Abstract
People living with a rare disease can wait months to years for a confirmed diagnosis after symptom onset, mainly due to low prevalence, lack of awareness of primary healthcare professionals, heterogeneous clinical presentation and/or peculiar inheritance patterns. This consensus paper aims to establish a set of guidelines to assist healthcare professionals-also without a specialized expertise in rare diseases-in optimizing the diagnostic pathway for these conditions. During Phase 1 of a real-time Delphi study, ten experts defined 26 statements addressing the identification of clinical features ("red flags", domain 1) and non-clinical tools/conditions ("clinical gateways", domain 2) that could trigger/support the diagnostic suspect of a rare disease. During Phase 2, the survey was extended to a multidisciplinary panel of 55 experts to reach a consensus on statements. Consensus was reached on 22 out of 26 statements across the two domains. Family history, clusters of birth defects, unusual presentations of common disease, neurodevelopmental delays or decline, and severe pathology emerged as key indicators to improve the identification and referral of cases of rare disease and should be integrated into primary care practices. Education, increased awareness in the community and use of technology are possible gateways to facilitate early diagnosis in rare disease.