ACE 2 Coding Variants: A Potential X-linked Risk Factor for COVID-19 Disease

William T Gibson; Daniel M Evans; Jianghong An; Steven JM Jones

The fact that ACE2 is X-linked means that rare variants that enhanced SARS-CoV-2 binding in vivo 290 would likely increase susceptibility to COVID-19 among males. Other functional effects are possible 291 also; for example, female variant carriers might have a shorter asymptomatic period, or be more likely 292 to develop symptoms, irrespective of viral shedding status. Given that a limited number of coding 293 variants in ACE2 are predicted to affect the binding of SARS-CoV-2 spike protein, these variants could 294 be genotyped rapidly in early-onset cases (e.g. paediatric cases, or even cases under age 40) as a pilot 295 study in the United States and/or in European countries where case numbers are high, case fatality 296 appears to be high and the rare alleles are likely to be found. The delivery of viral nucleic acid testing 297 to affected populations is a more urgent need, but given that many viral samples are already being 298 collected, the addition of a rapid assay targeting the SNVs listed here would be an efficient means to 299 gather data to test this hypothesis. Notably, tests of rare variant burden do lose power rapidly if neutral 300 variants and variants with opposing functional effects are grouped together, so we have restricted 301 ourselves to variants with prior evidence of involvement in SARS-CoV-2 Spike protein binding. There 302 are many more missense ACE2 variants in gnomAD; the aggregate crude prevalence of all rare (i.e. 303 excluding the common p.Asn720Asp) missense variants in gnomAD males is 2.49% and in gnomAD 304 females is 5.81%. Furthermore, among patients with extreme outcomes such as death from COVID-19 305 in childhood (or asymptomatic super-spreaders, if any are found), sequencing of the entire ACE2 306 coding region might conceivably identify ultra-rare "private" variants not catalogued in gnomAD, 307 enabling assessment of the role of these variants in the conversion from initial SARS-CoV-2 infection 308 to COVID-19. A properly-powered genome-wide study with correlation of genetic variants to multiple 309 . CC-BY-NC-ND 4.0 International license author/funder. It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.04.05.026633 doi: bioRxiv preprint other clinical risk factors and outcomes is also advisable, but cannot realistically be accomplished in 310 the near term. 311