Navigating Diagnostic Odysseys of Undiagnosed Diseases in Neurology: Emerging Paradigms Using Deep Phenotyping and Omics-based Approaches*
Date: September 15, 2025
Time: 8:45 am to 10:45 am
Track: Plenary
Session Description
Undiagnosed diseases, often characterized by complex, long-standing symptoms, remain a major challenge in neurology, with over 50% of undiagnosed cases presenting with a neurological phenotype. These conditions fall into four categories: atypical presentations of common or rare diseases, typical presentations of rare diseases, and entirely unknown disorders. Despite advancements in clinical diagnostics, including exome sequencing, over half of rare disease patients remain undiagnosed, hindering targeted treatments and therapeutic development. The economic burden is immense, stemming from unnecessary medical evaluations, ineffective treatments, and lost productivity.
The NIHās Undiagnosed Diseases Network has made significant progress in addressing these challenges through team science, advanced genomic technologies, and deep clinical phenotyping. This session will explore diagnostic strategiesāincluding emerging technologies like long-read sequencing and multiomicsāwhile addressing barriers to equitable access. By fostering collaboration and critical thinking, this symposium aims to bridge gaps in neurological diagnosis and improve patient outcomes.
Learning Objectives
At the conclusion of this symposium, attendees should be able to:
- Identify the key categories of undiagnosed neurological diseases and discuss the diagnostic approach to work up of an unknown neurological disease using first line diagnostics.
- Evaluate the role of advanced genomic technologies, including whole-genome sequencing, long-read sequencing, and multi-omics approaches, in diagnosing complex neurological conditions.
- Apply principles of deep clinical phenotyping, including detailed medical, neurological, and family history-taking, and team-based collaboration to improve diagnostic accuracy and reduce the diagnostic odyssey for patients with undiagnosed neurological diseases.
Speakers
Introduction to Undiagnosed Diseases, Current Challenges, and Translating Omics-based Tools to the Clinic
Description
Undiagnosed diseases are defined as complex conditions with long-standing symptoms or elusive medical presentations that remain undiagnosed despite extensive clinical evaluation. In this presentation, the speaker will discuss the utility of deep clinical phenotyping, whole-genome sequencing, and emerging technologies such as long-read sequencing, high-resolution genome mapping, and multiomics-based approaches in the evaluation of challenging undiagnosed neurological diseases.
Speakers
Commonly Underdiagnosed and Misdiagnosed Neurometabolic Disorders, and a Window to Personalized Medicine
Description
This presentation will discuss the use of targeted metabolic and untargeted metabolomics in the diagnosis of patients with treatable neurometabolic disorders, using a case-based approach.
Speakers
Diagnoses and Precision Therapeutics in Developmental Epileptic Encephalopathies: SCN2A
Description
This presentation will discuss how developmental epileptic encephalopathy is characterized by significant genotype-phenotype heterogeneity, including seizures, developmental delay, ataxia, autism, and choreoathetosis. Causal SCN2A variants include both toxic gain-of-function mutations and haploinsufficiency. Antisense oligonucleotides targeting SCN2A variants are currently in clinical trials, showing positive safety and efficacy signals. This represents a novel application of bridging variant identification with deep phenotyping to advance personalized medicine and targeted genetic therapy.
Speakers
