Several medications and treatments are being investigated for their potential effectiveness against coronavirus disease 2019 (COVID-19), including androgen and other sex hormones. However, the causal relationships between serum sex hormones and COVID-19 susceptibility and severity, particularly with regards to potentially sex-specific effects, remain largely unknown. In this study, we used the latest data from the UK Biobank (up to 424,907 individuals) and COVID-19 Host Genetics Initiative (up to 1,878,143 individuals) to systematically assess the sex-specific causal effects of serum sex hormone levels on COVID-19 outcomes within a two-sample Mendelian randomization (MR) framework. The inverse-variance weighted method was used in the main MR analysis. We additionally performed a series of sensitivity analysis to assess the robustness of MR effect estimates to potentially invalid genetic variants. Our MR analysis revealed novel causal associations between serum estradiol and bioavailable testosterone levels and SARS-CoV-2 infection in women, but not men, except for a suggestive inverse causal association between estradiol levels and COVID-19 severity in men. These novel findings improve our understanding of the sex-specific causal nature of sex hormones in relation to COVID-19 outcomes, and suggest that sex hormones may serve as potential therapeutic targets for preventing SARS-CoV-2 infection and improving patient outcomes.

This is the first study describing a cohort of Mainland China patients broaden the clinical and molecular spectrum of Phelan-McDermid syndrome (PMS) or 22q13 deletion syndrome. A total of 30 Mainland China patients were clinically and genetically evaluated. We discover that nineteen patients with 22q13.3 deletions, one patient with terminal deletions and duplications, one patient with duplications, and nine patients with SHANK3 mutations were included. Six novel heterozygous variants, c.3838_3839insGG, c.3088delC, c.3526G>T, c.3372dupC, c.3120delC and c.3942delC, were firstly reported. Besides, we demonstrated speech delay, DD/ID, ASD, hypotonia and hyperactivity were prominent clinical features. Since most reported cases used to genotype-phenotype analyses are caused by 22q13 deletions usually encompassing many genes including SHANK3, we performed genotype-phenotype analysis, and found hypotonia was 100% of cases with loss of SHANK3 alone and there was no significant difference between loss of SHANK3 alone and deletions encompass more than SHANK3 gene regarding hypotonia, DD/ID, ASD, increased pain tolerance, gait abnormalities, impulsiveness, repetitive behaviors, regression and nonstop crying which are high frequency in loss of SHANK3 alone group. This analysis improves the understanding that SHANK3 haploinsufficiency is a major contributor to the neurological phenotypes of PMS and also responsible for other important phenotypes such as hypotonia.