key: cord-0693874-k7zrq4yl
authors: Solanich, X.; Vargas-Parra, G.; van der Made, C. I.; Simons, A.; Schuurs-Hoeijmakers, J.; Antoli, A.; del Valle, J.; Rocamora-Blanch, G.; Setien, F.; Esteller, M.; Riera-Mestre, A.; Sabater-Riera, J.; Capella, G.; van de Veerdonk, F. L.; van der Hoven, B.; Corbella, X.; Hoischen, A.; Lazaro, C.
title: Genetic screening for TLR7 variants in young and previously healthy men with severe COVID-19: a case series
date: 2021-03-25
journal: nan
DOI: 10.1101/2021.03.14.21252289
sha: 8ad2ce2d47aaa23bee478c86c968a06f409d096e
doc_id: 693874
cord_uid: k7zrq4yl

Advanced age, male sex and chronic comorbidities are associated with severe COVID-19. However, these general risk factors cannot explain why critical illness occurs in young and apparently healthy individuals. In the past months, several publications have identified susceptibility loci and genes using comprehensive GWAS studies or genome, exome or candidate genes analysis. A recent study reported rare, loss-of-function TLR7 variants in otherwise healthy young brother pairs from two families with severe COVID-19. We aimed to prospectively study the prevalence of rare X-chromosomal TLR7 genetic variants in our cohort of young male patients with severe COVID-19. We recruited 13 patients [≤]50 years who had no risk factors known to be associated with severe disease. We studied the entire TLR7 coding region and identified two missense variants (p.Asn215Ser, c.644A>G and p.Trp933Arg, c.2797T>C) in two out of 13 cases (15.4%). These variants were not previously reported in population control databases (gnomAD) and were predicted to be damaging by all in silico predictors. The male index patients were between 25 and 30 years old and had no apparent comorbidities. The TLR7 p.Asn215Ser co-segregated in 2 first-degree relatives severely affected by COVID-19, in a younger previously healthy the variant was found in hemizygous state , and in an older than 60 was in heterozygous state. No family members were available for testing the segregation of the p.Trp933Arg variant. These results further support that susceptibility to severe COVID-19 could be determined by inherited rare genetic variants in TLR7. Understanding the causes and mechanisms of life-threatening COVID-19 is crucial and could lead to novel preventive and therapeutic options. This study supports a rationale for the genetic screening for TLR7 variants in young men with severe COVID-19 in the absence of other relevant risk factors. A diagnosis of TLR7 deficiency could not only inform on treatment options for the patient, but it also enables for pre-symptomatic testing of at-risk male relatives with the possibility of instituting early preventive and therapeutic interventions.

Advanced age, male sex and chronic comorbidities are associated with severe 19. However, these general risk factors cannot explain why critical illness occurs in 77 young and apparently healthy individuals. In the past months, several publications have 78 identified susceptibility loci and genes using comprehensive GWAS studies or genome, 79 exome or candidate genes analysis. A recent study reported rare, loss-of-function TLR7 80 variants in otherwise healthy young brother pairs from two families with severe 81 . We aimed to prospectively study the prevalence of rare X-chromosomal 82 TLR7 genetic variants in our cohort of young male patients with severe COVID-19. We 83 recruited 13 patients ≤50 years who had no risk factors known to be associated with 84 severe disease. We studied the entire TLR7 coding region and identified two missense 85 variants (p.Asn215Ser, c.644A>G and p.Trp933Arg, c.2797T>C) in two out of 13 cases 86 (15.4%). These variants were not previously reported in population control databases 87

(gnomAD) and were predicted to be damaging by all in silico predictors. The male 88 index patients were between 25 and 30 years old and had no apparent comorbidities. 89

The TLR7 p.Asn215Ser co-segregated in 2 first-degree relatives severely affected by 90 COVID-19, in a younger previously healthy the variant was found in hemizygous state , 91 and in an older than 60 was in heterozygous state. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in while other, relatively less rare variants may lead only to a partial TLR7 deficiency, and 266 therefore may impact a larger group of individuals, but exert a lower relative risk to 267 develop severe COVID-19. It is therefore interesting, that these latter variants have been 268 also be identified in individuals of elevated age and also compromise TLR7 function 269

[Fallerini, preprint MedRxiv 2020] . that can be used for early diagnosis and prophylaxis, and allow the identification of 285 possible molecular targets for treatment. This also applies to susceptibility to SARS-286

CoV-2 that could be determined by genes related to viral binding and entry, as well as 287 genes related with immune response to the SARS-CoV-2 [4]. The small cohort study 288

presented here, with an unexpectedly high yield (2/13) encourages that a screen for 289 TLR7 rare variants in severely affected men may be useful. While also elderly 290 individuals may carry rare TLR7 variants those individuals may be more difficult to 291 identify; we therefore suggest the following preliminary screening criteria: young men 292 All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted March 25, 2021. ;

(<50 year of age); previously healthy; suffering from severe COVID-19 in addition 293

affected young brother pairsas well as pedigrees suggestive for X-linked segregation -294

should be further prioritized. 295

Unfortunately, there is still a paucity of therapies that has been proven effective and safe 296

in perpetuity.

preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted March 25, 2021. ; https://doi.org/10.1101/2021.03.14.21252289 doi: medRxiv preprint

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