Ultra-rare RTEL1 gene variants associate with acute severity of COVID-19 and evolution to pulmonary fibrosis as a specific long COVID disorder

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)

Atopy and Elevation of IgE, IgG3, and IgG4 May Be Risk Factors for Post COVID-19 Condition in Children and Adolescents

“…As we focus on a cohort with childhood onset PCC, we discuss the genetic susceptibility towards immune dysregulation as a potential risk factor for the manifestation of PCC. Recent reports have discussed pathogenic genetic variants in transcription factors and innate immune response genes in patients developing PCC [42]. Allergies and obstructive lung disease were also identified in larger cohorts of adult patients with PCC [43].…”

The Aftermath of COVID-19: Exploring Long-Term Effects on the Organ Systems

“…There is also evidence of T-cell activation, potentially triggered by a superantigen associated with SARS-CoV-19 [85]. A study conducted in 2023, indicated that among 2246, 151 patients harbored at least one ultra-rare variant of RTEL1 (regulator of telomere elongation helicase 1), chosen as a distinctive marker for acute severity in diseases correlated to liver functions causing lung fibrosis [148].…”

Predictive Role of Cytokine and Adipokine Panel in Hospitalized COVID-19 Patients: Evaluation of Disease Severity, Survival and Lung Sequelae

“…Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has posed a significant threat to global health [ 1 , 2 ]. Symptoms can vary from none to acute respiratory distress syndrome (ARDS) (about 15% of cases) [ 3 ].…”