A breakthrough newborn screening (NBS) strategy in California to help diagnose cystic fibrosis (CF) has led to some key insights about CF and cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations, according to a paper published in the journal Pediatrics. But given some of the method’s shortcomings, it is premature to conclude that it will be immediately replacing more traditional approaches. 

CFTR panels used in the DNA component of the immunoreactive trypsinogen (IRT) two-tier method “are very important in identifying the risk for CF. If two CF-causing mutations are detected, it’s a presumptive diagnosis of CF,” Philip Farrell, MD, PhD, a co-author of the paper told CLN Stat. Farrell is a professor of pediatrics and population health sciences at the University of Wisconsin School of Medicine and Public Health. 

Screening implementation for CF in newborns has been a regional affair in the United States and has incorporated a number of strategies, although all them begin by measuring IRT and conclude by conducting a sweat chloride test.

California decided to implement a novel screening approach that involved a CFTR sequencing method, the detection of 2 mutations to designate positive screening, and a recommended sweat chloride test. “This NBS method relies heavily on the interpretation of CFTR variants, as not every CFTR genetic change will result in CF,” the study authors noted. 

Requiring detection of two CFTR mutations in order to proceed with a sweat test is what separated the California approach from other states, but also made it controversial, Farrell explained. In other states, babies with a high IRT and either a single CFTR mutation or two mutations are recommended for a sweat test.

The study’s ability to screen an ethnically diverse, large number of newborns, coupled with a strong surveillance component, counted as some of its greatest strengths. California’s approach placed an emphasis on minority populations, particularly its Hispanic-Latino population. “They’re the first state to really say, ‘We’ve got to concentrate on this minority population,’” Farrell said. 

In 5 years of data analysis, California’s NB CF method made a number of important discoveries, such as “identification of CFTR variants with disease liability and the overall influence of gene sequencing, including its contribution to relatively high positive predictive value, and the impact of their multistep system on diagnostic outcomes,” the article’s authors stated. 

In Farrell’s view, California surpassed many other states in its ability to plan and identify goals in advance. 

However, certain limitations of this method led to some troubling outcomes. As an example, the CFTR scanning and sequencing methods were detecting mutations that didn’t have any clinical significance or, in other words, didn’t cause CF, Farrell said. 

Another problem was that the approach had lower-than-optimal sensitivity than other two-tier protocols that use IRT/DNA methods. “The sensitivity of the multistep algorithm at 92% is less than ideal, and the identification of 4 deaths that were ‘likely CF related’ is alarming, especially in view of the very low mortality of CF after early diagnosis,” the study authors noted.

And although genetic counseling was offered as part of routine practice, rarely was it delivered. “We believe that every family who has a disease-causing CFTR mutation detected should have some genetic counseling,” and that didn’t happen routinely, Farrell said. 

The results suggest that innovation may not trump traditional methods. “California’s method was very innovative and had very impressive, sophisticated technology, but there is no reason to believe that it is any better than the traditional, straightforward IRT/DNA methods used in the United States over the last ten years,” Farrell offered. 

Despite its shortcomings, California’s unique NBS approach for CF did achieve the highest known positive predictive value for any screening method, which enabled the state to meet its objective on reducing the impact of false positive results. “Its evaluation of outcomes is second to none. The state did really outstanding work in evaluating what happened after the screening,” Farrell observed. 

California’s approach may in some ways be premature, but it signals the wave of the future, Farrell indicated. It means that public health labs doing newborn screening “should be preparing themselves for more molecular tests, including gene sequencing. We’re in an era of rapid development of next generation sequencing methods. I think labs need to recognize more of this is coming.”