(68) Improving Diagnostic Yield for Rare Genetic Disorders: Results from the University of Wisconsin-undiagnosed Disease Program

Background: The University of Wisconsin-Undiagnosed Disease Program (UW-UDP), established in 2020 and recognized as an Undiagnosed Disease Network Diagnostic Center of Excellence, aims to provide diagnostic clarity for patients with suspected rare genetic disorders who remain undiagnosed despite prior clinical genetic testing, including exome sequencing (ES). We employ advanced genomic technologies to improve diagnostic precision and uncover novel disease mechanisms. We also aim to promote health equity by engaging underrepresented and underinsured communities and addressing the challenges of living with an undiagnosed disease.

Objectives: Our objectives are to: 1) discover new disease genes; 2) advance understanding of genetic disorders; 3) provide actionable diagnoses; and 4) evaluate emerging technologies.

Design/Methods: We enrolled patients and families into our IRB-approved research study. Participants have received short-read genome sequencing (GS) as the frontline test. Additional analyses, such as long-read GS, RNA sequencing (RNA-seq), optical genome mapping (OGM), and functional studies were performed as needed.

Results: To date, we have received over 250 referrals and have enrolled 130 families, of whom 24% reside in highly disadvantaged areas and 9% in rural areas. Notably, 91.6% had prior ES without diagnosis. We identified disease-causing variants in 34.6% of cases analyzed. Key findings include: 1) detection of variants in newly recognized disease genes; 2) identification of intronic and noncoding RNA variants; 3) elucidation of structural rearrangements using long-read GS and OGM; and 4) functional insights gained from RNA-seq. We diagnosed ultra-rare and novel disorders caused by pathogenic variants in genes such as AFG3L2, AGO1, CAPZA2, EMC1, HECTD1, RNU4-2, SPTAN1, and VPS50, as well as two patients with multiple rare genetic conditions.

Conclusions: Through a comprehensive, research-driven approach that integrates advanced genomic technologies, the UW-UDP has diagnosed over a third of patients with suspected genetic disorders. Utilizing emerging technologies like long-read GS, RNA-seq, and OGM improves diagnostic rates and enables the practice of precision medicine through tailored genetic counseling and targeted interventions. Looking forward, we aim to expand our reach and impact by integrating new technologies, exploring the impact of social determinants of health on outcomes, and deepening collaboration to set new standards for diagnosing and managing rare diseases.