Rapid genomic sequencing for genetic disease diagnosis and therapy in intensive care units: a review

Abstract

Single locus (Mendelian) diseases are a leading cause of childhood hospitalization, intensive care unit (ICU) admission, mortality, and healthcare cost. Rapid genome sequencing (RGS), ultra-rapid genome sequencing (URGS), and rapid exome sequencing (RES) are diagnostic tests for genetic diseases for ICU patients. In 44 studies of children in ICUs with diseases of unknown etiology, 37% received a genetic diagnosis, 26% had consequent changes in management, and net healthcare costs were reduced by $14,265 per child tested by URGS, RGS, or RES. URGS outperformed RGS and RES with faster time to diagnosis, and higher rate of diagnosis and clinical utility. Diagnostic and clinical outcomes will improve as methods evolve, costs decrease, and testing is implemented within precision medicine delivery systems attuned to ICU needs. URGS, RGS, and RES are currently performed in <5% of the ~200,000 children likely to benefit annually due to lack of payor coverage, inadequate reimbursement, hospital policies, hospitalist unfamiliarity, under-recognition of possible genetic diseases, and current formatting as tests rather than as a rapid precision medicine delivery system. The gap between actual and optimal outcomes in children in ICUs is currently increasing since expanded use of URGS, RGS, and RES lags growth in those likely to benefit through new therapies. There is sufficient evidence to conclude that URGS, RGS, or RES should be considered in all children with diseases of uncertain etiology at ICU admission. Minimally, diagnostic URGS, RGS, or RES should be ordered early during admissions of critically ill infants and children with suspected genetic diseases.

Fig. 1. Timeline and process flow graph demonstrating that for clinical URGS to improve outcomes in children admitted to ICUs it must be incorporated within a multi-disciplinary healthcare delivery system.

While clinical grade URGS can be in performed in as little as 20 h, it typically takes at least 36 h. However, time-to-diagnosis by URGS is dependent upon four antecedent steps that typically take at least 24 h. Furthermore, improvements in outcome only start to occur upon implementation of precision dietary, drug, device, or surgical interventions. While almost every molecular diagnosis changes management, very few genetic diseases currently have curative treatments. Rx treatment, ID identification, EHR electronic health record. Icons: manual operation; decision; predefined process; data; extract; multidocument; summing junction; or; terminator.

Fig. 2. Temporal evolution of genetic disease knowledge and treatment, and genome sequencing since 2004.

Fastest time to diagnosis by URGS is in hours. The number of known genetic diseases (light blue) and approved genetic therapies (black) are integers. Reagent cost per GS (genome sequence) is in US dollars. The numbers in parentheses are citations for fastest times to URGS-based genetic disease diagnosis.

Fig. 3. Diagnosis of Silver-Russell syndrome by 5mC detection by LRGS.

Top section: Maternal and paternal features of the chromosome 11p15 region. IGF2, insulin-like growth factor 2. H19, imprinted maternally expressed noncoding transcript. KCNQ1, voltage-gated KQT-like potassium channel 1. CDKN1C, cyclin-dependent kinase inhibitor 1C. KCNQ1OT1, KCNQ1-opposite strand antisense transcript 1. TSS-DMR, transcriptional start side differentially methylated region. IG-DMR, intergenic differentially methylated region. Paternal hypomethylation of H19/IGF2 IG-DMR (green, nt 2,132,500-2,134,500) results in loss of paternal IGF2 expression (light blue) and gain of maternal H19 expression (pink), which lead to growth restriction. Middle section: Phased, aligned reads of 80X Oxford Nanopore LRGS to Chr 11 nt 2,132,000–2,134,520 in an infant with Silver-Russell Syndrome (above) and a control (below). Reads are shown as individual rows. Individual cytosine nt are highlighted in blue. 5mC are highlighted in red. In the affected infant, the paternal haplotype (black box) shows abnormal hypomethylation (blue) of the H19/IGF2 IG-DMR. In the control, the paternal haplotype shows normal methylation (red) of the H19/IGF2 IG-DMR. Bottom section: IGF2 introns and exons on the Chr 11 nt 2,132,000–2,134,520.