Carriers of single pathogenic variants of the CFTR (cystic fibrosis transmembrane conductance regulator) gene have a higher risk of severe COVID-19 and 14-day death. The machine learning post-Mendelian model pinpointed CFTR as a bidirectional modulator of COVID-19 outcomes. Here, we demonstrate that the rare complex allele [G576V;R668C] is associated with a milder disease via a gain-of-function mechanism. Conversely, CFTR ultra-rare alleles with reduced function are associated with disease severity either alone (dominant disorder) or with another hypomorphic allele in the second chromosome (recessive disorder) with a global residual CFTR activity between 50 to 91%. Furthermore, we characterized novel CFTR complex alleles, including [A238V;F508del], [R74W;D1270N;V201M], [I1027T;F508del], [I506V;D1168G], and simple alleles, including R347C, F1052V, Y625N, I328V, K68E, A309D, A252T, G542*, V562I, R1066H, I506V, I807M, which lead to a reduced CFTR function and thus, to more severe COVID-19. In conclusion, CFTR genetic analysis is an important tool in identifying patients at risk of severe COVID-19.
Baldassarri, M., Zguro, K., Tomati, V., Pastorino, C., Fava, F., Croci, S., et al. (2022). Gain- and Loss-of-Function CFTR Alleles Are Associated with COVID-19 Clinical Outcomes. CELLS, 11(24), 4096 [10.3390/cells11244096].
Gain- and Loss-of-Function CFTR Alleles Are Associated with COVID-19 Clinical Outcomes
Baldassarri, Margherita;Zguro, Kristina;Fava, Francesca;Croci, Susanna;Bruttini, Mirella;Renieri, Alessandra;Fallerini, Chiara;Francesca MariMembro del Collaboration Group
;Sergio DagaMembro del Collaboration Group
;Ilaria MeloniMembro del Collaboration Group
;Diana AlaverdianMembro del Collaboration Group
;Giada BeligniMembro del Collaboration Group
;Debora MaffeoMembro del Collaboration Group
;Elena PasquinelliMembro del Collaboration Group
;Loredaria AdamoMembro del Collaboration Group
;Viola Bianca SerioMembro del Collaboration Group
;Enrica AntoliniMembro del Collaboration Group
;Giulia BrunelliMembro del Collaboration Group
;Caterina Lo RizzoMembro del Collaboration Group
;Anna Maria PintoMembro del Collaboration Group
;Francesca ArianiMembro del Collaboration Group
;Francesca MontagnaniMembro del Collaboration Group
;Mario TumbarelloMembro del Collaboration Group
;Massimiliano Fabbiani;Elena BargagliMembro del Collaboration Group
;Laura BergantiniMembro del Collaboration Group
;Miriana D'AlessandroMembro del Collaboration Group
;Paolo CameliMembro del Collaboration Group
;David BennettMembro del Collaboration Group
;Federico AneddaMembro del Collaboration Group
;Simona MarcantonioMembro del Collaboration Group
;Sabino ScollettaMembro del Collaboration Group
;Federico FranchiMembro del Collaboration Group
;Maria Antonietta MazzeiMembro del Collaboration Group
;Susanna GuerriniMembro del Collaboration Group
;Edoardo ConticiniMembro del Collaboration Group
;Luca CantariniMembro del Collaboration Group
;Bruno FredianiMembro del Collaboration Group
;Serafina ValenteMembro del Collaboration Group
;Alessia GiorliMembro del Collaboration Group
;Lorenzo SalerniMembro del Collaboration Group
;Marco GoriMembro del Collaboration Group
;Roberto LeonciniMembro del Collaboration Group
;
2022-01-01
Abstract
Carriers of single pathogenic variants of the CFTR (cystic fibrosis transmembrane conductance regulator) gene have a higher risk of severe COVID-19 and 14-day death. The machine learning post-Mendelian model pinpointed CFTR as a bidirectional modulator of COVID-19 outcomes. Here, we demonstrate that the rare complex allele [G576V;R668C] is associated with a milder disease via a gain-of-function mechanism. Conversely, CFTR ultra-rare alleles with reduced function are associated with disease severity either alone (dominant disorder) or with another hypomorphic allele in the second chromosome (recessive disorder) with a global residual CFTR activity between 50 to 91%. Furthermore, we characterized novel CFTR complex alleles, including [A238V;F508del], [R74W;D1270N;V201M], [I1027T;F508del], [I506V;D1168G], and simple alleles, including R347C, F1052V, Y625N, I328V, K68E, A309D, A252T, G542*, V562I, R1066H, I506V, I807M, which lead to a reduced CFTR function and thus, to more severe COVID-19. In conclusion, CFTR genetic analysis is an important tool in identifying patients at risk of severe COVID-19.File | Dimensione | Formato | |
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https://hdl.handle.net/11365/1223537