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.

Rapid genome sequencing for critically ill infants: an inaugural pilot study from Turkey

“…RGS, rapid exome sequencing, and rapid NGS panels are increasingly considered the first-line diagnostic tests for genetic diseases in ICU patients ( 4 ). Considering the increasing daily costs of care in NICUs and PICUs and sophisticated investigations during the diagnosis process, it is likely that the current cost savings per patient diagnosed by rapid sequencing are remarkable ( 39 , 40 ).…”

“…Early diagnosis not only facilitates clinical management but also alleviates anxiety among healthcare workers and addresses concerns within the family, ultimately reducing morbidity and mortality rates ( 2 , 3 ). Recent advances in next-generation sequencing (NGS) techniques have decreased costs and time, along with increased availability ( 4 ). Over the last decade, more than 40 studies that involved over 3,500 critically ill pediatric patients suspected of having a genetic condition have used NGS for rapid diagnosis.…”

QAFI: A Novel Method for Quantitative Estimation of Missense Variant Impact Using Protein-Specific Predictors and Ensemble Learning

“…Broadening the application of NGS could significantly enhance its lifesaving potential (Owen et al 2023;Kingsmore et al 2024), as illustrated in a study by Owen et al (2023) that revealed that in a cohort of 112 infant deaths, a number of fatalities could have been prevented if rapid, diagnostic genome sequencing had been applied at the onset of symptoms or immediately upon ICU admission.…”