A prospective study has found that singleton whole-exome sequencing (WES) as a first-tier test in infants with suspected monogenic genetic disorders outperforms standard care. The team compared the rate of diagnosis, clinical utility and impact on management of singleton WES with that of standard investigations, such as single- or multigene panel sequencing, which were undertaken in parallel if clinically indicated. Overall, WES led to a diagnosis in 46 out of 80 participants (57.5%), whereas standard genetic tests led to a diagnosis in 13.75% of infants. Clinical management improved as a result of WES, as management was altered for 15 out of 46 participants after WES-based diagnosis. Finally, a greater number of relatives benefited from WES compared with standard care; a genetic diagnosis following additional testing was determined for 12 versus 5 cases, respectively, and 28 versus 13 couples were found to have a high recurrence risk for future pregnancies.