Purpose: To systematically investigate the longer-term clinical and health economic impacts of genomic sequencing for rare-disease diagnoses. Methods: We collected information on continuing diagnostic investigation, changes in management, cascade testing, and parental reproductive outcomes in 80 infants who underwent singleton whole-exome sequencing (WES). Results: The median duration of follow-up following result disclosure was 473 days. Changes in clinical management due to diagnostic WES results led to a cost saving of AU$1,578 per quality-adjusted life year gained, without increased hospital service use. Uninformative WES results contributed to the diagnosis of non-Mendelian conditions in seven infants. Further usual diagnostic investigations in those with ongoing suspicion of a genetic condition yielded no new diagnoses, while WES data reanalysis yielded four. Reanalysis at 18 months was more cost-effective than every 6 months. The parents of diagnosed children had eight more ongoing pregnancies than those without a diagnosis. Taking the costs and benefits of cascade testing and reproductive service use into account, there was an additional cost of AU$8,118 per quality-adjusted life year gained due to genomic sequencing. Conclusion: These data strengthen the case for the early use of genomic testing in the diagnostic trajectory, and can guide laboratory policy on periodic WES data reanalysis.