Ultra-rare RTEL1 gene variants associate with acute severity of COVID-19 and evolution to pulmonary fibrosis as a specific long COVID disorder
Authors: Bergantini Laura , Baldassarri Margherita , d’Alessandro Miriana , Brunelli Giulia , Fabbri Gaia , Zguro Kristina , Degl’Innocenti Andrea ,   GEN-COVID Multicenter study, Mari Francesca , Daga Sergio , Meloni Ilaria , Bruttini Mirella , Croci Susanna , Lista Mirjam , Maffeo Debora , Pasquinelli Elena , Serio Viola Bianca , Antolini Enrica , Basso Simona Letizia , Minetto Samantha , Tita Rossella , Mencarelli Maria Antonietta , Rizzo Caterina Lo , Pinto Anna Maria , Ariani Francesca , Montagnani Francesca , Tumbarello Mario , Rancan Ilaria , Fabbiani Massimiliano , Cameli Paolo , Bennett David , Anedda Federico , Marcantonio Simona , Scolletta Sabino , Franchi Federico , Mazzei Maria Antonietta , Guerrini Susanna , Conticini Edoardo , Cantarini Luca , Frediani Bruno , Tacconi Danilo , Raffaelli Chiara Spertilli , Emiliozzi Arianna , Feri Marco , Donati Alice , Scala Raffaele , Guidelli Luca , Spargi Genni , Corridi Marta , Nencioni Cesira , Croci Leonardo , Caldarelli Gian Piero , Romani Davide , Piacentini Paolo , Bandini Maria , Desanctis Elena , Cappelli Silvia , Canaccini Anna , Verzuri Agnese , Anemoli Valentina , Pisani Manola , Ognibene Agostino , Lorubbio Maria , Pancrazzi Alessandro , Vaghi Massimo , Monforte Antonella D.’Arminio , Miraglia Federica Gaia , Mondelli Mario U. , Mantovani Stefania , Bruno Raffaele , Vecchia Marco , Maffezzoni Marcello , Martinelli Enrico , Girardis Massimo , Busani Stefano , Venturelli Sophie , Cossarizza Andrea , Antinori Andrea , Vergori Alessandra , Rusconi Stefano , Siano Matteo , Gabrieli Arianna , Riva Agostino , Francisci Daniela , Schiaroli Elisabetta , Pallotto Carlo , Parisi Saverio Giuseppe , Basso Monica , Panese Sandro , Baratti Stefano , Scotton Pier Giorgio , Andretta Francesca , Giobbia Mario , Scaggiante Renzo , Gatti Francesca , Castelli Francesco , Quiros-Roldan Eugenia , Antoni Melania Degli , Zanella Isabella , Monica Matteo della , Piscopo Carmelo , Capasso Mario , Russo Roberta , Andolfo Immacolata , Iolascon Achille , Fiorentino Giuseppe , Carella Massimo , Castori Marco , Merla Giuseppe , Squeo Gabriella Maria , Aucella Filippo , Raggi Pamela , Perna Rita , Bassetti Matteo , Di Biagio Antonio , Sanguinetti Maurizio , Masucci Luca , Guarnaccia Alessandra , Valente Serafina , Di Florio Alex , Mandalà Marco , Giorli Alessia , Salerni Lorenzo , Zucchi Patrizia , Parravicini Pierpaolo , Menatti Elisabetta , Trotta Tullio , Giannattasio Ferdinando , Coiro Gabriella , Lena Fabio , Lacerenza Gianluca , Mussini Cristina , Tavecchia Luisa , Crotti Lia , Parati Gianfranco , Menè Roberto , Sanarico Maurizio , Gori Marco , Raimondi Francesco , Stella Alessandra , Biscarini Filippo , Bachetti Tiziana , La Rovere Maria Teresa , Bussotti Maurizio , Ludovisi Serena , Capitani Katia , Dei Simona , Ravaglia Sabrina , Giliberti Annarita , Gori Giulia , Artuso Rosangela , Andreucci Elena , Pagliazzi Angelica , Fiorentini Erika , Perrella Antonio , Bianchi Francesco , Bergomi Paola , Catena Emanuele , Colombo Riccardo , Luchi Sauro , Morelli Giovanna , Petrocelli Paola , Iacopini Sarah , Modica Sara , Baroni Silvia , Micheli Giulia , Falcone Marco , Urso Donato , Tiseo Giusy , Matucci Tommaso , Grassi Davide , Ferri Claudio , Marinangeli Franco , Brancati Francesco , Vincenti Antonella , Borgo Valentina , Lombardi Stefania , Lenzi Mirco , Di Pietro Massimo Antonio , Vichi Francesca , Romanin Benedetta , Attala Letizia , Costa Cecilia , Gabbuti Andrea , Bellucci Alessio , Colaneri Marta , Casprini Patrizia , Pomara Cristoforo , Esposito Massimiliano , Leoncini Roberto , Cirianni Michele , Galasso Lucrezia , Bellini Marco Antonio , Gabbi Chiara , Picchiotti Nicola , Furini Simone , Fallerini Chiara , Bargagli Elena , Renieri Alessandra 
Published: June 2023

Abstract
Background
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a novel coronavirus that caused an ongoing pandemic of a pathology termed Coronavirus Disease 19 (COVID-19). Several studies reported that both COVID-19 and RTEL1 variants are associated with shorter telomere length, but a direct association between the two is not generally acknowledged. Here we demonstrate that up to 8.6% of severe COVID-19 patients bear RTEL1 ultra-rare variants, and show how this subgroup can be recognized.

Methods
A cohort of 2246 SARS-CoV-2-positive subjects, collected within the GEN-COVID Multicenter study, was used in this work. Whole exome sequencing analysis was performed using the NovaSeq6000 System, and machine learning methods were used for candidate gene selection of severity. A nested study, comparing severely affected patients bearing or not variants in the selected gene, was used for the characterisation of specific clinical features connected to variants in both acute and post-acute phases.

Results
Our GEN-COVID cohort revealed a total of 151 patients carrying at least one RTEL1 ultra-rare variant, which was selected as a specific acute severity feature. From a clinical point of view, these patients showed higher liver function indices, as well as increased CRP and inflammatory markers, such as IL-6. Moreover, compared to control subjects, they present autoimmune disorders more frequently. Finally, their decreased diffusion lung capacity for carbon monoxide after six months of COVID-19 suggests that RTEL1 variants can contribute to the development of SARS-CoV-2-elicited lung fibrosis.

Conclusion
RTEL1 ultra-rare variants can be considered as a predictive marker of COVID-19 severity, as well as a marker of pathological evolution in pulmonary fibrosis in the post-COVID phase. This notion can be used for a rapid screening in hospitalized infected people, for vaccine prioritization, and appropriate follow-up assessment for subjects at risk.
Trial Registration NCT04549831 (www.clinicaltrial.org)