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Most of the 7000 rare diseases described to date have a genetic component, typically highly penetrant. However, this vast spectrum of genetic variability remains yet unexplored with respect to possible interactions with COVID-19. Here, a mathematical mechanistic model of the COVID-19 molecular disease mechanism has been used to detect potential interactions between rare disease genes and the COVID-19 infection process and downstream consequences. Out of the 2518 disease genes analyzed, causative of 3854 rare diseases, a total of 254 genes have a direct effect on the COVID-19 molecular disease mechanism and 207 have an indirect effect revealed by a significant strong correlation. This remarkable potential of interaction occurs for &amp;gt;300 rare diseases. Mechanistic modeling of COVID-19 disease map has allowed a holistic systematic analysis of the potential interactions between the loss of function in known rare disease genes and the pathological consequences of COVID-19 infection. The results identify links between disease genes and COVID-19 hallmarks and demonstrate the usefulness of the proposed approach for future preventive measures in some rare diseases.<\/jats:p>","DOI":"10.1093\/hmg\/ddac007","type":"journal-article","created":{"date-parts":[[2022,1,10]],"date-time":"2022-01-10T20:10:47Z","timestamp":1641845447000},"page":"2078-2089","source":"Crossref","is-referenced-by-count":2,"title":["Discovering potential interactions between rare diseases and COVID-19 by combining mechanistic models of viral infection with statistical modeling"],"prefix":"10.1093","volume":"31","author":[{"given":"Macarena","family":"L\u00f3pez-S\u00e1nchez","sequence":"first","affiliation":[{"name":"Clinical Bioinformatics Area, Fundaci\u00f3n Progreso y Salud (FPS), CDCA, Hospital Virgen del Rocio , Sevilla 41013, Spain"},{"name":"Computational Systems Medicine, Institute of Biomedicine of Seville (IBIS), Hospital Virgen del Rocio , Sevilla 41013, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9598-6965","authenticated-orcid":false,"given":"Carlos","family":"Loucera","sequence":"additional","affiliation":[{"name":"Clinical Bioinformatics Area, Fundaci\u00f3n Progreso y Salud (FPS), CDCA, Hospital Virgen del Rocio , Sevilla 41013, Spain"},{"name":"Computational Systems Medicine, Institute of Biomedicine of Seville (IBIS), Hospital Virgen del Rocio , Sevilla 41013, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda","family":"Pe\u00f1a-Chilet","sequence":"additional","affiliation":[{"name":"Clinical Bioinformatics Area, Fundaci\u00f3n Progreso y Salud (FPS), CDCA, Hospital Virgen del Rocio , Sevilla 41013, Spain"},{"name":"Computational Systems Medicine, Institute of Biomedicine of Seville (IBIS), Hospital Virgen del Rocio , Sevilla 41013, Spain"},{"name":"Bioinformatics in Rare Diseases (BiER), Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras (CIBERER), FPS, Hospital Virgen del Roc\u00edo , Sevilla 41013, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3318-120X","authenticated-orcid":false,"given":"Joaqu\u00edn","family":"Dopazo","sequence":"additional","affiliation":[{"name":"Clinical Bioinformatics Area, Fundaci\u00f3n Progreso y Salud (FPS), CDCA, Hospital Virgen del Rocio , Sevilla 41013, Spain"},{"name":"Computational Systems Medicine, Institute of Biomedicine of Seville (IBIS), Hospital Virgen del Rocio , Sevilla 41013, Spain"},{"name":"Bioinformatics in Rare Diseases (BiER), Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras (CIBERER), FPS, Hospital Virgen del Roc\u00edo , Sevilla 41013, Spain"},{"name":"FPS\/ELIXIR-es, Hospital Virgen del Roc\u00edo , Sevilla 42013, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,1,12]]},"reference":[{"key":"2022062822111209600_ref1","doi-asserted-by":"crossref","first-page":"906","DOI":"10.1016\/j.jval.2015.05.008","article-title":"Rare disease terminology and definitions\u2014a systematic global review: report of the ISPOR rare disease special interest group","volume":"18","author":"Richter","year":"2015","journal-title":"Value Health"},{"key":"2022062822111209600_ref2","first-page":"77","article-title":"How many rare diseases are there?","author":"Haendel","year":"2019","journal-title":"Nat. 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