Severe childhood epilepsies with developmental delay, known as developmental and epileptic encephalopathies (DEE), are often caused by genetic changes. However, standard DNA tests, such as exome sequencing and short-read genome sequencing, sometimes fail to identify the underlying genetic cause. In this study, we used long-read genome sequencing (LR-GS) to analyze patients with DEE who remained undiagnosed after standard testing. We identified the genetic cause in 21% of these cases. Most diagnoses involved large missing DNA segments that earlier tests could not detect. Our findings show that LR-GS can help end the diagnostic journey for affected families. (https://jmg.bmj.com/content/early/2026/04/27/jmg-2026-111514)