Abstract
Genetic disorders are a leading cause of morbidity and mortality in infants. Rapid whole-genome sequencing (rWGS) can diagnose genetic disorders in time to change acute medical or surgical management (clinical utility) and improve outcomes in acutely ill infants. We report a retrospective cohort study of acutely ill inpatient infants in a regional children’s hospital from July 2016–March 2017. Forty-two families received rWGS for etiologic diagnosis of genetic disorders. Probands also received standard genetic testing as clinically indicated. Primary end-points were rate of diagnosis, clinical utility, and healthcare utilization. The latter was modelled in six infants by comparing actual utilization with matched historical controls and/or counterfactual utilization had rWGS been performed at different time points. The diagnostic sensitivity of rWGS was 43% (eighteen of 42 infants) and 10% (four of 42 infants) for standard genetic tests (P = .0005). The rate of clinical utility of rWGS (31%, thirteen of 42 infants) was significantly greater than for standard genetic tests (2%, one of 42; P = .0015). Eleven (26%) infants with diagnostic rWGS avoided morbidity, one had a 43% reduction in likelihood of mortality, and one started palliative care. In six of the eleven infants, the changes in management reduced inpatient cost by $800,000–$2,000,000. These findings replicate a prior study of the clinical utility of rWGS in acutely ill inpatient infants, and demonstrate improved outcomes and net healthcare savings. rWGS merits consideration as a first tier test in this setting.
Highlights
Of 14% of US newborns admitted to neonatal intensive care units (NICU), those with genetic disorders have longer hospitalizations and higher resource utilization.[1,5]
While early etiologic diagnosis in such infants enables optimal outcomes, it is exceptionally difficult to deliver for genetic diseases since they number over 8000 and presentations are often atypical from classical descriptions.[6]
The severity of illness was high: 71% were in a regional NICU, paediatric intensive care unit (PICU) or cardiovascular intensive care unit, 76% received respiratory support and 40% inotropic support
Summary
Genetic disorders and congenital anomalies affect ~6% of live births, and are the leading reason for hospitalization and mortality in infants.[1,2,3,4] Of 14% of US newborns admitted to neonatal intensive care units (NICU), those with genetic disorders have longer hospitalizations and higher resource utilization.[1,5] While early etiologic diagnosis in such infants enables optimal outcomes, it is exceptionally difficult to deliver for genetic diseases since they number over 8000 and presentations are often atypical from classical descriptions.[6]. Rapid whole-genome sequencing (rWGS) provides a faster diagnosis, enabling precision medicine interventions in time to decrease the morbidity and mortality of infants with genetic diseases.[6] rWGS facilitates end-of-life care decisions that can alleviate suffering and aid the grieving process. Published evidence demonstrating the effectiveness of rWGS in improving outcomes in infants is insufficient to endorse largescale implementation;[8] It is limited to case reports, and one retrospective study (Level III evidence).[9] Examination of reproducibility is imperative.
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