A new study in The Journal of Molecular Diagnostics found that the genetic screening panel for cystic fibrosis (CF) — based on a list of 23 known mutations — is not adequate for diagnosing nonwhite populations.
CF is caused by mutations in the transmembrane conductance regulator (CFTR) gene. These mutations cause either a decreased CFTR protein production or a faulty function of the protein. CFTR is necessary for the normal function of cellular chloride channels, ensuring the epithelial surface of the lungs receives enough liquid. The defective secretion of surface liquid makes the lungs secrete a heavy mucus, blocking the airways.
CF is less common in nonwhite populations and frequently diagnosed at a later stage. CF in many nonwhite patients is not detected in the screening of newborns or other molecular tests, and these patients frequently do not receive a diagnosis until symptoms occur. This diagnostic and therapeutic delay can result in a more rapid deterioration of lung function.
To investigate which mutations were present in different ethnic groups, a team from Stanford University screened a large number of CF patients. They found that 90% of white and 83% of Native American patients carried a particular mutation (known as p.Phe508del). This mutation can be present in one or two copies. However, the team found that 40% of Asian, 38% of black, and 30% of Hispanic people did not carry this mutation at all.
In order to learn more about genetic mutations responsible for CF in nonwhite populations, researchers decided to sequence DNA from 140 nonwhite patients, a more detailed approach to detecting mutations with the capacity to also find novel variants.
The sequencing revealed that seven of the observed mutations had not been described previously. Also, the study found that rearrangements of larger sections of DNA – such as deletions and duplications – were more common in this group compared to white patients, finding six previously unknown DNA rearrangements in the nonwhite study sample.
Today, the technique for detecting DNA rearrangements – multiplex ligation-dependent probe amplification (MLPA) – is not included in the CF diagnostic procedure. Considering the results of the study, the team suggests MPLA be used in future diagnostics.
In a press release, Dr. Iris Schrijver, professor of pathology at the Stanford University School of Medicine, and director of the Stanford Molecular Genetic Pathology Service, said, “Our results confirm the widely held notion that the American College of Medical Genetics and Genomics list of 23 mutations that was specifically designed for carrier screening is inadequate for diagnostic testing, even though it is used widely.”
She also believes the results will be influential for clinical practice in CF diagnostics: “We think that this information can be used to optimize newborn screening programs, taking into account the ethnic composition of state populations, resulting in earlier diagnosis and intervention, timely clinical treatment, and enhanced prognosis. We believe it could propel equity in mutation detection for white and nonwhite CF patients.”