Full Gene Sequencing Might Detect CF Mutations in Babies of Any Ethnicity, Study Says

Babies with a mutation known to cause cystic fibrosis (CF) and a second mutation called the 5T allele should be screened for additional mutations to predict their risk of developing CF later in life, according to a study by researchers at Children’s Hospital Los Angeles (CHLA), Brigham and Women’s Hospital (BWH), and the California Department of Public Health.

These full genetic screens could allow an early diagnosis and treatment, likely easing the disease’s impact over the long term.

The study, “Phenotypes of California CF Newborn Screen-Positive Children with CFTR 5T Allele by TG Repeat Length,” was published in the journal Genetic Testing and Molecular Biomarkers.

Researchers evaluated the effect of a variant called the 5T allele in the CF Transmembrane Conductance Regulator (CFTR) gene, the defective gene in CF. They followed infants who, through CF newborn screening, were found to have one copy of a severe CF causing mutation, and one 5T allele, over a period of eight years.

They found that the length of the TG repeat region in the DNA situated just next to the 5T allele could influence whether the babies developed CF or not. Babies who had 11 TG repeats and one severe CF causing mutation did not develop CF during the eight years in which they were followed. However, 6 percent of the babies who had 12 TG repeats alongside the severe mutation did develop CF, and a striking 40 percent of those babies with 13 TG repeats also developed the disease within eight years.

The researchers concluded that the length of the TG repeat in the 5T allele could predict whether or not a baby will develop CF.

Although newborns are screened for CF in all 50 states in the U.S., the screen most in use is not able to detect these genetic variants. In most states, the screen consists of a first measure of the amount of a pancreatic enzyme called immunoreactive trypsinogen, which is elevated in CF, and those babies whose enzyme levels are very high go through a second screen, which looks at a selected list of 23 to 140 CFTR mutations known to cause the disease.

This genetic list, however, is based on the most prevalent mutations among severely affected individuals, most of whom are Caucasians. Therefore, screens using that list may not detect mutations in other parts of the gene that may exist in people of other ethnic origins, such as African-American and Hispanics. For these infants, CF may not be tackled until it is evident later in life, when irreversible lung damage has already occurred.

One solution, the researchers suggest, would be to sequence the whole CFTR gene as it is done in the state of California, where upon the detection of one CFTR mutation, the blood sample is sent for full CFTR gene sequencing.

“Having CFTR-DNA sequencing as part of a newborn screening model can unveil the full spectrum of this disorder, through early detection of mild to severe cases in an ethnically diverse population,” Dr. Danieli Salinas, the first author of the study, said in a press release. “Studies like this are important to better guide providers and families, by determining which individuals with which mutation combinations should be clinically monitored.”