Which CFTR variants should laboratories test for? ACMG Releases Updated Carrier Screening Recommendations for Cystic Fibrosis

The American College of Medical Genetics and Genomics (ACMG) has released updated recommendations for CFTR carrier screening. “Updated Recommendations for CFTR Carrier Screening: Position Statement of the American Society of Medical Genetics and Genomics.” Pathogenic mutations in the CFTR gene can lead to cystic fibrosis (CF) and CF-related disorders. The newly updated ACMG CFTR variant list contains a set of 100 variants. *

The new CFTR variant list represents an updated minimum recommended variant set for CF carrier screening and replaces the previous group of 23 CFTR variants recommended by the ACMG. These revised recommendations apply to carrier screening. Carrier screening is a gene used to determine whether a person carries a genetic mutation associated with a condition that usually requires the presence of two pathogenic mutations to be phenotypically expressed. A type of inspection. These revised recommendations do not apply to her CFTR mutation testing for diagnosis or newborn screening. All other aspects of the updated 2020 ACMG CFTR Technical Standards continue to apply.

“When first developed, the previous variant list set the standard for CF carrier screening in the country. Now that databases and technology have evolved, it is time to raise the bar and set new minimum standards. This new recommended variant set should help ensure that detection of CFTR variants is more equitable among individuals representing different biogeographic ancestry,” said lead author Joshua of FACMG. Dr. L. Deignan said.

The current minimal variant set for CF carrier screening, for which the variant has been established as causative of CF, is the largest publicly available and most widely used population variation by harmonic sequencing. based on evidence that it exists in the Aggregated Genome Database (gnomAD), a collection of data. This 2023 version will incorporate only well-established and probable pathogenic variants to minimize concerns about individuals making reproductive decisions based on limited information. A conservative approach with frameworks was used. Future versions of this minimal variant set should re-evaluate the feasibility and usefulness of incorporating additional information from other population databases to be as biogeographically diverse as possible.

History of ACMG CFTR Career Screening Recommendations

ACMG has long been involved in addressing the challenges of CFTR carrier screening. In 2001, several professional organizations joined to recognize the importance and technological advances in making CF applicable to population-based carrier screening. However, technology and knowledge were not advanced enough to allow equitable application. Sequencing technology was also in the early stages of development. This limited screen was applied only to a small set of mutations most commonly characterized in Ashkenazi Jewish and Nordic populations. For this reason, the recommendation at the time was that screening should be ‘offered’ to Ashkenazi Jews and people of Nordic descent, and ‘made available’ to other groups.

The ACMG eventually recommended a set of 25 disease-causing variants, which was later reduced to 23.Represents a minimal variant set for pan-ethnic carrier screening in individuals with no family history of CF. This minimal mutation set (often referred to as ‘ACMG-23’) has not changed since then, despite dramatic advances in molecular diagnostic techniques and genetic knowledge.

Although the original recommendation allowed laboratories the option of providing an extended CFTR variant set beyond the recommended set, there was some controversy over the extended variant set at the time. However, several aspects have now evolved, including the widespread availability of cost-effective, high-throughput DNA sequencing and more standardized classification and interpretation of variants. In 2020, the ACMG issued an updated set of technical standards for CFTR variant testing, recommending that laboratories use targeted or comprehensive methods for testing, and at the time: We reconfirmed that the original set of 23 mutants was the minimum set for CF carrier screening.

In 2021, the ACMG will release a new Carrier Screening Clinical Practice Resource and continue to recommend that CFTR (now with many additional genes) testing be offered to all pregnant women, not just those planning a pregnancy. ing.

*Note: The authors discourage the use of the term “ACMG-100” to refer to the new minimal variant set.

with the American College of Medical Genetics and Genomics (ACMG)

ACMG Foundation

Founded in 1991, the American College of Medical Genetics and Genomics (ACMG) is a prominent authority in the field of medical genetics and genomics and the only national association dedicated to improving health through the practice of medical genetics and genomics. is a recognized medical professional organization. ACMG is the only professional medical association in the United States to represent all areas of the medical genetics field in a single organization, educating and resourced more than 2,600 clinical and laboratory geneticists, genetic counselors, and other health professionals. , offers a say. ACMG’s mission is to improve health through the clinical and laboratory practice of medical genetics, as well as advocacy, education, and clinical research, and to safely and effectively integrate genetics and genomics into all medicines and healthcare. It is about guiding people to do things that result in improved personal and health outcomes. public health. Genetics in Medicine and the new open access gold journal Genetics in Medicine Open are official journals of ACMG. ACMG’s website, www.acmg.net, provides resources such as policy statements, practice guidelines, and educational programs. The ACMG Genetic and Genomic Medicine Foundation works to advance ACMG’s educational and public health programs through charitable donations from companies, foundations, and individuals.

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