Caution advised in the use of CFTR modulator treatment for individuals harboring specific CFTR variants

Karen S Raraigh; Michelle H Lewis; Joseph M Collaco; Mary Corey; Christopher M Penland; Anne L Stephenson; Johanna M Rommens; Carlo Castellani; Garry R Cutting

doi:10.1016/j.jcf.2022.04.019

Caution advised in the use of CFTR modulator treatment for individuals harboring specific CFTR variants

J Cyst Fibros. 2022 Sep;21(5):856-860. doi: 10.1016/j.jcf.2022.04.019. Epub 2022 May 5.

Authors

Karen S Raraigh¹, Michelle H Lewis², Joseph M Collaco³, Mary Corey⁴, Christopher M Penland⁵, Anne L Stephenson⁶, Johanna M Rommens⁷, Carlo Castellani⁸, Garry R Cutting⁹

Affiliations

¹ McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States.
² Berman Institute of Bioethics, Johns Hopkins University, Baltimore, MD 21287, United States.
³ Eudowood Division of Pediatric Respiratory Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States.
⁴ Child Health Evaluative Sciences, The Hospital for Sick Children, Toronto, Ontario, Canada.
⁵ Cystic Fibrosis Foundation, Bethesda, MD 20814, United States.
⁶ Department of Respirology, Adult Cystic Fibrosis Program, St. Michael's Hospital, Toronto, Ontario, Canada.
⁷ Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
⁸ IRCCS Istituto Giannina Gaslini, Cystic Fibrosis Center, Genoa, Italy.
⁹ McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States. Electronic address: [email protected].

PMID: 35527187
DOI: 10.1016/j.jcf.2022.04.019

Abstract

In December 2020, the U.S. Food and Drug Administration (FDA) expanded the list of CFTR variants approved for treatment with CFTR modulators drugs from 39 to 183. Clinicians should be aware that individuals harboring certain variants approved for treatment may not respond to or benefit from this therapy. After review, the expert panel leading the CFTR2 project identified four categories of variants that may not result in a clinical response to modulator treatment: 15 variants assigned as non CF-causing; 45 variants of unknown significance; six variants known or suspected to cause mis-splicing as their primary defect rather than an amino acid substitution; and eight variants known to occur together in cis with another deleterious variant not expected to lead to CFTR protein (nonsense or frameshift). The potential risks and benefits of CFTR modulator therapy should be considered carefully for individuals harboring these variants.

Keywords: CFTR modulator; CFTR variant; Clinical outcomes; Non CF-causing variant; Variant interpretation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cystic Fibrosis Transmembrane Conductance Regulator* / genetics
Cystic Fibrosis Transmembrane Conductance Regulator* / metabolism
Cystic Fibrosis* / drug therapy
Cystic Fibrosis* / genetics
Cystic Fibrosis* / metabolism
Humans
Mutation
RNA Splicing

Substances

CFTR protein, human
Cystic Fibrosis Transmembrane Conductance Regulator