NEW YORK – The US Cystic Fibrosis Foundation (CFF) has released new guidelines for screening newborns for cystic fibrosis (CF)-causing gene variants.
The recommendations, published on Wednesday in the International Journal of Neonatal Screening, aim to make newborn CF screening more equitable by expanding the number of variants tested for, including sequencing of the CFTR gene in cases where panels don't include all variants, and changing cutoff values for biochemical tests.
CF is a genetic disorder in which the body produces an abnormally thick and sticky form of mucus that impedes breathing and digestion. Although over 1,000 CF-causing gene variants in the CFTR gene have been recognized, the most common one –– called F508del –– is found predominantly in people of European ancestry. F508del, along with several other common variants, is significantly rarer in people of other ancestries, though, leading to disparities in obtaining accurate diagnoses and treatments.
Variants currently included in state screening panels vary widely, ranging from only F508del to nearly every known variant. Although the American College of Medical Genetics and Genomics (ACMG) recommends a panel that covers the 23 most frequent disease-related CFTR mutations, the new guidelines recommend including all known CF-causing variants as a screening standard.
A standard CF screening test consists of measuring levels of immunoreactive trypsinogen (IRT), a protein made in the pancreas that accumulates to high levels in the blood of CF patients. Current IRT assays typically involve a fixed cutoff for determining whether an individual's levels are high.
The new guidelines, however, note that IRT can also be elevated for other reasons, including ambient temperature, nutritional needs, and ancestry. Furthermore, infants with CF frequently present with IRT values below the cutoff. They therefore recommend that the fixed cutoff be replaced by a floating cutoff that can be adjusted on the basis of other clinical factors. The guideline authors noted, however, that a floating cutoff will not adjust for certain infant-specific circumstances, such as birth stress.
The CFF also recommended using a "very high" IRT referral strategy (VHIRT) in newborn screening programs whose variant panels do not include all CF-relevant CFTR mutations, or whose variant panel does not achieve a minimum 95 percent sensitivity across all ancestry groups within that state. Evidence from state health department reports and academic studies, the CFF researchers wrote, showed that VHIRT identified between 5 and 8 percent of infants with CF that would otherwise have been missed. They also found that in New York, 75 percent of CF cases identified through VHIRT were of infants from non-European backgrounds.
In addition to screening for all CFTR variants, the CFF recommended twice-weekly screening to facilitate earlier diagnosis. Newborn screening programs should also consider evaluating other time-sensitive factors, such as second specimen collections, sample shipping and processing, batch size, and staffing, which would support the more frequent screening.
The CFF also recommended including CFTR sequencing following IRT and CFTR variant panel testing, noting that states where this is already the case, such as California, have reduced false positive results and improved CF detection in genetically heterogeneous populations.
Finally, the CFF advised that both a patient's primary care physician and a CF specialist be notified of any abnormal newborn screening results. The authors noted that newborn screening programs vary across the US in terms of notification requirements. Although both types of doctors are currently notified in some cases, all too often only one or the other is notified. Making dual notification the standard, the CFF wrote, increases the likelihood of correctly assessing an infant's CF risk and that accurate information about CF is shared with families.
Particularly with respect to infants from non-European backgrounds, the CFF noted that there exists a "misguided perception" within the medical field that CF only affects non-Hispanic White infants, leading to delayed referrals following positive newborn screening findings.
"It is crucial for programs to engage in continued process improvement to ensure that all infants with CF benefit from timely and accurate identification," the authors wrote.