Rapid exome sequencing as a first-tier test in neonates with suspected genetic disorder: results of a prospective multicenter clinical utility study in the Netherlands

Abstract

The introduction of rapid exome sequencing (rES) for critically ill neonates admitted to the neonatal intensive care unit has made it possible to impact clinical decision-making. Unbiased prospective studies to quantify the impact of rES over routine genetic testing are, however, scarce. We performed a clinical utility study to compare rES to conventional genetic diagnostic workup for critically ill neonates with suspected genetic disorders. In a multicenter prospective parallel cohort study involving five Dutch NICUs, we performed rES in parallel to routine genetic testing for 60 neonates with a suspected genetic disorder and monitored diagnostic yield and the time to diagnosis. To assess the economic impact of rES, healthcare resource use was collected for all neonates. rES detected more conclusive genetic diagnoses than routine genetic testing (20% vs. 10%, respectively), in a significantly shorter time to diagnosis (15 days (95% CI 10–20) vs. 59 days (95% CI 23–98, p < 0.001)). Moreover, rES reduced genetic diagnostic costs by 1.5% (€85 per neonate).Conclusion: Our findings demonstrate the clinical utility of rES for critically ill neonates based on increased diagnostic yield, shorter time to diagnosis, and net healthcare savings. Our observations warrant the widespread implementation of rES as first-tier genetic test in critically ill neonates with disorders of suspected genetic origin. What is Known:• Rapid exome sequencing (rES) enables diagnosing rare genetic disorders in a fast and reliable manner, but retrospective studies with neonates admitted to the neonatal intensive care unit (NICU) indicated that genetic disorders are likely underdiagnosed as rES is not routinely used.• Scenario modeling for implementation of rES for neonates with presumed genetic disorders indicated an expected increase in costs associated with genetic testing. What is New:• This unique prospective national clinical utility study of rES in a NICU setting shows that rES obtained more and faster diagnoses than conventional genetic tests.• Implementation of rES as replacement for all other genetic tests does not increase healthcare costs but in fact leads to a reduction in healthcare costs.

Universal Exome Sequencing in Critically Ill Adults: A Diagnostic Yield of 25% and Race-Based Disparities in Access to Genetic Testing

“…The high yield of broad exome sequencing that we report in critically ill adults can be put in the context of a number of recent similar studies of broad exome/genome sequencing in the critically ill pediatric and neonatal patient populations that have reported diagnostic rates of 21-38%. 2–4,9,10 The diagnostic yield that we report here is essentially the same as those reported in these studies, suggesting that critical illness is a strong predictor of Mendelian disease across the life span. Importantly, many of these studies found significant cost savings and important changes in management due to rapid exome/genome sequencing.…”

Idiopathic ventricular fibrillation: is it a case for genetic testing?

“…In general clinical care, there is a growing tendency to perform genetic testing at an early stage in critically ill patients without a clear clinical diagnosis, firstly via whole exome sequencing. Indeed, the introduction of rapid exome sequencing in critically ill neonates has proven to increase diagnostic yield, reduce time to diagnosis and decrease healthcare costs [ 20 ]. In SCA survivors, the indication for and timing of genetic testing will differ between individual patients.…”

Future of Dutch NGS-Based Newborn Screening: Exploring the Technical Possibilities and Assessment of a Variant Classification Strategy

“…As IMDs are hereditary, genetic testing using next-generation sequencing (NGS) techniques can overcome these shortcomings. NGS-based genetic testing is an all-in-one assay that can easily be modified to include new disorders, and NGS is already widely used in clinical care to diagnose patients with a suspected genetic condition [ 7 , 8 , 9 , 10 , 11 ]. Several recent studies also started to explore the use of NGS-based tests in NBS [ 12 , 13 ].…”