Sorting Out Cystic Fibrosis’ Uncategorized Genetic Mutations

A new study screened thousands of children in California with CF and uncovered which mutations are disease-causing and which are benign. [NIH]

Cystic fibrosis (CF) is a progressive, inherited, autosomal recessive disease that preferentially affects the lungs, causing persistent lung infections and limiting the ability to breathe over time. Although there have been more than 2000 different genetic mutations reportedly associated with CF, only 200 of them have been categorized—leaving behind a genetic milieu of about 1800 others for geneticists to resolve.

Now, a new study led by researchers at Children's Hospital Los Angeles (CHLA) and the Genetic Disease Screening Program of the California Department of Public Health may have just shed light on some of those genetic mutations and the impact for those who carry them. In the current analysis, children in California were assessed and screened between 2007 and 2011 and followed for 2 to 6 years.

According to the Cystic Fibrosis Foundation, in the United States alone about 12 million people are genetic carriers, and every year 2500 babies are born with the disease, which occurs when a child inherits two defective genes. CF causes a thick, buildup of mucus in the lungs, clogging the airways and trapping bacteria. This leads to infections, extensive lung damage, and eventually respiratory failure. Moreover, in the pancreas, the mucus prevents the release of digestive enzymes that allow the body to break down food and absorb vital nutrients. 

The benefits of early diagnosis and nutritional treatment for CF patients cannot be overstated, which is why mandatory newborn screening for CF is conducted throughout the U.S. and other countries. However, with the multitude of mutations identified to date in the CF transmembrane conductance regulator (CFTR) gene—and contributions to the disease undefined for most—physicians and researchers are not always sure to how to interpret screening results.

In July of 2007, California began newborn screening for CF, establishing a three-step model that was employed and included CFTR DNA sequencing to explore the full range of the CF spectrum and help scientists to understand the various mutations and their clinical significance. The three genotypic groups the investigators created for this study include those with two CF-causing mutations, those with one mutation of varying clinic consequences (VCC), and those with one mutation of unknown liability (unknown).

“Our study focused on children who have one CF-causing mutation and a second of varying or unknown clinical consequences, and followed them over time to see which mutations eventually resulted in disease symptoms and those that resulted in no disease,” explained lead study author Danieli Salinas, M.D., a pediatric pulmonologist in CHLA's Division of Pulmonology.

The findings from this study were published recently in PLoS ONE in an article entitled “Benign and Deleterious Cystic Fibrosis Transmembrane Conductance Regulator Mutations Identified by Sequencing in Positive Cystic Fibrosis Newborn Screen Children from California.”

Interestingly, while most infants with VCC and unknown CFTR mutations did not meet diagnostic criteria for CF, a small proportion did. The research team found that about 5% of VCC and 11% of unknown developed CF. Children carrying unknown mutations were determined to be at risk, whereas other mutations were benign.

Specifically, the study results showed that children carrying previously unclassified mutations 2215insG with D836Y and T1036N had early and classical CF characteristics; others carrying 1525-42G>A, L320V, L967S, R170H, and 296+28A>G were benign, suggesting that these are non-CF-causing mutations.

“It is vital to determine and identify these mutations, because if we know the specific genetic mutation that causes the disease, we can possibly correct it,” Dr. Salinas noted. Adding that nine different mutations, or about 4% of the population with CF, can be treated with a drug called Kalydeco, while another drug, Orkambi, effectively treats about 70% of CF patients—each by targeting a specific, known genetic mutation. “If we know early, we can make a significant difference in the life of a child with CF.”

Alternatively, if parents know that the mutation has been found to be benign, meaning the infant has been screened with a positive genetic profile for CF, but not the disease, it saves them considerable worry, and they know their baby no longer has to be seen for follow-up tests.