(21) Advanced Diagnostics for Rare Genetic Diseases: Insights from the UW-Undiagnosed Disease Program

Background: The University of Wisconsin-Undiagnosed Disease Program (UW-UDP) evaluates patients with suspected genetic diseases where standard of care genetic testing is negative. Despite over 9,000 rare disorders having a known cause, conventional clinical whole exome sequencing (WES) often fails to diagnose most patients.

Objectives: The UW-UDP's main objectives are to 1) discover new disease genes, 2) improve our understanding of genetic disorders, 3) provide patients with actionable diagnoses, and 4) evaluate emerging technologies.

Design/Methods: The UW-UDP enrolls families into our IRB-approved research study, obtaining written informed consent from all participants. DNA isolated from patient samples is comprehensively analyzed using short-read and/or long-read whole genome sequencing (WGS). Additionally, some patients receive further research testing, including RNA sequencing, optical genome mapping, and other advanced techniques.

Results: To date, the UW-UDP has enrolled 108 families, including 124 affected individuals and 190 unaffected relatives. 92.6% of probands had previously received clinical WES. We identified candidate causal variants for 35.7% of the cases analyzed. Successes stem from reanalyzing WES data to identify variants in newly discovered disease genes, collaborating with researchers via GeneMatcher, identifying intronic variants, and characterizing structural rearrangements. Notable case examples include:
• A 12-year-old boy with global developmental delay/intellectual disability (GDD/ID) and congenital hypotonia, identified as the fourth reported case of CAPZA2-related disorder, with a de novo CAPZA2 missense variant (c.776G>T, p.Arg259Leu).
• A 13-year-old boy with GDD/ID, microcephaly, and seizures, identified with a de novo in-frame deletion in AGO1 (c.901_903delGAG; p.Glu376del), causative of an ultra-rare disorder termed Neurodevelopmental disorders with language delay and behavioral abnormalities, with or without seizures (NEDLAS).

Conclusion: Our initial findings indicate that an undiagnosed disease program can be an important component of a comprehensive center for rare diseases. By augmenting clinical testing with comprehensive research, access to emerging technologies, and a growing body of scientific literature, we have observed an increase in diagnostic rates for patients previously undiagnosed with standard methods. Together, these advancements improve diagnostic accuracy and contribute to better patient outcomes.