Presence of rare potential pathogenic variants in subjects under 65 years old with very severe or fatal COVID-19
Authors: López-Rodríguez Rosario , Del Pozo-Valero Marta , Corton Marta , Minguez Pablo , Ruiz-Hornillos Javier , Pérez-Tomás María Elena , Barreda-Sánchez María , Mancebo Esther , Villaverde Cristina , Núñez-Moreno Gonzalo , Romero Raquel ,   The STOP_Coronavirus Study Group,   Associated Clinical and Researchgroup of Fundación Jiménez Díaz University Hospital, Fernández-Caballero Lidia , Fernández Sanchez Ruth , García Vara Inés , Marzal Gordo Laura , Martinez-Ramas Andrea , Ondo Lorena , Górgolas Miguel , Cabello Alfonso , Barba Germán Peces , Heili Sara , Calvo César , Ríos María Dolores Martín , Santos Arnoldo , Sánchez-Pernaute Olga , Llanos Lucía , Zazo Sandra , Rojo Federico , Villar Felipe , de Andrés Raimundo , Alfaro Ignacio Jiménez , Gadea Ignacio , Perales Celia , Juarez Yolanda Cañadas , Mahillo Ignacio , Herrero Antonio , Taracido Juan Carlos ,   Associated Clinical and Research group of IMIB-Arrixaca/Virgen de la Arrixaca University Clinical Hospital, García-Vázquez Elisa , Jara-Rubio Rubén , Pons-Miñano José A. , Marín-Martínez Juana M. , Herranz-Marín M. Teresa , Bernal-Morell Enrique , García-García Josefina , de Dios González-Caballero Juan , Chirlaque-López M. Dolores , Minguela-Puras Alfredo , Muro-Amador Manuel , Moreno-Docón Antonio , Yagüe-Guirao Genoveva , Abellán-Perpiñán José M. , Martínez-Pérez Jorge E. , Sánchez-Martínez Fernando I. ,   Associated Clinical and Research Group of 12 de Octubre University Hospital, Utrero-Rico Alberto , Fernández-Ruiz Mario , Carretero Octavio , Aguado José María , Laguna-Goya Rocio ,   Associated Clinical Group of Infanta Elena University Hospital, Jiménez Ángel , Abián María Herrera , Salmones Mercedes García , Alarcon Lidia Gagliardi , Oliveira María Rubio , Romero Carlos Fabian Castaño , Cosgaya Carlos Aranda , Palomares Virginia Víctor , Rodríguez Leticia García , Abad Maria Sanchez Carpintero , Torrejón Mª Carmen García , Paz-Artal Estela , Guillén-Navarro Encarna , Almoguera Berta , Ayuso Carmen 
Published: June 2022

Rare variants affecting host defense against pathogens could be involved in COVID-19 severity and may help explain fatal outcomes in young and middle-aged patients. Our aim was to report the presence of rare genetic variants in certain genes, by using whole exome sequencing, in a selected group of COVID-19 patients under 65 years who required intubation or resulting in death (n = 44). To this end, different etiopathogenic mechanisms were explored using gene prioritization-based analysis in which genes involved in immune response, immunodeficiencies or blood coagulation were studied. We detected 44 different variants of interest, in 29 different patients (66%). Some of these variants were previously described as pathogenic and were located in genes mainly involved in immune response. A network analysis, including the 42 genes with candidate variants, showed three main components, consisting of 25 highly interconnected genes related to immune response and two additional networks composed by genes enriched in carbohydrate metabolism and in DNA metabolism and repair processes. In conclusion, we have detected candidate variants that may potentially influence COVID-19 outcome in our cohort of patients. Further studies are needed to confirm the ultimate role of the genetic variants described in the present study on COVID-19 severity.