Increased COVID-19 related mortality rate for patients with rare diseases: a retrospective cohort study with data from Genomics England

BACKGROUND: The ongoing COVID-19 pandemic has had a high incidence and mortality so far. Several common conditions have been widely recognised as risk factors for COVID-19-related death, but the risks for patients with rare diseases are largely unknown. Therefore, we aimed to estimate the difference in the risk of mortality for patients with rare diseases compared to the risk for the general population. METHODS: To estimate the correlation between rare diseases and COVID-19-related death, we performed a retrospective cohort study of Genomics England participants who tested positive for SARS-CoV-2 (n=283) during the first wave (March 16 to July 31, 2020) of the COVID-19 pandemic in the UK. Participants with one of 190 rare diseases and their biological relatives (mostly to the first or second degree) were recruited by Genomics England, where patients had a provisional diagnosis but not a molecular diagnosis. COVID-19-related mortality rates were calculated in two groups: patients with rare diseases and unaffected relatives. Univariable analysis on the associations between rare diseases and COVID-19-related death was done with Fisher's exact test. Adjusted odds ratio (OR; for age and number of common comorbidities) was calculated with multivariable logistic regression. The study was approved by Genomic England (reference GEL-79143). FINDINGS: There were 20 (13%) COVID-19-related deaths in patients with rare diseases (n=158) and five (4%) COVID-19-related deaths in unaffected relatives (n=125), translating to an increased risk of mortality in patients with rare diseases (OR 3·47 [95% CI 1·21–12·2], Fisher's exact p=0·011). A greater OR was observed in participants younger than 60 years (univariable 5·11 [0·56–245·16]; p=0·212), although the trend was not significant. Having a rare disease (multivariable 1·94 [0·65–5·80]; p=0·233) and the number of comorbidities (multivariable 2·10 [0·79–5·58]; p=0·135) contributed similarly to COVID-19-related death in multivariable logistic regression analysis in this cohort. Sex was not found to affect the mortality rate. INTERPRETATION: Our results show that patients with rare diseases in the Genomics England cohort had an increased risk of COVID-19-related mortality during the first wave of the pandemic in UK. The high risk is probably associated with the rare diseases themselves, but we cannot rule out possible mediators due to the small sample size. We would like to raise the awareness that patients with rare diseases might face increased risk for COVID-19-related death. Proper considerations for these patients should be taken when relevant decisions (eg, returning to a workplace) are made. FUNDING: HZ is supported by Wellcome Trust ITPA funding (grant number PIII026/013). HW is supported by Wellcome Trust ITPA (grant number PIII0054/005) and Medical Research Council (grant number MR/S004149/2).