Rapid Whole-Exome Sequencing as a Diagnostic Tool in a Neonatal/Pediatric Intensive Care Unit

Abstract

Genetic disorders are the leading cause of infant morbidity and mortality. Due to the large number of genetic diseases, molecular and phenotype heterogeneity and often severe course, these diseases remain undiagnosed. In infants with a suspected acute monogenic disease, rapid whole-exome sequencing (R-WES) can be successfully performed. R-WES (singletons) was performed in 18 unrelated infants with a severe and/or progressing disease with the suspicion of genetic origin hospitalized in an Intensive Care Unit (ICU). Blood samples were also collected from the parents. The results from the R-WES were available after 5-14 days. A conclusive genetic diagnosis was obtained in 13 children, corresponding to an overall diagnostic yield of 72.2%. For nine patients, R-WES was used as a first-tier test. Eight patients were diagnosed with inborn errors of metabolism, mainly mitochondrial diseases. In two patients, the disease was possibly caused by variants in genes which so far have not been associated with human disease (NARS1 and DCAF5). R-WES proved to be an effective diagnostic tool for critically ill infants in ICUs suspected of having a genetic disorder. It also should be considered as a first-tier test after precise clinical description. The quickly obtained diagnosis impacts patient’s medical management, and families can receive genetic counseling.

Application of Next-Generation Sequencing for Genetic Diagnosis in Neonatal Intensive Care Units: Results of a Multicenter Study in China

“…The high diagnostic rate and 180-day mortality rate derived from this work proved that NGS was an effective tool for critically ill infants suspected of a genetic disorder ( French et al, 2019 ; Australian Genomics Health Alliance Acute Care Flagship et al, 2020 ; Śmigiel et al, 2020 ). Firstly, our diagnostic yield was similar to those reported in Western countries; with diagnostic rates of 36–57% ( Willig et al, 2015 ; Meng et al, 2017 ; Powis et al, 2018 ; Brunelli et al, 2019 ; French et al, 2019 ) even though there were differences among the disease spectrum.…”

Rare genetic mutation triggering acute liver failure in a toddler requiring a liver transplant

“…One challenge for clinicians is the time required for various NGS tests, including WES, whole‐genome sequencing, and targeted‐gene panels, to provide results. Rapid WES can often provide results within 2 weeks and therefore may impact clinical decision‐making for a patient hospitalized with ALF 23 . Chung et al 24 reported that the median turnaround for rapid WES was 11 days and changed clinical management in 88% of patients with suspected monogenic disorders.…”

Prenatal Versus Postnatal Diagnosis of Meckel–Gruber and Joubert Syndrome in Patients with TMEM67 Mutations

“…Proband’s DNA isolated from amniocytes was subjected to NGS-based WES performed in the RAPID form according to a previously described protocol [ 7 ]. Venous blood samples were collected from the proband’s parents.…”