Background: Genomic testing transforms the diagnosis and management of rare conditions. However, uncertainty exists on how to best measure genomic outcomes for informing healthcare priorities. Using the HTA-preferred method should be the starting point to improve the evidence-base. This study explores the responsiveness of SF-6D, EQ-5D-5L and AQoL-8D following genomic testing across childhood and adult-onset genetic conditions. Method: Self-reported patient-reported outcomes (PRO) were obtained from: primary caregivers of children with suspected neurodevelopmental disorders (NDs) or genetic kidney diseases (GKDs) (carers' own PRO), adults with suspected GKDs using SF-12v2; adults with suspected complex neurological disorders (CNDs) using EQ-5D-5L; and adults with dilated cardiomyopathy (DCM) using AQol-8D. Responsiveness was assessed using the standardised response mean effect-size based on diagnostic (having a confirmed genomic diagnosis), personal (usefulness of genomic information to individuals or families), and clinical (clinical usefulness of genomic information) utility anchors. Results: In total, 254 people completed PRO measures before genomic testing and after receiving results. For diagnostic utility, a nearly moderate positive effect size was identified by the AQoL-8D in adult DCM patients. Declines in physical health domains masked any improvements in mental or psychosocial domains in parents of children affected by NDs and adult CNDs and DCM patients with confirmed diagnosis. However, the magnitude of the changes was small and we did not find statistically significant evidence of these changes. No other responsiveness evidence related to diagnostic, clinical, and personal utility of genomic testing was identified. Conclusion: Generic PRO measures may lack responsiveness to the diagnostic, clinical and personal outcomes of genomics, but further research is needed to establish their measurement properties and relevant evaluative space in the context of rare conditions. Expected declines in the physical health of people experiencing rare conditions may further challenge the conventional application of quality of life assessments. Key points: While a growing body of literature has examined the validity of generic and disease-specific patient-reported outcome measures (PROMs) in rare conditions and discussed the challenges of using PROMs in the context of genomic medicine, there is limited empirical evidence exists to demonstrate the responsiveness of generic PROMs in the context of genomic testing. We aimed to provide empirical evidence on the responsiveness of three common generic PROMs (SF-6D, EQ-5D-5L and AQoL-8D) in terms of the presence of diagnostic, personal, and clinical utility of genomics, by using data from four cohorts recruited within the Australian and Melbourne Genomics Health Alliances, 2016–2019. Generic PROMs may lack responsiveness to the diagnostic, clinical and personal outcomes of genomics. Expected declines in the physical health of people experiencing rare conditions may further challenge the conventional qapplication of uality of life assessments. [ABSTRACT FROM AUTHOR]