A three-year follow up study on 104 exome-sequenced patients with paediatric-onset diseases: Exome reanalysis and the impacts on clinical management and outcome

Abstract

Introduction: Whole exome sequencing (WES) has become one of the important diagnostic tools in clinical genetics with mean diagnostic rate of 36%. Many studies have illustrated the diagnostic and immediate clinical impact of WES. However, a vast majority of patients remain undiagnosed and there is little documentation of the long-term(>1year) clinical utility. Methods: This is a three-year follow-up analysis to our previous publication(PMID:30109123). The diagnostic yield was 41% (43/104). 46 non-diagnosed patients consented for the reanalysis. Depending on the availability, either raw sequencing data were reanalyzed, or stored DNA were re-sequenced. The long-term outcome of 36 diagnosed patients were measured by clinical follow-up and review of medical records.Results: WES reanalysis gave rise to twelve additional diagnoses (table), boosting the overall diagnostic yield from 41% to 53%. The reanalysis of one patient had lead the discovery of MN1 C-Terminal Truncation (MCTT) syndrome caused by mutations in MN1(PMID:31834374). Currently, we are prospectively collecting and sharing more clinical information on the disease. If you have a patient with MCTT syndrome or would like to learn more, please visit https://humandiseasegenes.nl/mn1/. After three years of follow-up, change in clinical management was observed in 72.2% of the families(26/36), leading to positive change in outcome in four patients(11%). Conclusion: WES reanalysis provides promising additional diagnoses to patients. Longitudinal follow-up showed that a genetic diagnosis gave rise to positive management and outcomes for patients.