The American College of Medical Genetics and Genomics (ACMG) has increased the recommended number of pathogenic variants in CFTR gene that can cause cystic fibrosis (CF) from 23 to a set of 100 variants. The new list supersedes the previous smaller group of variants for carrier screening, a form of genetic testing that used to determine whether a person possesses a genetic variant associated with a disease that typically requires the presence of two pathogenic variants to manifest the disease.
The new recommendations do not apply to CFTR testing for diagnosis of CF or newborn screening and all other aspects of the updated 2020 ACMG CFTR technical standards still apply.
The updated CF carrier screening minimum variant set was developed based on evidence that a variant has been established as causative of CF and is included in the Genome Aggregation Database, commonly called gnomAD, which is the largest collection of publicly available population variants derived from harmonized sequencing data.
“When it was originally developed, the previous variant list set the standard for CF carrier screening in the country,” noted lead author Joshua Deignan, PhD. “Now that our databases and technologies have evolved, it was time to raise the bar and set a new minimum standard. This new recommended variant set should help ensure that CFTR variant detection is more equitable among individuals representing a variety of biogeographic ancestries.”
ACMG noted that it used a “conservative approach” to developing the 2023 version of the screening variant list and only incorporated well-established pathogenic and likely pathogenic variants. This approach was taken to lessen concerns that people who are screened would make reproductive decisions based on limited information. The College indicates that any future revisions to the minimum variant list would assess the potential of incorporating information from other population databases to better represent overall population diversity.
ACMG first began developing population-based carrier screening for CF in 2001, though the technology and knowledge of the disease had not advanced far enough at the time to allow for an equitable application of screening. For this reason, limited screening applied to only the small sets of variants that were characterized in the Ashkenazi Jewish an Northern European population groups. Early on it was recommended that screening should be offered to these two populations, and also “made available” to other groups.
The initial set of 25 variants was ultimately reduced to 23 as a representative minimum variant set for pan-ethnic carrier screening for people with no family history of CF. Often referred to as the “ACMG 23,” this recommended list of variants remained unchanged for nearly 20 years. Over that time the availability of affordable, high-throughput genetic testing, along with a more standardized approach to variant classification and interpretation have been developed.
As a result, in 2020, ACMG published updated technical standards for CFTR variant testing which provided recommendations that labs could use either targeted or comprehensive testing methods for screening and also reaffirmed the set of 23 variants. A year later, the College published a new carrier screening clinical practice resource which continued to recommended offering testing of CFTR (now along with many additional genes) to all pregnant individuals as well as those planning a pregnancy.