The University of Wisconsin Undiagnosed Disease Program: Unveiling Rare Neurodevelopmental Disorders in Exome-Negative Patients

Introduction: The University of Wisconsin Undiagnosed Disease Program employs a “beyond the exome” approach to diagnose rare disease patients.

Case presentations: We present 2 cases of rare neurodevelopmental disorders identified by whole genome sequencing. The first is a 12-year-old boy with global developmental delay/intellectual disability (GDD/ID) and congenital hypotonia who was diagnosed with CAPZA2-related disorder. The second is a 13-year-old boy with microcephaly, GDD/ID, and seizures who was diagnosed with neurodevelopmental disorder with language delay and behavioral abnormalities, with or without seizures (NEDLAS).

Discussion: Our use of whole genome sequencing identified the fifth reported case of CAPZA2-related neurodevelopmental disorder. Fewer than 40 patients have been reported with NEDLAS, and we identified the fourth patient with the AGO1 in-frame deletion p.Glu376del.

Conclusions: Whole genome sequencing can be effective in diagnosing patients with suspected genetic disorders despite negative standard of care clinical genetic testing and enables the practice of precision medicine.