Here, we use five case examples to illustrate the unique ability of broad-based testing to improve diagnostic yield, resulting in identification of <i>SORD-</i>neuropathy, <i>HADHB</i>-related disease, <i>ATXN2</i>-ALS, <i>MECP2</i> related progressive gait decline and spasticity, and <i>DNMT1</i>-related cerebellar ataxia, deafness, narcolepsy, and hereditary sensory neuropathy type 1E. Here, HADHB is linked to aceruloplasminemia.