The American College of Medical Genetics and Genomics (ACMG) has quadrupled the number of CFTR variants it recommends for cystic fibrosis (CF) carrier screening.
Pathogenic variants in the CFTR gene cause cystic fibrosis. Being a carrier of a variant has no impact on health but creates a risk that the person could have a child with CF. If both parents are carriers, there is a 25% chance that their child will have CF. Screening can identify people who carry the variants and enable them to make informed decisions about having children and prenatal testing.
In 2001, ACMG recommended screening for a set of 25 disease-causing variants. The list was reduced to 23 in 2004, when ACMG eliminated one variant because it was much rarer than previously thought, and another because it was found to be benign. Since then, the core panel has included 23 variants.
ACMG has now reconsidered its core panel in light of the widespread availability of cost-effective, high-throughput DNA sequencing and more standardized variant classification and interpretation. The new ACMG CFTR list, which was published on Tuesday in Genetics in Medicine, has a set of 100 variants.
Joshua Deignan, the lead author of the paper and associate clinical professor of pathology and laboratory medicine at the University of California, Los Angeles, outlined the thinking behind the new list in a statement.
“When it was originally developed, the previous variant list set the standard for CF carrier screening in the country. Now that our databases and technologies have evolved, it was time to raise the bar and set a new minimum standard,” Deignan said. “This new recommended variant set should help ensure that CFTR variant detection is more equitable among individuals representing a variety of biogeographic ancestries.”
Assessments of the effectiveness of screening for the original 23 variants found that, while the panel has an almost 90% detection rate in white or Ashkenazi Jewish populations, it does not perform equally in all races. The findings spurred interest in adding race- or region-specific alleles to the original 23 variants.
Deignan and his collaborators included variants that have been established as CF-causing and are present in the Genome Aggregation Database, the largest publicly available collection of population variation from harmonized sequencing data. The collaborators took a conservative approach to picking variants, focusing on well-established pathogenic and likely pathogenic variants, to minimize concerns that people would “make reproductive decisions based on limited information.”