Nature Biotechnology, Published online: 05 January 2026; doi:10.1038/s41587-025-02931-2Our understanding of the genetic mechanisms underlying rare diseases has rapidly advanced over the past decade, largely because of technological innovations. Yet clinical practice still has a strong monogenic focus, leaving many individuals undiagnosed. This Comment outlines how technological advances such as long-read sequencing should be adopted to increase multivariant testing in the clinic.