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Perforin gene variant A91V in young patients with severe COVID-19.

Since early 2020 SARS-CoV-2 infectious disease (COVID-19) has been responsible for more than 300.000 deaths across the globe. Advanced age and previous comorbidities are clearly related to the development of severe forms of the disease (sCOVID) and an increased mortality risk. However young healthy subjects with sCOVID are also admitted to intensive care units (ICU) and die, suggesting that individual variations and/or genetic predisposing factors might play a role in modifying the clinical course and severity of the disease. sCOVID-19 is characterized by fever, bilateral pneumonia, lymphopenia, hyperferritinemia, elevated acute phase reagents and cytokine storm, altogether conforming a hyperinflammation scenario similar to that in secondary hemophagocytic lymphochystiocytosis (sHLH), also known as macrophage activation syndrome. In adults, sHLH is mostly triggered by viral infections and approximately 50% of patients experience pulmonary disease. In contrast, familial HLH (fHLH) is genetically determined by mutations in genes coding for proteins related to lymphocyte cytotoxicity such as perforin (PRF1 gene). Studies in juvenile idiopathic arthritis or systemic lupus erithematosus patients show that up to 40% of individuals suffering sHLH carry heterozygous mutations in fHLH genes. In a fatal influenza A (H1N1) series, 36% of patients carried one or several mutations in fHLHrelated genes. These findings suggest an important, not yet totally recognized overlap between primary and secondary forms of HLH. It has been previously observed that the highly prevalent, fHLH-associated c.272C>T variant (p.A91V; rs35947132) in the PRF1 gene impairs the processing to the active form of perforin protein. Published reports associate this variant with immune diseases but it has not been validated as pathological in larger cohorts. The A91V PRF1 gene translates into a protein with reduced stability and abnormal trafficking which associates with a significant decrease of NK-cell cytotoxicity. Previous studies reported higher prevalence of the A91V variant in