Implementation of Rapid Genome Sequencing for Critically Ill Infants With Complex Congenital Heart Disease

Abstract

BACKGROUND: Rapid genome sequencing (rGS) has been shown to improve care of critically ill infants. Congenital heart disease (CHD) is a leading cause of infant mortality and is often caused by genetic disorders, yet the utility of rGS has not been prospectively studied in this population. METHODS: We conducted a prospective evaluation of rGS to improve the care of infants with complex CHD in our cardiac neonatal intensive care unit. RESULTS: In a cohort of 48 infants with complex CHD, rGS diagnosed 14 genetic disorders in 13 (27%) individuals and led to changes in clinical management in 8 (62%) cases with diagnostic results. These included 2 cases in whom genetic diagnoses helped avert intensive, futile interventions before cardiac neonatal intensive care unit discharge, and 3 cases in whom eye disease was diagnosed and treated in early childhood. CONCLUSIONS: Our study provides the first prospective evaluation of rGS for infants with complex CHD to our knowledge. We found that rGS diagnosed genetic disorders in 27% of cases and led to changes in management in 62% of cases with diagnostic results. Our model of care depended on coordination between neonatologists, cardiologists, surgeons, geneticists, and genetic counselors. These findings highlight the important role of rGS in CHD and demonstrate the need for expanded study of how to implement this resource to a broader population of infants with CHD.

Prevalence and Clinical Significance of Commonly Diagnosed Genetic Disorders in Preterm Infants

“…These data may help clinicians provide more informed guidance to families and lead to better clinical decision-making in rare presentations. 29 These data indicate the need for a greater index of suspicion for multiple critical illnesses, such as sepsis in the setting of trisomy 21 and NEC in the setting of cystic fibrosis. Given the trend towards greater adjusted odds of multiple morbid outcomes, clinicians should also consider genetic evaluation when caring for preterm infants with critical illnesses.…”

“…outcome.full$`Genetic Disorder`[8] <-"Klinefelter syndrome" outcome.full$`Genetic Disorder`[9] <-"Turner syndrome" outcome.full$`Genetic Disorder`[10] <-"Unspecified Aneuploidy" outcome.full$`Genetic Disorder`[12] <-"13q deletion syndrome" outcome.full$`Genetic Disorder`[13] <-"Cri-du-chat syndrome" outcome.full$`Genetic Disorder`[14] <-"DiGeorge syndrome" outcome.full$`Genetic Disorder`[15] <-"Unspecified CNV" outcome.full$`Genetic Disorder`[18] <-"Thalassemia" outcome.full$`Genetic Disorder`[19] <-"Hemoglobin bart's" #should i name this as Alpha Thalassemia? outcome.full$`Genetic Disorder`[20] <-"Sickle cell disease" outcome.full$`Genetic Disorder`[21] <-"G6PD deficiency" outcome.full$`Genetic Disorder`[22] <-"Hemophilia A" outcome.full$`Genetic Disorder`[23] <-"Hemophilia B" outcome.full$`Genetic Disorder`[25] <-"Cystic fibrosis" outcome.full$`Genetic Disorder`[26] <-"Fragile X syndrome" outcome.full$`Genetic Disorder`[27] <-"Hypophosphatasia" outcome.full$`Genetic Disorder`[28] <-"Fanconi Anemia" outcome.full$`Genetic Disorder`[29] <-"Multiple Disorders" # outcome.full$`Genetic Disorder`[29] <-"Absent" colnames(outcome.full)[3] <-"ICH" colnames(outcome.full)[4] <-"NEC" colnames(outcome.full)[5] <-"BPD" colnames(outcome.full)[9] <-"Mortality" colnames(outcome.full)[10] <-"Mortality or Any Severe Morbidity" corrected.outcomes <-outcome.full[, c(1, 10, 9, 2, 3, 4, 5, 6, 7, 8)] library(dplyr) library(tidyverse) library(pixiedust) library(kableExtra) library(knitr) outcome.counts <-dust(corrected.outcomes, rownames = F) %>% sprinkle(col = 1:9, round = 0) %>% #bold = T, part = "head") sprinkle(col = 10, halign = "center") %>% kable(align=c(rep('lcc'))) %>% kable_styling(font_size = 20) %>% kable_classic(full_width = F, html_font = "Cambria") tmp.1 <-add_indent(outcome.counts, c(1:2, 4:10, 12:15, 17, 24), level_of_indent = 1, all_cols = FALSE) tmp.2<-add_indent(tmp.1, c(18:23, 25:28), level_of_indent = 2, all_cols = FALSE) outcome.finals <-tmp.2 %>% row_spec(0,bold = T) %>% row_spec(1:2, italic = T) %>% column_spec(1, width = "20em") outcome.n.…”

Clinical Decision Analysis of Genetic Evaluation and Testing in 1013 Intensive Care Unit Infants with Congenital Heart Defects Supports Universal Genetic Testing

“…Several studies support the use of CMA and exome sequencing for CHD [10][11][12]14,16,[53][54][55][56][57][58]. However, additional research is needed to determine performance and cost-effectiveness of genome sequencing for CHD, and some groups have begun exploring this [59][60][61]. GS has the ability to ascertain a fuller spectrum of CHD genetic etiologies singularly and efficiently-aneuploidies, copy-number variants, monogenic disorders, multiple co-occurring genetic disorders, and non-coding variation previously elusive to gene panels and exome sequencing.…”

Genetic Architecture of CHD in NICU patients – UMC Ljubljana Experience

“…However, diagnostic rates still differ across the studies and tested phenotypes [17][18][19]. In addition, rapid WGS demonstrated the yield in 27% of individuals with CHD, leading to changes in clinical management in 62% of patients with diagnostic results [20].…”