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#10\/2021"],"award-info":[{"award-number":["FFC #10\/2021"]}]},{"name":"Italian Ministry of Health","award":["PEDEMO20G0"],"award-info":[{"award-number":["PEDEMO20G0"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/cells11244096","type":"journal-article","created":{"date-parts":[[2022,12,19]],"date-time":"2022-12-19T07:27:30Z","timestamp":1671434850000},"page":"4096","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Gain- and Loss-of-Function CFTR Alleles Are Associated with COVID-19 Clinical Outcomes"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0391-1980","authenticated-orcid":false,"given":"Margherita","family":"Baldassarri","sequence":"first","affiliation":[{"name":"Medical Genetics, University of Siena, 53100 Siena, Italy"},{"name":"Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, 53100 Siena, 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