The University of Wisconsin Undiagnosed Disease Program: Unveiling Rare Neurodevelopmental Disorders in...

The University of Wisconsin Undiagnosed Disease Program employs a "beyond the exome" approach to diagnose rare disease patients.

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).

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.

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.