Provision of a molecularly confirmed diagnosis in a timely manner for children and adults with rare genetic diseases shortens their "diagnostic odyssey," improves disease management, and fosters genetic counseling with respect to recurrence risks while assuring reproductive choices. In a general clinical genetics setting, the current diagnostic rate is approximately 50%, but for those who do not receive a molecular diagnosis after the initial genetics evaluation, that rate is much lower. Diagnostic success for these more challenging affected individuals depends to a large extent on progress in the discovery of genes associated with, and mechanisms underlying, rare diseases. Thus, continued research is required for moving toward a more complete catalog of disease-related genes and variants. The International Rare Diseases Research Consortium (IRDiRC) was established in 2011 to bring together researchers and organizations invested in rare disease research to develop a means of achieving molecular diagnosis for all rare diseases. Here, we review the current and future bottlenecks to gene discovery and suggest strategies for enabling progress in this regard. Each successful discovery will define potential diagnostic, preventive, and therapeutic opportunities for the corresponding rare disease, enabling precision medicine for this patient population.

More than 50% of patients with non–Shiga toxin–associated hemolytic uremic syndrome (non–Stx-HUS) progress to ESRD. Kidney transplant failure for disease recurrence is common; hence, whether renal transplantation is appropriate in this clinical setting remains a debated issue. The aim of this study was to identify possible prognostic factors for renal transplant outcome by focusing on specific genetic abnormalities associated with the disease. All articles in literature that describe renal transplant outcome in patients with ESRD secondary to non–Stx-HUS, genotyped for CFH, MCP, and IF mutations, were reviewed, and data of patients who were referred to the International Registry of Recurrent and Familial HUS/TTP and data from the Newcastle cohort were examined. This study confirmed that the overall outcome of kidney transplantation in patients with non–Stx-HUS is poor, with disease recurring in 60% of patients, 91.6% of whom developed graft failure. No clinical prognostic factor that could identify patients who were at high risk for graft failure was found. The presence of a factor H (CFH) mutation was associated with a high incidence of graft failure (77.8 versus 54.9% in patients without CFH mutation). Similar results were seen in patients with a factor I (IF) mutation. In contrast, graft outcome was favorable in all patients who carried a membrane co-factor protein (MCP) mutation. Patients with non–Stx-HUS should undergo genotyping before renal transplantation to help predict the risk for graft failure. It is debatable whether a kidney transplant should be recommended for patients with CFH or IF mutation. Reasonably, patients with an MCP mutation can undergo a kidney transplant without risk for recurrence.

Background: Limited resources and expanding expectations push all countries and types of health systems to adopt new approaches in priority setting and resources allocation. Despite best efforts, it is difficult to reconcile all competing interests and trade-offs are inevitable. This is why multi-criteria decision analysis (MCDA) has played a major role in recent uptake of value-based reimbursement. MCDA framework enables exploration of stakeholders’ preferences, as well as explicit organization of broad range of criteria on which real-world decisions are made. Assessment and appraisal of orphan drugs tend to be one of the most complicated health technology assessment (HTA) tasks. Access to market approved orphan therapies remains an issue. Early constructive dialogue among rare disease stakeholders and elaboration of orphan drug-tailored decision support tools could set the scene for ongoing accumulation of evidence, as well as for proper reimbursement decision-making. Objective: The objective of this study was to create a MCDA value measurement model to assess and appraise orphan drugs. This was achieved by exploring the preferences on decision criteria’s weights and performance scores through a stakeholder-representative survey and a focus group discussion that were both organized in Bulgaria. Results/Conclusions: Decision criteria that describe the health technology’s characteristics were unanimously agreed as the most important group of reimbursement considerations. This outcome, combined with the high individual weight of disease severity and disease burden criteria underlined some of the fundamental principles of healthcare – equity and fairness. Our study proved that strength of evidence may be a key criterion in orphan drug assessment and appraisal. Evidence is not only used to shape reimbursement decision-making, but also to lend legitimacy to policies pursued. The need for real-world data on orphan drugs was largely stressed. Improved knowledge on MCDA feasibility and integration to HTA is of paramount importance, as progress in medicine and innovative health technologies should correspond to patient, healthcare system and societal values.

The European Union (EU) policy for healthcare requires the establishment of a system of European Reference Networks, union-wide information databases, and registries for rare diseases (RDs) based on shared criteria. In pursuing its goals, the ‘Building Consensus and Synergies for the EU Registration of RD Patients in Europe' (EPIRARE) project convened a meeting with experts of the competent health authorities to discuss the role of national institutional RD patient registries in supporting EU patient registration and the room for international cooperation. With this aim, this paper comparatively analyses the current situation of national institutional RD registries in the EU.