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Enhancing Ultra-Rare Disease Diagnoses through Multi-Omics Integration and Multi-Site Collaboration in the Indiana University Undiagnosed Rare Disease Clinic (URDC) Cohort

Health Services and Implementation
  • Primary Categories:
    • Health services and Implementation
  • Secondary Categories:
    • Health services and Implementation
Introduction:
In the United States, rare disease (RD) is defined as a condition, which affects fewer than 200,000 individuals, or about 1 in 1,600 people in the current population. Globally, approximately 300 million affected individuals worldwide, RDs are a leading cause of child mortality and disability in high-income countries. However, collectively, there are about 7,000 of these disorders affecting 6–8% of the US population, representing a significant public health and socioeconomic cost.  Beyond the medical, financial, and emotional burdens faced by patients, the full scope of RDs remains unclear, with estimates suggesting over 8,000 conditions exist. People living with rare diseases often struggle for years before receiving an accurate diagnosis, and often remain undiagnosed for a decade or longer. The diagnostic odyssey often includes many clinical visits, medical testing that is sometimes invasive, and possible incorrect diagnoses. Furthermore, even with a diagnosis only about 5 percent of rare diseases have approved treatments. Established in January 2020, the Undiagnosed Rare Disease Clinic (URDC) is a multidisciplinary center dedicated to offering genetic diagnoses for patients and families navigating the uncertainty of undiagnosed rare diseases. In September 2023, URDC has been designated as Indiana University Diagnostic Center of excellence as clinical site of Undiagnosed disease network (UDN).

 

Methods:
The URDC team enroll only those patients which have been suffering from genetic disorder and are undiagnosed even after extensive genetic testing. Upon enrollment, patient samples are collected during clinic visits for reanalysis, including exome sequencing (ES), research-based genome sequencing (GS), RNA sequencing (RNA-Seq), and targeted metabolomic testing. Clinically negative exome sequencing (ES) data is reanalyzed periodically and GS data is analyzed to identify the causative variant in non-coding regions, mitochondrial, STR and Copy number alterations (CNV) that are usually not captured by ES. The RNA-Seq data is analyzed to validate splice-altering variants.

 

Results:
Out of 133 enrolled patients, 110 cases have been analyzed resulted in 17 solved 7 possibly solved cases, with approximately 20% diagnostic rate. The remaining undiagnosed patients present a unique opportunity for further research and novel gene discovery. The team developed multi-site collaborations with various research and clinical groups to study the functional effect of genes and variant candidates. The teamwork of URDC is especially important in the state of Indiana as it has been markedly underserved regarding genetic services. Thankfully, URDC can provide this specialty care and serve health disparities populations everywhere.

 

Conclusion:
In conclusion, we describe the experience of URDC, the analytical strategy and the results obtained in the last four years, and our experience and learned lessons with URDC as it relates to ultra-rare disease patients. We summarize the results of this pilot project and emphasize the importance of a sustainable institutional URDC program.

Agenda

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