ABSTRACT
BACKGROUND: Genomic assessment previously took months to result and was unable to impact clinical care in the pediatric intensive care unit (PICU). The advent of rapid exome sequencing potentially changes this. We investigated the impact of rapid exome sequencing in a pilot study on pediatric patients admitted to a single PICU with new-onset metabolic/neurologic disease. METHODS: Rapid exome sequencing (7 days to verbal result) was performed on (n = 10) PICU patients age < 6 years admitted with new-onset metabolic/neurologic disease. The primary outcome of interest was inpatient LOS, which served as a proxy for inpatient cost. RESULTS: A significant reduction in median LOS was identified when comparing PICU patients who underwent rapid exome sequencing to historical controls. From those patients who underwent rapid sequencing, five had likely pathogenic variants. In three cases with diagnostic genetic results, there was a modification to clinical care attributable to information provided by exome sequencing. CONCLUSIONS: This pilot study demonstrates that rapid exome sequencing is feasible to do in the PICU, that genetic results can be returned quickly enough to impact critical care decision-making and management. In a select population of PICU patients, this technology may contribute to a decrease in hospital length of stay. IMPACT: Ten prospectively enrolled PICU patients with defined clinical criteria and their parents underwent rapid exome sequencing. Fifty percent received a genetic diagnosis, and medical management was affected for 60% of those patients. Median hospital LOS was significantly decreased in this selective subset of PICU patients. Genetic disorders and congenital anomalies are a leading cause of pediatric mortality. Genomic assessment previously took weeks to months for results and was therefore unable to acutely impact clinical care in the pediatric intensive care unit (PICU). The recent advent of rapid exome sequencing changes this in selected patients. Rapid exome sequencing is feasible to do in a PICU. Genetic results can be returned quickly enough to impact critical care decision-making. When done in a carefully selected subset of pediatric patients, rapid exome sequencing can potentially decrease hospital LOS.
Subject(s)
Exome Sequencing , Genetic Variation , Intensive Care Units, Pediatric , Metabolic Diseases/genetics , Nervous System Diseases/genetics , Case-Control Studies , Child , Child, Preschool , Clinical Decision-Making , Female , Genetic Predisposition to Disease , Humans , Infant , Infant, Newborn , Length of Stay , Male , Metabolic Diseases/diagnosis , Metabolic Diseases/therapy , Nervous System Diseases/diagnosis , Nervous System Diseases/therapy , Pilot Projects , Predictive Value of Tests , Prognosis , Prospective Studies , Time Factors , WorkflowABSTRACT
BACKGROUND: Human genomes harbor copy number variants (CNVs), which are regions of DNA gains or losses. Although pathogenic CNVs are associated with congenital heart disease (CHD), their effect on clinical outcomes is unknown. This study sought to determine whether pathogenic CNVs among infants with single ventricle physiology were associated with inferior neurocognitive and somatic growth outcomes. METHODS AND RESULTS: Genomic DNAs from 223 subjects of 2 National Heart, Lung, and Blood Institute-sponsored randomized clinical trials in infants with single ventricle CHD and 270 controls from The Cancer Genome Atlas project were analyzed for rare CNVs>300 kb using array comparative genomic hybridization. Neurocognitive and growth outcomes at 14 months from the CHD trials were compared among subjects with and without pathogenic CNVs. Putatively pathogenic CNVs, comprising 25 duplications and 6 deletions, had a prevalence of 13.9%, significantly greater than the 4.4% rate of such CNVs among controls. CNVs associated with genomic disorders were found in 13 cases but not in controls. Several CNVs likely to be causative of single ventricle CHD were observed, including aberrations altering the dosage of GATA4, MYH11, and GJA5. Subjects with pathogenic CNVs had worse linear growth, and those with CNVs associated with known genomic disorders had the poorest neurocognitive and growth outcomes. A minority of children with pathogenic CNVs were noted to be dysmorphic on clinical genetics examination. CONCLUSIONS: Pathogenic CNVs seem to contribute to the cause of single ventricle forms of CHD in ≥10% of cases and are clinically subtle but adversely affect outcomes in children harboring them.