U.S. Department of Health and Human Services

Improving Genetic Testing for Cystic Fibrosis

​New research has greatly expanded knowledge of the speciic mutations capable of causing cystic fibrosis (CF). Previous landmark research established that CF is caused by mutations in a gene, CFTR, encoding a critical channel protein that enables the movement of chloride in and out of cells. Everyone has two copies of CFTR, one inherited from each parent. Those with CF have mutations that disrupt the function of both of their CFTR copies. People with a single CF‑causing 
mutation are often unaware of it, because their one functioning CFTR copy is enough to keep them healthy. Therefore, when considering having children, couples with CF in one of their families will often pursue genetic testing and counseling to determine the likelihood that one of their children will have the disease. If one copy of a known CF‑causing mutation 
is found through either prenatal or newborn screening, it may be uncertain whether a variant in the baby’s other copy of CFTR would lead to the development of CF. However, although research has identiied over 2,000 variations in the CFTR gene, only 23 of these were previously shown to be capable of causing CF. While most of the other known variants are likely to be harmless, sometimes genetic testing reveals a variant of unknown signiicance in potential parents, so genetic counselors cannot tell them with conidence what their odds are of conceiving a child with CF.

To better understand which CFTR mutations pose a risk of causing CF, researchers examined genetic records of almost 40,000 people diagnosed with CF— estimated to be more than half of the world population with the disease—for whom clinical measurements of CFTR chloride channel function had been recorded. Conining their analysis to 159 variants found in at least 0.01 percent (one in 10,000) of people with CF in the database they had assembled, the researchers 
tested how these CFTR mutations affect chloride transport when introduced into cells grown in the laboratory, and compared the results of those tests to clinical measurements of CF from their database. As a result, they were able to unambiguously identify 104 speciic CF‑causing CFTR variants in addition to those already known, for a total of 127. For the remaining 32 variants, the clinical data appeared inconsistent with CF, or the laboratory function tests indicated a variant that should function reasonably well, or both. This may at irst seem surprising, since a person with CF should not have a fully functional copy of CFTR, but in some cases a benign change may lie alongside a second CFTR mutation that does cause disease. Other variants may ordinarily be harmless, but might have the capacity to promote CF symptoms in people with other (unknown) genetic or environmental risk factors. Because men carrying a CF‑causing mutation must also have one normally functioning copy of the CFTR gene in order to be fertile, the researchers furthered their analysis by examining fathers of CF patients to see if any of them had one of the remaining 32 variants in one copy of their CFTR genes, along with a known disease‑causing variant in the other. Ten of the 32 variants were found to occur more frequently among the healthy fathers than among people with CF, indicating they do not normally cause disease, even 
when the other CFTR copy contains a disease‑causing mutation. Two more were ruled out as disease‑causing for other reasons. The remaining 20 variants were not more common among the healthy fathers and could not be ruled out in other ways, so it remains possible that they contribute to disease. As a result of these indings, CF genetic testing will be much more comprehensive, and provide greater certainty to parents concerned about their children’s chance of having the disease. Moreover, the laboratory models of the different CFTR variants created through this research may promote better understanding of the physiology of the CFTR chloride channel, and may one day lead to improvements in Cpatient care.

Sosnay PR, Siklosi KR, Van Goor F, et al. Deining the disease 
liability of variants in the cystic ibrosis transmembrane 
conductance regulator gene. Nat Genet 45: 1160‑1167, 2013.