Abstract
Rare genetic diseases present formidable challenges to diagnosis, management, and clinical trials due to their low prevalence, geographic dispersion of patients, protracted diagnostic odysseys, and scarcity of specialized expertise. These factors lead to significant logistical, financial, and emotional burdens on patients and caregivers, often prolonging trial timelines and limiting participant pools. Telemedicine offers transformative solutions by bridging geographical distances and disseminating specialized knowledge. It encompasses traditional approaches like video conferencing, digital health technologies for remote monitoring using mHealth and wearables and enables Decentralized Clinical Trials, significantly enhancing patient access and accelerating recruitment. European Reference Networks, utilizing the Clinical Patient Management System, facilitate cross-border expert collaboration and knowledge sharing for complex cases. Telegenetics democratizes access to genetic counseling and diagnostic services, while digital platforms provide crucial information and educational resources, fostering patient empowerment and self-management. The integration of Real-World Evidence from wearables and IoT devices, combined with advanced analytics like AI/ML, provides objective and continuous data, supporting regulatory decisions. Despite these benefits, challenges remain, including the inability to perform comprehensive physical examinations remotely, concerns about diagnostic accuracy, the digital divide and user adherence, and the lack of harmonized regulatory and policy frameworks across borders. Ethical considerations, data security, and the need for robust evidence and validated remote outcome measures are also critical. The consensus points towards a hybrid model of care and research, strategically combining telemedicine with essential in-person interactions. Future directions include rigorously evaluating clinical outcomes of telemedicine, developing user-friendly and validated technologies, harmonizing international policies, investing in digital literacy, and fostering coordinated collective intelligence networks to maximize patient knowledge capital and accelerate therapeutic development. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12687-026-00887-7.