A global survey about Undiagnosed Rare Diseases: perspectives, challenges, and solutions

Simone Baldovino ^1* Savino Sciascia ^1,2* Claudio Carta ³ Marco Salvatore ⁴ Laura L Cellai ³ Luca Ferrari ³ Aimè Lumaka ⁵ Stephen Groft ⁶ Yasemin Alanay ⁷ Maleeha Azam ⁸ Gareth Baynam ⁹ Helene Cederroth ¹⁰ Eva Maria Cutiongco-de la Paz ¹¹ Vajira Dissanayake ¹² Roberto Giugliani ¹³ Claudia Gonzaga-Jauregui ¹⁴ Dineshani Hettiarachchi ¹² Oleg Kvlividze ¹⁵ Guida Landouré ¹⁶ Prince Makay ⁵ Béla Melegh ¹⁷ Ugur Ozbek ⁷ Karaman Pagava ¹⁸ Ratna Dua Puri ¹⁹ Vanessa Romero ²⁰ Vinod Scaria ²¹ Saumya Jamuar ²² Vorasuk Shotelersuk ²³ Dario Roccatello ² William Gahl ²⁴ Samuel Wiafe ²⁵ Olaf Bodamer ²⁶ Manuel Posada ²⁷ Domenica Taruscio ^4*

• ¹ Department of Clinical and Biological Sciences, School of Medicine, University of Turin, Turin, Italy
• ² University Center of Excellence on Nephrologic, Rheumatologic and Rare Diseases, San Giovanni Bosco Hospital, Turin, Piedmont, Italy
• ³ National Center for Rare Diseases, National Institute of Health (ISS), Rome, Lazio, Italy
• ⁴ National Center Rare Diseases - Undiagnosed Rare Diseases Interdepartmental Unit, National Institute of Health (ISS), Rome, Italy
• ⁵ Reference Center for Rare and Undiagnosed Diseases, University of Kinshasa, Kinshasa, Democratic Republic of Congo
• ⁶ National Center for Advancing Translational Sciences (NIH), Bethesda, Maryland, United States
• ⁷ ACURARE-Rare and Undiagnosed Diseases Center, Acibadem University, Istanbul, Istanbul, Türkiye
• ⁸ Comsats University Islamabad, Islamabad, Pakistan
• ⁹ Rare Care Centre, Perth Children's Hospital, Perth, Western Australia, Australia
• ¹⁰ Wilhelm Foundation, Brottby, Stockholm, Sweden
• ¹¹ Institute of Human Genetics, National Institutes of Health, University of the Philippines Manila, Manila, Philippines
• ¹² Department of Anatomy, Genetics & Biomedical Informatics, Faculty of Medicine, University of Colombo, Colombo, Western Province, Sri Lanka
• ¹³ House of Rares, Medical Genetics Service, HCPA, Department Genetics UFRGS and DASA, Porto Alegre, Brazil
• ¹⁴ International Laboratory for Human Genome Research, National Autonomous University of Mexico, Querètaro, Mexico
• ¹⁵ Georgian Foundation for Genetic and Rare Diseases (GeRaD), Tbilisi, Tbilisi, Georgia
• ¹⁶ Faculté de Médecine et d'Odontostomatologie, Université des Sciences, des Techniques et des Technologies de Bamako, Bamako, Mali
• ¹⁷ Department of Medical Genetics, Medical School, University of Pécs, Pécs, Hungary
• ¹⁸ Department of Child & Adolescent Medicine, Tbilisi State Medical University, Georgia, Georgia
• ¹⁹ Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi,, Delhi, India
• ²⁰ College of Health Sciences, San Francisco de Quito University, Quito, Pichincha, Ecuador
• ²¹ Institute of Genomics and Integrative Biology, Council of Scientific and Industrial Research (CSIR), Delhi, Delhi, India
• ²² SingHealth Duke-NUS Institute of Precision Medicine (PRISM), Singapore, Singapore
• ²³ Medical Excellence Center in Genomics and Precision Medicine, King Chulalongkorn Memorial Hospital, Bangkok, Thailand
• ²⁴ National Human Genome Research Institute (NIH), Bethesda, Maryland, United States
• ²⁵ Rare Disease Ghana Initiative, Accra, Ghana
• ²⁶ Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States
• ²⁷ Rare Diseases Research Institute, Carlos III Health Institute (ISCIII), Madrid, Madrid, Spain

BackgroundUndiagnosed rare diseases (URDs) are a complex and multifaceted challenge, especially in low—and medium-income countries. They affect individuals with unique clinical features and lack a clear diagnostic label. Although the Undiagnosed Diseases Network International (UDNI) definition of URDs is not universally accepted, it is widely recognized.MethodsWe surveyed UDNI members and participants from other countries to explore the challenges posed by URDs and identify possible solutions. Participation in the survey was completely voluntary.ResultsThe survey revealed a need for more consensus on a universally accepted definition for URDs. Still, the UDNI definition gained widespread recognition and serves as a valuable framework for understanding and addressing the challenges of URDs. In addition to national or international networks, fostering a more substantial engagement and resource-sharing ethos among member countries is critical.Despite advances in genomics and diagnostic tools, the diagnostic journey for people living with URDs (PLRUD) remains arduous and often inconclusive. The availability of specialized centers and the utilization of whole exome sequencing (WES) and whole genome sequencing (WGS) vary across countries, with disparities due to healthcare systems, economic status, and government policies. Advocacy groups play a crucial role in supporting PLRUD.ConclusionsA unified commitment to prioritizing URDs on the global health agenda, paired with targeted funding, stipulated national strategies, and aligned international cooperation, is imperative to leveling the playing field for the diagnosis and management of URDs and capitalizing on the potential of Advocacy Groups as allies in this endeavor.