Determining Risk for Cystic Fibrosis

Pregnant women face a growing number of options to detect, prevent or avoid disease in their expected children. These options include testing a fetus during pregnancy (prenatal testing) and checking for disease in the child shortly after birth (newborn testing).

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.

charts for cystic fibrosis risk genetics

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.

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