Rare diseases (RD) are a health priority for many countries, altogether affecting up to 6–8% of the population (1). RD, including those of genetic, epigenetic, or environmental origins, are defined as having low prevalence in the population, e.g., not more than 5 persons per 10,000 in the EU population (2), fewer than 200,000 individuals in the US population (330 million) (3), and fewer than 50,000, or one in 2,500, in Japan (4). There are 7,000–8,000 RD; many are complex clinical entities, life-threatening and/or chronically debilitating with multisystem dysfunction. Due to the heterogeneous etiologies and phenotypes, as well as low prevalence of each condition, achieving a timely diagnosis is particularly difficult. Hence, despite increased access to new tools, the diagnosis of RD remains challenging and a strength synergy among all parties involved (clinicians, researchers, patient associations, etc.) and technologies (including genome sequencing and clinical tests, metabolic measurement, neurological measurement etc.) are fundamental. Available information indicates that the mean delay in diagnosis is ~7 years, with high variability (1–18 years) across countries or regions (5, 6). Early and accurate diagnosis is essential to ensure proper access to clinical management of RD. Undiagnosed RDs (URD) account for a significant portion of the overall RD burden in all countries.

Combined national and international efforts are needed to shorten the diagnostic odyssey, improve the management of RD patients, reduce their morbidity and early mortality, and improve their quality of life and socio-economic potential. Those efforts include enhancing diagnostic services through initiatives such as the NIH Undiagnosed Diseases Network (UDN) (7) in the USA, the Deciphering Developmental Disorders project (DDD-Africa) (8) in Africa, the iHOPE Foundation (9), the SWIFT Foundation (10), the Western Australia public health system (11), the Global Commission on Diagnostic Odyssey (12), and private funding. The Solve-RD project (Solving the Unsolved RD) (2018–2022), funded by the EU Commission, is an example of a research project on URD (13). Finally, the International Rare Disease Research Consortium (IRDiRC) is lending support for the global coordination of research initiatives (14).

The survey was developed within the WG to explore the main needs for diagnosing undiagnosed patients, correlating those needs to national health care organizations, tracing resources dedicated to these purposes, estimating the presence or absence of dedicated expertise centers, and evaluating translational research activities. The UDNI members of the 20 countries provided their responses based on their own knowledge of the country situation on a comprehensive array of RD-related challenges. All participant members are engaged in RD at high level in their respective countries.

The survey was organized into eight domains, each interrogated through a dedicated open question with a free text box for the answer. Each country was represented by one respondent and each respondent replied to the questions on the basis of his/her specific knowledge of the country's situation regarding RD and URD. The results were structured based upon the most recurrent descriptions provided by each country's representative and summarized in tables and figures.

Hence, the identification of target unmet needs included the availability of centers for expert genomic diagnosis (domains 1 and 5); the depiction of the countries' health care organizations (domain 2); the presence of insurance systems (domain 3); the availability of resources and the implementation of sample and scientific exchange for translational research (domains 4 and 7); and the regulations governing data sharing (domain 6).

The survey was first piloted among WG four co-chairs and some researchers from their teams in order to test its technical functionality and general consistency. Its contents and aims were then shared and agreed with all 20 countries' WG representatives before being administered.

All WG members (N = 20; 100%) responded and completed the survey. Table 1 shows the UDNI countries contributing to the survey; it also includes the roles and affiliations of the country representatives and gives information about participation in the UDNI and other undiagnosed disease program initiatives. Table 2 and Figure 2 describe the unmet needs to tackle undiagnosed patients with rare diseases across all participating countries.

Eighty percent of all countries (N = 16) indicated limited financing and/or insurance coverage for genetic tests/services (Figure 2) which underscores that most countries are aware of ongoing challenges regarding rare diseases among clinicians and patient communities (e.g., Democratic Republic of Congo), complexity of rare diseases preventing identification and subsequent diagnosis (e.g., Ghana, Mexico), limited availability of specific tests in the public healthcare system, and lack of governance to assess the burden of genetic disorders (e.g., India).

Additionally, inequality in accessing services has been reported within almost all countries in terms of: financial accessibility of genetic testing (e.g., Georgia); limited number of local labs proficient in Next Generation Sequencing (e.g., Singapore); patients living in remote areas (e.g., Brazil); absence of a unique health care plan for URD across the country (e.g., Sweden); individual efforts rather than an institutional stand (e.g., Turkey); high cost of the investigations (e.g., Ghana); and absence of appropriate diagnostic facilities in the country (e.g., Pakistan).

A key difference among countries seems to be the percentage of the population that lacks appropriate access to diagnostic services; see “Limited availability of genetics testing” (Table 2) (25, 26). Beyond the specific RD aspects, this may also reflect the general development differences embodied by allocated and sustainable funding and the capacity of the countries to develop regulations and policies targeted to the unmet diagnostic needs.

Our study involved 20 countries in six continents, with highly diverse socio-economic and demographic scenarios. To our best knowledge, this is the first international overview on a comprehensive array of issues related to the needs and opportunities for undiagnosed RD.

Our results show that while the scientific and medical centers of most respondent countries are making substantial efforts to meet the unmet needs of patients, most health policies and frameworks do not adequately address RD needs, nor have they translated to adequate funding. Indeed, the scarcity of resources for genetic tests/services for multidisciplinary investigations and care for RD patients have been highlighted as the main problems. This is reflected by comments on the lack of a governmental strategy for undiagnosed patients and a general lack of awareness about the difficulties of achieving a diagnosis for RD patients. These systemic weaknesses translate into problems such as the scarcity of experts in genomic analysis and lack of interest of researchers and clinicians driving most initiatives.

In a substantial minority of countries, the medical structures appear utterly insufficient. Health care organization for diagnosis of RD is absent in 20% of cases. In 35% of cases, either one or no Expert Center for RD diagnosis is available for millions of inhabitants.

Furthermore, each health service, whether federated, centralized, or hybrid, has its own specific challenges. Federated systems, representing a relative majority, have difficulty achieving a nationally coordinated UDP, while centralized health services have limitations due to incomplete or inequitable access to services and scarcity of resources. Importantly, most countries do not have systemic or systematic coverage of WES/WGS analyses for undiagnosed cases.

Costs are a further barrier, creating substantial issues of inequity and lack of accessibility. NHSs do not always cover all undiagnosed patient expenditures, nor do they extend to 100% of the population. The contribution of the private sector, while useful to provide other options, does not address the equity problems. Overall, the cost of analyses for RD diagnosis is still high in most countries; in some countries, RD diagnosis is accessed only through research studies. Besides diagnostic services, patient registries and biobanks are available in many countries, but their access and functionality remain to be determined. These observations were confirmed when analyzing the responses of the participants addressing the unmet needs of RD and URD; “funding,” “facilities,” and “biobank” were the most frequently used terms.

On the other hand, the regulatory aspects of data sharing present several favorable aspects. Regulations are in place regarding the use of informed consent, as well as the existence of IRBs to assure the appropriate use of human samples and data. However, in some countries, strict regulations on sending DNA samples to foreign laboratories create additional diagnostic delays. Other possible challenges involve the protection of intellectual property from discoveries and the presence of possible conflicts of interest among researchers.

This survey highlighted some evident differences in responses by participants, likely related to different healthcare systems, policies and available funding to access exome / genome sequencing.

There is also a difference in availability of adequate genomic and human resource expertise for rare, undiagnosed diseases for specific populations. More pressing social and healthcare needs for commoner diseases like infections may result in diversion of funds and efforts in countries with lower socioeconomic status. In addition, these countries may not report inequity as there is lack of awareness of URD concept and thereby a limited felt need by them.

The findings of our survey are consistent, from a different perspective, with the insights collected by parents of children with RD in West Australia (26). Besides the needs for health and social care, the parents emphasized their diagnostic odysseys and the key role of a timely and appropriate diagnosis also as a “starting point” for making sense of their conditions.

Our results also provide information on research and professional training. Research is relatively well-advanced compared to other health policy aspects, since most countries have centers developing translational research programs and there is widespread interest in translating results and sharing information (27–35). Nevertheless, international cooperation needs to be promoted and strengthened. The need for international cooperation and sharing of best practices extends also to professional training, as acknowledged and enabled by the UEMS. Beyond expert specialist training, RD should become part of the general syllabus of medical schools and of the education of other health professionals.

The results of this survey, although retrospective and involving a relatively small number of responders, represent a snapshot of the concerns of a broad range of clinicians and scientists with extensive expertise in rare diseases, identifying a range of issues that call for tailored investigation in specific world areas. Hence, the findings provide a framework for the future advancement of rare disease research and healthcare, particularly in low and medium income countries. A possible drawback of this work is that the individuals who created the questions also completed the survey. We note, however, that the survey responses represent answers to those questions and those answers are based upon experience and facts. Moreover, the authors of the survey are not a homogeneous group but have varied backgrounds and experiences, so that one member's questions address issues not previously considered by other individuals in the group. At times, individual survey results might also confirm issues raised by other group members. Therefore, the survey results portray a valuable perspective on a comprehensive array of issues relevant to the unmet needs of persons with RD.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent was not required to participate in this study in accordance with the local legislation and institutional requirements.

DT, MS, CC, LC, SS, and AL analyzed the data and were the major contributor in drafting the manuscript. GF, SG, YA, MA, GB, HC, EC-d, VD, RG, CG-J, DH, OK, GL, PM, BM, UO, RP, VR, VSc, SJ, VSh, DR, WG, SW, OB, and MP carefully revised draft, tables and figures, and approved final manuscript. All authors contributed to the article and approved the submitted version.