Rapid Whole-Genome Sequencing for Genetic Disease Diagnosis in Neonatal Intensive Care Units

TLDR

Monogenic disorders cause significant neonatal morbidity and mortality, yet over 3500 are known but many lack routine testing, and rapid heterogeneous disease progression demands prompt molecular diagnosis. The study aims to provide a rapid 50‑hour whole‑genome sequencing prototype with automated analysis to meet the unmet need for timely molecular diagnosis in infants. The prototype uses 50‑hour WGS with automated bioinformatics, including parental or sibling sequencing, to accelerate gene identification. Retrospective WGS confirmed diagnoses in two children, prospective WGS identified a severe GJB2 skin disease, BRAT1 lethal syndrome, a novel BCL9L visceral heterotaxy gene, and ruled out candidates in another infant, demonstrating that rapid WGS can broaden differential diagnosis, reduce empirical treatments, and speed counseling.

Abstract

Monogenic diseases are frequent causes of neonatal morbidity and mortality, and disease presentations are often undifferentiated at birth. More than 3500 monogenic diseases have been characterized, but clinical testing is available for only some of them and many feature clinical and genetic heterogeneity. Hence, an immense unmet need exists for improved molecular diagnosis in infants. Because disease progression is extremely rapid, albeit heterogeneous, in newborns, molecular diagnoses must occur quickly to be relevant for clinical decision-making. We describe 50-hour differential diagnosis of genetic disorders by whole-genome sequencing (WGS) that features automated bioinformatic analysis and is intended to be a prototype for use in neonatal intensive care units. Retrospective 50-hour WGS identified known molecular diagnoses in two children. Prospective WGS disclosed potential molecular diagnosis of a severe GJB2-related skin disease in one neonate; BRAT1-related lethal neonatal rigidity and multifocal seizure syndrome in another infant; identified BCL9L as a novel, recessive visceral heterotaxy gene (HTX6) in a pedigree; and ruled out known candidate genes in one infant. Sequencing of parents or affected siblings expedited the identification of disease genes in prospective cases. Thus, rapid WGS can potentially broaden and foreshorten differential diagnosis, resulting in fewer empirical treatments and faster progression to genetic and prognostic counseling.