identifiable genes are, as a group, the latest of these factors to be discovered. They have also served as fuel for excitement over potential clues to ways that drugs may be designed to battle the varied disease.

Long known to occur repeatedly in families, cancer is one of the primary groups of diseases geneticists have fought long and hard to unravel at the molecular level. Research on organisms ranging from yeast to humans have identified three primary groups of genetic players which, when mutated, allow cells to grow at a rate more rapid than normal:

• Oncogenes – Oncogenes promote cell proliferation and stop cell death, at times resulting in cancer.
• Tumor suppressor genes – These protective genes normally limit the development and/or growth of tumors; when a tumor suppressor gene is mutated, it may fail to prevent a cancer from growing.
• DNA mismatch repair genes – These genes maintain integrity of the genome and the fidelity of information transfer from one generation of cells to the next; loss of function of DNA mismatch repair genes could make a cell error-prone.

Cancer-associated genetic mutations may occur in an individual’s somatic, or body, cells such as breast tissue; certain breast tumors, for instance, are associated with non-inherited mutations in the HER2 gene.

Mutations in these important types of genes may also occur in an individual’s germ cells – eggs or sperm. In these cases, a mutation can be passed on from one generation to the next. Such mutations – called germ line or heritable mutations – are often associated with hereditary cancer. This group includes genes such as BRCA1, a gene associated with hereditary breast and ovarian cancer.

In the relatively short history of cancer genetics, the following ten genes stand out prominently for their research and/or clinical significance.

APC

This tumor suppressor gene is named for a condition with which it is associated – familial adenomatous polyposis coli, a viciously premalignant disease with thousands of polyps contributing to inherited colorectal cancer in certain untreated gene carriers.

BRCA1

Mutations in this tumor suppressor gene, which encodes breast cancer type 1 susceptibility protein, are thought to be responsible for nearly half (45 percent) of inherited breast cancer (five percent of all breast cancer) cases and more than four in five cases of inherited breast and ovarian cancer.

A positive family history for breast cancer, which affects one in eight women during their lifetime, has been identified as major contributor to risk of development of the disease. This link is particularly striking for early- onset breast cancer.

BRCA1 mutation carriers are also four times as likely to develop colon cancer as their non-carrier counterparts; male carriers face a three-fold increased risk of prostate cancer.

BRCA2

This gene codes for a protein believed to play a role in the repair of DNA and/or exchange of DNA during cell division, or homologous recombination.

Believed to be responsible for some inherited breast cancer in women, BRCA2 is also linked with male breast cancer.

CDK4

Research suggests that cyclin-dependent kinase 4, the protein encoded by the CDK4 gene, is involved in regulating the natural circadian rhythm of cells (cell cycle). Mutations in this gene have been shown to be involved in formation of certain non-hereditary cancers.

CMM1

Mutations in the CMM1 gene are associated with familial malignant cutaneous melanoma.

HER2

Also referred to as NEU or ERBB2, this gene encodes for a protein which is essential component of a complex of molecules on the surface of cells called the neuregulin-receptor complex.

Associated with non-hereditary breast cancer, HER2 made headlines when biotechnology giant Genentech released its anti-cancer drug, Herceptin, which is used to treat patients whose breast tumors display an excess of HER2 protein.

MLH1

Believed to play a role in fixing erroneous DNA replication, the MLH1 gene is associated with familial hereditary nonpolyposis colon cancer (HNPCC). HNPCC is one of the most common genetic diseases in the western world, accounting for up to ten percent of all colon cancers.

MSH2

Named for a mutation first discovered in the bacterial counterpart of the human gene, the MSH2 gene is associated with a hereditary form of colon cancer (hereditary nonpolyposis colorectal cancer, HNPCC), which accounts for up to one in ten cases of the disease.

Alterations in the MSH2 and MLH1 genes are the most common mutations in families with multiple cases of HNPCC – together, they account for over 90 percent of mutations found in these individuals.

Like MLH1, the MSH2 protein is also involved in repairing errors during DNA replication.

p16

Also called CDKN2, protein 16 has been shown to slow the growth and division of normal cells. Errors in the gene, presumably resulting in unbridled growth and division, are involved in tumor formation in a wide range of tissues, including skin (resulting in melanoma).

p53

Normal protein 53 suppresses the development of many tumor types. It has been shown that to do so in a number of ways, including arresting the growth or even actually programming cells to die, depending on the physiological circumstances or cell type.

The protein is mutated or inactivated in about 60 percent of cancer cases; it is found in increased amounts in a wide variety of transformed cells.

For instance, variants in p53 cause a familial cancer syndrome called Li-fraumeni syndrome; in these families, the affected relatives develop a diverse set of malignancies including leukemia, breast carcinomas, sarcomas (bone tumors), and brain tumors at unusually early ages.

p53 mutations are also the cause of Barrett’s adenocarcinomas, a disease of the lower esophagus which develops as a complication in about one in ten patients with chronic untreated heartburn (gastroesophageal reflux disease).

Defects in p53 cause additional cancers, including head and neck squamous carcinomas.

Rb1

One of the most important examples of a gene associated with hereditary cancer, Rb1 was used to describe the “two-hit theory” for hereditary cancers, which holds that in individuals carrying predisposing germ line mutations, cancer may occur as a result of an additional, non-inherited mutation.

Deletion or alteration of this protein results in the childhood eye cancer, retinoblastoma. This disease represents about two percent of all childhood malignancies

Although most cases of retinoblastoma appear sporadically, about one in five are transmitted as a genetic trait which may or may not show clinical symptoms.

The Rb1 protein is believed to regulate the expression of other genes, acting as a tumor suppressor.

Related Websites:

Cancer.net

In the 1960s, the US Congress, under pressure from patient support groups, provided funds to the states to enable newborn screening programs using the Guthrie method. While all states took up this money and its associated mandate, the range of disorders included in these programs (generally part of the state’s public health department) and the quality of the service delivered varied.

There were also other problems. Phenylketonuria (PKU) was included in all states’ screening panels. But standards for defining what was “benign hyperphenlyalanemia,” an innocuous form of the disorder, and what levels of the amino acid phenylalanine indicated PKU were not yet developed.

Some children identified early in the evolution of these state screening efforts (before the implementation science was complete), who were at no risk for PKU, suffered significant developmental toxicity as a result of being put on a treatment in the absence of disease.

Also, in those states that included screening for hemoglobin S (a gene product associated with carriers and those affected with sickle cell anemia), proper education, consent and follow-up were not always offered.

As a result, identified HbS carriers who have no risk of developing sickle cell anemia were often ignorant of their unaffected state, and suffered stigmatization and discrimination. For this reason, some states passed laws prohibiting discrimination against carriers of genes linked to recessively inherited conditions. Other states suspended the screening.

Nonetheless, it is clear that despite implementation flaws which continue to require surveillance and improvement, the federal mandate and resulting state programs have averted suffering and illness that was indeed preventable.

Yet some of those gains are again being made more complex.

Since PKU screening became widespread, we have learned that women with PKU must be on a phenylalanine reduced diet prior to conception and during pregnancy. If they aren’t, their children are at risk for delayed development and mental retardation irrespective of their genotype for PKU genes.

But compliance with these arduous diets is not universal. Thus some cases of preventable PKU associated mental retardation are occurring in newborns who by the dint of their own genes would not be detected on state screening programs. The occurrence of their PKU is complicating assessment of the outcomes of the state screening programs.

I review this history as we consider recent reports of enhancements to prenatal testing including that reviewed by Maimon Cohen in this issue of GeneLetter. Clearly, technology that is accurate, more patient-friendly and less costly will allow detection of prenatal chromosome and specific gene anomalies in a larger and larger cohort. Offering universal prenatal screening with newer methods is within sight.

But before mandates for such programs exist and bureaucracies are erected for delivery and regulation, we may need to pause and consider what data we want beforehand, what issues in implementation and care will likely result and what is the best way to really make benefits universal.

Of primary importance, of course, is our continued commitment to research and care of those born with disorders that were missed by screening or to those who decline its offer.

Given our experiences with the newborn screening programs, I suspect that universal application of prenatal screening will restate the complexity of human genetics and life experience.

A third choice – carrier testing – is a way in which couples planning a pregnancy can assess their own risk of having a child with a particular genetic condition. This risk, determined by detecting the presence of disease-associated mutations in the parents, can help couples make informed decisions about having a family.

Carrier testing has enabled couples at high risk for conditions including Tay Sachs and sickle cell anemia to make such decisions for over 20 years.

Efforts are now underway to allow prospective parents to determine their risk of having a child with cystic fibrosis (CF), a genetic disease that most commonly affects the lungs and digestive system and often results in death before the age of 30.

Though CF affects less than one in 3,000 individuals in the US, the risk of having a child with CF is as high as one in 30 among certain ethnic groups. This risk is highest among Caucasians.

The genetics of cystic fibrosis

Learning more about the genetics and clinical attributes of CF has paved the way for a better understanding of couples’ risk of having a child with the disease.

To begin with, CF is an autosomal recessive disease. This means that carriers of a single CF-associated genetic mutation have no symptoms, while individuals who inherit two copies of a mutation – one received from each parent – may get sick.

For example, a child born to a carrier and a non-carrier of CF-related mutations faces almost no risk of developing CF. But a child born to two carriers faces up to a one in four chance of having the disease. (See figures, right.)

Yet how sick they can get varies greatly. And scientists have discovered over 900 disease-associated mutations in the CF-associated gene (though most are extremely rare), challenging the development of cost-effective screening. Further, the ethnic diversity in the US results in widely varied CF risks within the population.

The 1989 discovery of the CF-associated gene, formally called CFTR, gave hope that there would soon be ways of improving how the disease is diagnosed and treated. It also created the potential for new ways of assessing couples’ risk of having a child with the disease.

Professional medical genetics societies, including the American College of Medical Genetics (ACMG), are attempting to overcome these challenges to population carrier screening for CFTR mutations.

While publication of this group’s overall recommendations is still being finalized, last spring, the ACMG published a paper outlining standards and guidelines for the laboratory approach to the program. The paper deals primarily with a description of the mutation panel to be used and the target populations it covers.

Testing for 25 mutations

Over 900 disease-associated variations have been found in the CFTR gene. Of these, 25 variations are considered to be the major contributors to CF, as they occur in at least one in 1,000 people in the general population. This number includes mutations exhibiting high frequency in certain key ethnic groups, such as Ashkenazi Jews and African Americans.

The British health minister announced in April that their cystic fibrosis prenatal and newborn screening programs will be extended to all children born in the UK.

It is these 25 mutations that the ACMG committee recommends be included in CF carrier screening tests.

Why not include all 900 mutations in a CF carrier test?

While incorporating too few mutations would diminish the screening test’s sensitivity, including too many would add inordinately to the cost of the procedure – and it is fundamental that a test used for screening large numbers of people in the general population must be kept as inexpensive as possible.

A mutation which causes infertility but no CF

Part of the difficulty of approaching screening for a disease like CF is its clinical variability, with a minority of patients only mildly affected.

In fact, one of the most common genetic mutations, called R117H, can cause male infertility – but without the lung disease and other manifestations of classical CF.

Since the intent of the screening program is to identify couples at risk of having children with CF rather than this form of infertility – called bilateral absence of the vas deferens (CBAVD) – one might think that R117H should not be included in the test panel.

But in some cases, this mutation can also cause classical CF. For this reason, and because R117H is such a common mutation, the ACMG committee agreed it should not be left out of a standard CF screening panel. It was included with the proviso that if detected in an individual, that person must then be further tested so that appropriate genetic counseling regarding risk of CF vs. infertility can be offered.

What CF carrier screening can tell prospective parents

In those with no family history of CF, screening for the panel of mutations recommended by the ACMG committee would help identify:

• 80 percent of non-Jewish Caucasian carriers
• 97 percent of Ashkenazi Jewish carriers
• 69 percent of African American carriers
• 57 percent of Hispanic American carriers, and
• probably less than 10 percent of Asian American carriers.

These numbers are very important for test interpretation and genetic counseling because they reflect the proportions of carriers who will be missed by the standard screening panel simply because they have a rarer CFTR mutation that is not tested for.

Testing positive

Because CF is a recessive disease, which requires inheritance of mutations from both the mother and father to produce an affected child, the carrier screening results are most relevant in the context of the couple rather than the individual. Some laboratories go to the extreme of this concept and report out only the risk for that particular couple rather than individual test results, the aim being to avoid undue anxiety in those couples testing positive/negative.

The ACMG committee chose not to endorse this model because it felt that some of the benefits of widespread screening would be lost by withholding test result information from individuals identified as carriers. Instead, reporting of results to both the man and the woman was recommended, though it was left up to the physicians whether to test them simultaneously or serially (i.e., testing the second person only if the first person’s result is positive).

Testing negative

It is crucial that patients testing negative understand that their risk of having a child with CF is not zero, though it is substantially reduced. This can be a tricky concept to grasp, especially when dealing with a couple in which one member tests positive and the other tests negative. It is hoped that the primary care providers who order these tests will handle most of the results explanation, especially in those patients testing negative, which will be the vast majority.

However, in its discussions, the ACMG committee recognized that some more complex or unusual situations may require referral to a medical genetics professional, including positive/negative couples with residual concerns, patients with mutation combinations associated with CBAVD, and positive/positive couples who will then face decisions regarding prenatal diagnosis and possible pregnancy termination.

Testing a heterogeneous population

Because ethnic groups with the highest test sensitivity are also the populations with the highest incidence and carrier frequency of CF, screening should be offered uniformly to those groups.

However, given the extreme ethnic mixture of the US population, it would be a mistake to restrict screening only to Caucasians, and so the recommendations are carefully worded so that the test also “be made available” to all other patients.

This recommendation is intended to get around the difficult task of accurate ascertainment of ethnicity in mixed populations as a means to decide who should be tested. It should also preclude the need to set up ethnic-specific mutation panels.

Nonetheless, groups for whom the test has particularly low yield, such as Asians and Native Americans, are to be cautioned of that fact prior to embarking on testing.

What will happen next?

Needless to say, a genetic screening program of this magnitude, especially one performed at the DNA level, is unprecedented. Theoretically, the entire adult population of reproductive age in the US could be offered testing within the span of the next few years.

There are yet many uncertainties surrounding how such a program will play out:

• Will third-party payers such as health plans cover the cost?
• Will individuals with no family history or familiarity with CF be interested in being tested?
• Will primary care providers (predominantly obstetricians) be able to handle the complex information exchange inherent in test offering and reporting?
• Will DNA diagnostic laboratories be able to incorporate and validate the newly recommended list of 25 mutations?
• Will enough genetic counselors be available to take referrals of couples testing positive or positive/negative or coming up with unusual results such as those associated with CBAVD?

While the answers to many of these questions are unknown at this time, it is clear that the lessons we learn from the CF screening experience will set the stage for other large-scale genetic screening programs yet to come.