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

      Highlights

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      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.

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      References

        • Sosnay P.R.
        • Siklosi K.R.
        • Van Goor F.
        • Kaniecki K.
        • Yu H.
        • Sharma N.
        • Ramalho A.S.
        • Amaral M.D.
        • Dorfman R.
        • Zielenski J.
        • et al.
        Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene.
        Nat Genet. 2013; 45: 1160-1167
        • Dagenais R.V.E.
        • Su V.C.H.
        • Quon B.S.
        Real-World Safety of CFTR Modulators in the Treatment of Cystic Fibrosis: A Systematic Review.
        J Clin Med. 2020; 10: 23
        • Burgel P.R.
        • Munck A.
        • Durieu I.
        • Chiron R.
        • Mely L.
        • Prevotat A.
        • Murris-Espin M.
        • Porzio M.
        • Abely M.
        • Reix P.
        • et al.
        Real-Life Safety and Effectiveness of Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis.
        Am J Respir Crit Care Med. 2020; 201: 188-197
        • Hubert D.
        • Chiron R.
        • Camara B.
        • Grenet D.
        • Prévotat A.
        • Bassinet L.
        • Dominique S.
        • Rault G.
        • Macey J.
        • Honoré I.
        • et al.
        Real-life initiation of lumacaftor/ivacaftor combination in adults with cystic fibrosis homozygous for the Phe508del CFTR mutation and severe lung disease.
        J Cyst Fibros. 2017; 16: 388-391
        • Sergeev V.
        • Chou F.Y.
        • Lam G.Y.
        • Hamilton C.M.
        • Wilcox P.G.
        • Quon B.S.
        The Extrapulmonary Effects of Cystic Fibrosis Transmembrane Conductance Regulator Modulators in Cystic Fibrosis.
        Ann Am Thorac Soc. 2020; 17: 147-154
        • Dryden C.
        • Wilkinson J.
        • Young D.
        • Brooker R.J.
        The impact of 12 months treatment with ivacaftor on Scottish paediatric patients with cystic fibrosis with the G551D mutation: a review.
        Arch Dis Child. 2018; 103: 68-70
        • Hubert D.
        • Dehillotte C.
        • Munck A.
        • David V.
        • Baek J.
        • Mely L.
        • Dominique S.
        • Ramel S.
        • Danner-Boucher I.
        • Lefeuvre S.
        • et al.
        Retrospective observational study of French patients with cystic fibrosis and a Gly551Asp-CFTR mutation after 1 and 2years of treatment with ivacaftor in a real-world setting.
        J Cyst Fibros. 2018; 17: 89-95
        • McKinzie C.J.
        • Goralski J.L.
        • Noah T.L.
        • Retsch-Bogart G.Z.
        • Prieur M.B.
        Worsening anxiety and depression after initiation of lumacaftor/ivacaftor combination therapy in adolescent females with cystic fibrosis.
        J Cyst Fibros. 2017; 16: 525-527
        • Salvatore D.
        • Pepe A.
        • Carnovale V.
        • Majo F.
        • Padoan R.
        • Quattrucci S.
        • Salvatore M.
        • Taruscio D.
        • Amato A.
        • Ferrari G.
        • Campagna G.
        Elexacaftor/tezacaftor/ivacaftor for CFTR variants giving rise to diagnostic uncertainty: Personalised medicine or over-medicalisation?.
        J Cyst Fibros. 2021; ([online ahead of print; doi])https://doi.org/10.1016/j.jcf.2021.09.011
        • Clain J.
        • Lehmann-Che J.
        • Girodon E.
        • Lipecka J.
        • Edelman A.
        • Goossens M.
        • Fanen P.
        A neutral variant involved in a complex CFTR allele contributes to a severe cystic fibrosis phenotype.
        Human Genetics. 2005; 116: 454-460
        • Cotten J.F.
        • Ostedgaard L.S.
        • Carson M.R.
        • Welsh M.J.
        Effect of cystic fibrosis-associated mutations in the fourth intracellular loop of cystic fibrosis transmembrane conductance regulator.
        J Biol. Chem. 1996; 271: 21279-21284
        • Yoshimura K.
        • Wakazono Y.
        • Iizuka S.
        • Morokawa N.
        • Tada H.
        • Eto Y.
        A Japanese patient homozygous for the H1085R mutation in the CFTR gene presents with a severe form of cystic fibrosis.
        Clin Genet. 1999; 56: 173-175
        • Yu H.
        • Burton B.
        • Huang C.J.
        • Worley J.
        • Cao D.
        • Johnson Jr., J.P.
        • Urrutia A.
        • Joubran J.
        • Seepersaud S.
        • Sussky K.
        • et al.
        Ivacaftor potentiation of multiple CFTR channels with gating mutations.
        J. Cyst. Fibros. 2012; 11: 237-245
        • De Boeck K.
        • Munck A.
        • Walker S.
        • Faro A.
        • Hiatt P.
        • Gilmartin G.
        • Higgins M.
        Efficacy and safety of ivacaftor in patients with cystic fibrosis and a non-G551D gating mutation.
        J. Cyst. Fibros. 2014; 13: 674-680
        • Fidler M.C.
        • Buckley A.
        • Sullivan J.C.
        • Statia M.
        • Boj S.F.
        • Vries R.G.J.
        • Munck A.
        • Higgins M.
        • Moretto Zita M.
        • Negulescu P.
        • et al.
        G970R-CFTR Mutation (c.2908G>C) Results Predominantly in a Splicing Defect.
        Clin Transl Sci. 2021; 14: 656-663