Study Identifies Clinical Relevance of CFTR Mutations in Cystic Fibrosis Development

To date, 2,007 mutations have been identified in the CFTR gene, but their contribution for cystic fibrosis (CF) development has not been defined for the majority of these mutations. Now, researchers at Children’s Hospital Los Angeles and the Genetic Disease Screening Program of the California Department of Public Health have characterized some of these genetic mutations and shed some light on their health impact.

The finding were published in the journal PLOS One in a study titled “Benign and Deleterious Cystic Fibrosis Transmembrane Conductance Regulator Mutations Identified by Sequencing in Positive Cystic Fibrosis Newborn Screen Children from California.”

Cystic fibrosis is a disease caused by mutations in the CFTR gene that affects approximately 2,500 new babies every year in the U.S. alone. Because early diagnosis and treatment have proven beneficial, mandatory newborn screening for cystic fibrosis is performed throughout the U.S., as well as in other countries, which includes DNA analysis to detect CFTR mutations.

However, given the considerable amount of known CFTR mutations, and the fact that only a few of them have been studied, it is difficult to understand if having a given CFTR mutation is predictive of developing the disease.

In fact, of the 2,007 known mutations, only 202 have been categorized as part of the CFTR2 project, including 178 that cause the disease, 12 that are non CF-causing mutations, and 12 of varying clinical consequence (VCC), leaving more than 1,800 mutations with unknown contribution to cystic fibrosis.

Kalydeco and Orkambi are two drugs developed to treat cystic fibrosis patients with specific known mutations, effectively treating approximately 75 percent of the patients with this disease.

“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,” said first author Danieli B. Salinas, M.D., of CHLA’s Division of Pulmonology, in a press release. “If we know early, we can make a significant difference in the life of a child with CF.”

In California, newborn screening includes CFTR sequencing, which allows scientists to explore the clinical relevance of mutations of varying or unknown clinical significance in the development of the disease. The research team conducted a retrospective study that examined newborns who screened positive for CFTR mutations, and who were followed for two to six years to see if they developed cystic fibrosis.

Newborns who screened positive were divided into three genotype subgroups: those with two cystic fibrosis-causing mutations, those with one mutation of VCC, and those with one Unknown mutation.

“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,” Salinas explained.

The results showed that newborns with two CF-causing mutations had a classical cystic fibrosis phenotype, and that a small proportion of VCC (5 percent) and Unknown (11 percent) also met the diagnostic criteria for cystic fibrosis.

Investigators found that children carrying the Unknown mutations 2215insG with D836Y, and T1036N had an early and classical CF phenotype. Other carrying 1525-42G>A, L320V, L967S, R170H, and 296+28A>G, however, had a benign clinical presentation, suggesting that these are non-cystic fibrosis causing mutations.