Cystic Fibrosis Genetics Breakthrough
August 26, 2013

Genetic Breakthrough In Predicting Cystic Fibrosis

Brett Smith for - Your Universe Online

With over 1,900 mutations in the genes responsible for cystic fibrosis (CF), separating the harmful alterations form the benign ones has been a long, arduous undertaking for geneticists.

In a new report published in Nature Genetics, researchers describe major progress in determining which mutations are which, increasing the number of recognized CF-causing mutations from 22 to 127. The new findings represent 95 percent of the significant variations found in the so-called cystic fibrosis transmembrane conductance regulator (CFTR) gene.

"Since not all mutations cause disease, sequencing the DNA in both copies of your CFTR gene and finding an abnormality in one wouldn't tell us if you are a carrier for CF unless we knew if that abnormality causes CF," said Dr. Garry Cutting, professor of pediatrics at the Johns Hopkins University School of Medicine and study co-author.

"Until this new work, more than a quarter of couples in which both partners were found to carry a CFTR mutation were left wondering if their mutations were going to affect their offspring,” he added. “Now it's down to 9 percent.”

When a child inherits two copies of a flawed CFTR gene, he or she will not be able to encode functioning CFTR proteins, which results in thicker mucous in the lungs and digestive system. While some treatments allow individuals with CF to cope with their condition, most will still die a premature death from respiratory disease.

If two carriers of the defective CFTR have a child, their offspring still has only a 1-in-4 chance of inheriting two bad copies of the gene. The severity of the disease will depend on which mutation variations are inherited by the child.

"There is very important information in each of these naturally occurring mutations that teaches us more and more about the disease," said co-author Dr. Patrick Sosnay, assistant professor of pulmonary and critical care medicine at Johns Hopkins. "We want to get to a point where we can say, 'This is your mutation, this is what it means and this is how you can treat it.'”

The new work is based on a genetic database containing information on almost 40,000 patients with CF. The geneticists looked at nearly 160 mutations that occurred in the database at a frequency of at least 0.01 percent. Each of these mutations was then examined to determine its clinical relevance and impact on the function of the CFTR protein.

Of the identified mutations, 127 were shown to cause CF if they are inherited with another CF-causing mutation. Over 100 are newly identified.

"This new information will give clear answers to tens of thousands of people each year: those being screened as potential carriers, parents of infants who have been flagged during newborn screening and children and adults who are looking for a diagnosis," said co-author Karen Siklosi, a genetic counselor from Johns Hopkins.

"It's our hope that the functional data we have provided for these other mutations can be used to find additional drugs for specific CF mutations," Cutting said. "We also believe that the process we followed in this study can be repeated to help characterize many other rare genetic disorders."