BACKGROUND: The Global Burden of Disease Study has provided key evidence to inform clinicians, researchers, and policy makers across common diseases, but no similar effort with a single-study design exists for hundreds of rare diseases. Consequently, for many rare conditions there is little population-level evidence, including prevalence and clinical vulnerability, resulting in an absence of evidence-based care that was prominent during the COVID-19 pandemic. We aimed to inform rare disease care by providing key descriptors from national data and explore the impact of rare diseases during the COVID-19 pandemic. METHODS: In this nationwide retrospective observational cohort study, we used the electronic health records (EHRs) of more than 58 million people in England, linking nine National Health Service datasets spanning health-care settings for people who were alive on Jan 23, 2020. Starting with all rare diseases listed in Orphanet (an extensive online resource for rare diseases), we quality assured and filtered down to analyse 331 conditions mapped to ICD-10 or Systemized Nomenclature of Medicine-Clinical Terms that were clinically validated in our dataset. For all 331 rare diseases, we calculated population prevalences, analysed patients' clinical and demographic details, and investigated mortality with SARS-CoV-2. We assessed COVID-19-related mortality by comparing cohorts of patients for each rare disease and rare disease category with controls matched for age group, sex, ethnicity, and vaccination status, at a ratio of two controls per individual with a rare disease. FINDINGS: Of 58 162 316 individuals, we identified 894 396 with at least one rare disease and assessed COVID-19-related mortality between Sept 1, 2020, and Nov 30, 2021. We calculated reproducible estimates, adjusted for age and sex, for all 331 rare diseases, including for 186 (56·2%) conditions without existing prevalence estimates in Orphanet. 49 rare diseases were significantly more frequent in female individuals than in male individuals, and 62 were significantly more frequent in male individuals than in female individuals
47 were significantly more frequent in Asian or British Asian individuals than in White individuals
and 22 were significantly more frequent in Black or Black British individuals than in White individuals. 37 rare diseases were significantly more frequent in the White population compared with either the Black or Asian population. 7965 (0·9%) of 894 396 patients with a rare disease died from COVID-19, compared with 141 287 (0·2%) of 58 162 316 in the full study population. In fully vaccinated individuals, the risk of COVID-19-related mortality was significantly higher for eight rare diseases, with patients with bullous pemphigoid (hazard ratio 8·07, 95% CI 3·01-21·62) being at highest risk. INTERPRETATION: Our study highlights that national-scale EHRs provide a unique resource to estimate detailed prevalence, clinical, and demographic data for rare diseases. Using COVID-19-related mortality analysis, we showed the power of large-scale EHRs in providing insights to inform public health decision making for these often neglected patient populations. FUNDING: British Heart Foundation Data Science Centre, led by Health Data Research UK.