Meeting Patients’ Right to the Correct Diagnosis: Ongoing International Initiatives on Undiagnosed Rare Diseases and Ethical and Social Issues

Abstract

The time required to reach a correct diagnosis is a key concern for rare disease (RD) patients. Diagnostic delay can be intolerably long, often described as an “odyssey” and, for some, a diagnosis may remain frustratingly elusive. The International Rare Disease Research Consortium proposed, as ultimate goal for 2017–2027, to enable all people with a suspected RD to be diagnosed within one year of presentation, if the disorder is known. Subsequently, unsolved cases would enter a globally coordinated diagnostic and research pipeline. In-depth analysis of the genotype through next generation sequencing, together with a standardized in-depth phenotype description and sophisticated high-throughput approaches, have been applied as diagnostic tools to increase the chance of a timely and accurate diagnosis. The success of this approach is evident in the Orphanet database. From 2010 to March 2017 over 600 new RDs and roughly 3600 linked genes have been described and identified. However, combination of -omics and phenotype data, as well as international sharing of this information, has raised ethical concerns. Values to be assessed include not only patient autonomy but also family implications, beneficence, non-maleficence, justice, solidarity and reciprocity, which must be respected and promoted and, at the same time, balanced among each other. In this work we suggest that, to maximize patients’ involvement in the search for a diagnosis and identification of new causative genes, undiagnosed patients should have the possibility to: (1) actively participate in the description of their phenotype; (2) choose the level of visibility of their profile in matchmaking databases; (3) express their preferences regarding return of new findings, in particular which level of Variant of Unknown Significance (VUS) significance should be considered relevant to them. The quality of the relationship between individual patients and physicians, and between the patient community and the scientific community, is critically important for optimizing the use of available data and enabling international collaboration in order to provide a diagnosis, and the attached support, to unsolved cases. The contribution of patients to collecting and coding data comprehensively is critical for efficient use of data downstream of data collection.

Improving diagnosis for rare diseases: the experience of the Italian undiagnosed Rare diseases network

“…In our study, gender distribution was very similar for both sexes (1 M:1F). When only pediatric patients (< 16 years of age) were considered, the distribution showed a higher number of males (62%) than female (36%) as observed by other authors [ 37 , 38 ]. Syndromes with intellectual disabilities and multiple congenital anomalies were the most represented categories among the undiagnosed conditions.…”

“…In our study, gender distribution was very similar for both sexes (1 M:1F). When only pediatric patients (< 16 years of age) were considered, the distribution showed a higher number of males (62%) than female (36%) as observed by other authors [37,38].…”

“…Stark et al reported a high diagnostic rate by using genomic analysis together with a clear benefit in clinical management and genetic counselling in a relevant percentage of infants enrolled in their study [ 30 ]. Advantages were also referable to health and psychosocial impact, reproductive outcome and likely cost-effectiveness [ 37 ]. Nonetheless, the adoption of exome sequencing as first line investigation (as we did in some of our cases) for undiagnosed cases deserves further evaluation among specialists and stakeholders as this attitude could lessen in some circumstance the optimal clinical reasoning of health care in practice and education.…”

Initial experience from a renal genetics clinic demonstrates a distinct role in patient management

“…Some patients with rare genetic disorders have been on a diagnostic odyssey, and having a diagnosis avoids unnecessary testing and continued uncertainty. 13,14 Furthermore, with a diagnosis comes the ability to provide a meaningful prognosis and, if appropriate, counseling for family members who may be at risk. In some situations, the recognition that a common renal disease like FSGS may be genetic in origin can also have an impact on management.…”

Children with rare diseases: ethical, social, psychological and medical issues

“…В качестве диагностических инструментов предложено применять анализ генотипа путем секвенирования методом NGS (next generation sequencing), а также использовать стандартизированное описание фенотипа. Успех очевиден: с 2010 г. по март 2017 г. в базу данных Orphanet было включено более 600 новых наименований болезней и примерно 3600 связанных с ними генов [9]. В 2008 г. в Национальном институте здравоохранения США была разработана Программа по выявлению трудно диагностируемых заболеваний, успех которой привел к ее внедрению в 7 клинических исследовательских институтах на территории США.…”