Structural Variants in Severe COVID-19: Clinical Impact Assessment

Background: Several genes and genomic regions have been implicated in COVID-19 susceptibility and severity, but their clinical relevance remains uncertain. We comprehensively assessed both copy number variants (CNVs) and single-nucleotide variants (SNVs) disrupting genes implicated in COVID-19 in a Swedish cohort of ICU-treated COVID-19 patients with detailed phenotype data. Methods: Patients (n = 301) with severe COVID-19 treated in intensive care units (ICU) between March 2020 and January 2021 at two large Swedish university hospitals were included. Whole exome sequencing (WES) was performed to identify both large copy number variations (CNVs) and single-nucleotide variants (SNVs), including small indels, using the Genome Analysis Toolkit (GATK) pipelines. We focused our analyses on variants disrupting coding genes implicated in severe COVID-19, but also assessed variants known to cause human disease. Results: We identified 11 rare CNVs and several SNVs potentially linked to severe COVID-19. Patients carrying a CNV spanning a COVID-19-implicated gene had higher levels of the heart failure marker NT-proBNP (median 4440 [1558–8160] vs. 1170 [329–3152], p = 0.017), worse renal function at ICU admission (p = 0.0026), and a higher need for continuous renal replacement therapy (CRRT) (28% vs. 10%, p = 0.045) compared to patients without a potentially damaging CNV. Conclusions: Although patients with a potentially damaging CNV or SNV exhibited some differences in cardiac and renal markers, our findings do not support broad genetic screening as a predictive tool for COVID-19 severity.