Rapid Targeted Genomics in Critically Ill Newborns

Abstract

Rapid targeted genomics combined with copy number variant detection adds important value in the neonatal and pediatric intensive care setting. It led to a fast diagnosis in 30% of critically ill children for whom the routine clinical workup was unsuccessful.

Targeted gene panel sequencing for the rapid diagnosis of acutely ill infants

“…We have shown multiple clinical benefits with potential total cost reduction when a rapid targeted gene panel is used. The success rate of RapSeq was at least as high as previously reported for rES and rGS (Soden et al, ; van Diemen et al, ). Moreover, the cost of RapSeq is about one half as much as rES and one third of rGS, and data interpretation is simplified by examining a panel of genes with known function.…”

Genetic counseling in pediatric acute care: Reflections on ultra‐rapid genomic diagnoses in neonates

“…Trio genomic sequencing in pediatric acute care settings may increase diagnostic yield compared to singleton sequencing and enhances ease of analysis (Baxter & King, ; Meng et al, ; Wright, FitzPatrick, & Firth, ). Additionally, trio sequencing simultaneously elucidates recurrence risk, allowing for timely preconception genetic counseling (van Diemen et al, ; Meng et al, ; Willig et al, ). Despite the increased costs and resource barriers, there is growing evidence for the health economic benefits of expedited genomic sequencing in acutely unwell infants with suspected monogenic conditions (Farnaes et al, ; Stark, Lunke, et al, Stark, Lunke, et al, ).…”

“…Technological and bioinformatic advancements, along with the availability of analytical expertise, have significantly reduced genomic sequencing turnaround times , enabling this powerful diagnostic tool to be used in pediatric acute care settings, such as neonatal or pediatric intensive care units (NICUs or PICUs), in place of or alongside traditional diagnostic strategies (van Diemen et al, 2017;Farnaes et al, 2018;Meng et al&&, 2017;Mestek-Boukhibar et al, 2018;Petrikin et al, 2015;Stark, Lunke, et al, 2018;Willig et al, 2015). Multiple studies have shown that a definitive molecular diagnosis in the pediatric acute care setting can provide prognostic information, altering management decisions and clinical outcomes Meng et al, 2017;Mestek-Boukhibar et al, 2018;Stark, Lunke, et al, Stark, Lunke, et al, 2018;Stark, Schofield, et al, Stark, Schofield, et al, 2018;Stark et al, 2016;van Diemen et al, 2017;Willig et al, 2015), and evidence is emerging that turnaround times impact clinical utility (Meng et al, 2017;Stark, Lunke, et al, Stark, Lunke, et al, 2018;van Diemen et al, 2017;Willig et al, 2015). However, the clinical value of rapid genomic sequencing can be difficult to rigorously demonstrate (Friedman et al, 2018;Grosse & Farnaes, 2018;Petrikin et al, 2015Petrikin et al, , 2018.…”

“…Trio genomic sequencing in pediatric acute care settings may increase diagnostic yield compared to singleton sequencing and enhances ease of analysis (Baxter & King, 2017;Meng et al, 2017;Wright, FitzPatrick, & Firth, 2018). Additionally, trio sequencing simultaneously elucidates recurrence risk, allowing for timely preconception genetic counseling (van Diemen et al, 2017;Meng et al, 2017;Willig et al, 2015).…”

“…These factors can contribute to cognitive disorganization and inhibit parents' ability to process complex medical information, and therefore to make informed, autonomous decisions regarding their infant's healthcare (McCarthy Veach, LeRoy, & Bartels, 2003;Woolley, 1990). Obtaining a diagnosis in a critically unwell infant may guide management, treatment, or decision-making around palliative care (Meng et al, 2017;Mestek-Boukhibar et al, 2018;Petrikin et al, 2015;Stark, Lunke, et al, Stark, Lunke, et al, 2018;van Diemen et al, 2017;Willig et al, 2015). Additionally, genomic sequencing has the potential to diagnose ultra-rare conditions (Friedman et al, 2018;Wright et al, 2018), which we define as conditions for which there are two or fewer relevant publications in the scientific literature and therefore limited information regarding natural history.…”