SEMINAR: Grey-zone patients in rare disease: how to operate in the AI era?

Guest: Serdar Ceylaner, Intergen, Lokman Hekim University

Title: Grey-zone patients in rare disease: how to operate in the AI era? (BIO, CS, DS)

Date/Time: December, 15, 2025, 13:40-14:30

Location: FENS L045

Abstract: Rare disease diagnostics includes a growing “grey-zone” population: patients who remain undiagnosed, resemble other disorders without fully matching any established phenotype, and yield no definitive findings on genetic testing. Many carry variants of uncertain significance (VUS), have complex or non-classical presentations, or may even represent previously unrecognized conditions. Moving these patients from uncertainty to a working diagnosis has become an emerging discipline—one that only a small number of teams worldwide actively pursue. AND MORE THEN 90 PERCENT OF THE CHRONIC PATIENTS AND HALF OF THE PEDIATRIC CHRONIC PATIENTS ARE IN THE GREY ZONE.The challenge is inherently multifactorial. Clinically, symptoms may be incomplete, evolving, or overlapping across multiple disease categories. Genetically, the signal may be distributed across multiple variants of different effect sizes, complicated by structural variation, mosaicism, regulatory changes, or non-coding mechanisms that are not captured well by routine testing. Beyond genetics, patients may have one disease, multiple coexisting conditions, or modifying factors that increase or decrease severity. Lifestyle, environmental exposures, and social determinants can add further complexity. In addition, prolonged diagnostic odysseys can lead to psychological exhaustion, reduced motivation to pursue further investigations, and reluctance to engage in complex diagnostic pathways. Although computational methods such as polygenic risk scores and other integrative algorithms exist, they have not yet achieved the performance needed for routine resolution of these grey- zone cases. This is partly because real patients rarely follow single-variable models: disease expression is shaped by interacting factors, competing explanations, and context-dependent modifiers that cannot be fully captured by current tools. At the same time, the clinical reality is stark: the physician attempting to integrate thousands of pathways, drugs, rare disease entities, and heterogeneous patient-level variables may have as little as 30 minutes with a patient—sometimes after years of uncertainty. Progress in this space therefore cannot rely on individual effort alone. Meaningful acceleration requires a team-based approach and structured technical support for clinicians, including coordinated input from molecular geneticists, bioinformaticians, laboratory specialists, and—when needed—experts in metabolics, immunology, neurology, and therapeutics. This meeting will focus on defining the grey-zone in rare disease diagnostics, examining its major causes (biological, technical, and psychosocial), and developing a shared pathway forward. The central goal is to move beyond isolated perspectives: for progress to be possible, all stakeholders must understand each other’s constraints, align on common language and priorities, and work as a single diagnostic and therapeutic team.
 

Bio: Prof. Dr. Serdar Ceylaner is a medical doctor - medical geneticist who focuses on rare and undiagnosed diseases for both diagnosis and scientific studies. He is the director, partner and founder of Intergen Genetics and Rare Diseases Diagnostic and Research Center and Lokman Hekim University, Department of Medical Genetics.

Serdar Ceylaner is also,

• European Union of Medical Specialists (UEMS), President of the Rare and Undiagnosed Diseases Committee,

• UEMS -Department of Medical Genetics- Turkis representative

• UDNI- Undiagnosed Disease Network International, Member

• UDNI- Low Middle Income Countries working Group, Co-Chair

• Rare Diseases International (RDI)- CGN4RD Member

He is the former president of the Turkish Medical Genetics Association and was a board member between 2009-2017. He was the founder of the Genetics Department of Zekai Tahir Burak Women’s Health and Training Hospital between 1997 and 2017.

He has focused on genetics and rare diseases and studies in this field for 30 years. He established a center for diagnosis, research and educational work in this field. Undiagnosed diseases, medical complications, and intensive care unit patients are the main research areas in recent years. He has experience in more than 250 international publications, 1 book, 20 book chapters, more than 500 conferences, and more than 80 scientific projects.