Next-generation sequencing for diagnosis of rare diseases in the neonatal intensive care unit

TLDR

Rare diseases often present in the first days and weeks of life, requiring complex NICU management, yet exhaustive consultations and traditional investigations are costly and frequently fail to yield a diagnosis when no recognizable syndrome is suspected. This pilot project assessed the feasibility of next‑generation sequencing to improve diagnosis of rare diseases in newborns in the NICU. We retrospectively identified and prospectively recruited NICU infants referred for suspected genetic or metabolic conditions, performed panel‑based enrichment and MiSeq sequencing of DNA from newborns and parents, and interpreted the data with a standard informatics pipeline to report genotype‑phenotype correlations to clinicians. Among 20 newborns, next‑generation sequencing yielded a diagnosis in 8 (40 %), identifying conditions such as renal tubular dysgenesis, SCN1A‑related encephalopathy, myotubular myopathy, FTO deficiency, cranioectodermal dysplasia, congenital myasthenic syndrome, autosomal dominant intellectual disability type 7, and Denys–Drash syndrome, demonstrating a high success rate that could transform NICU care.

Abstract

<h3>Background:</h3> Rare diseases often present in the first days and weeks of life and may require complex management in the setting of a neonatal intensive care unit (NICU). Exhaustive consultations and traditional genetic or metabolic investigations are costly and often fail to arrive at a final diagnosis when no recognizable syndrome is suspected. For this pilot project, we assessed the feasibility of next-generation sequencing as a tool to improve the diagnosis of rare diseases in newborns in the NICU. <h3>Methods:</h3> We retrospectively identified and prospectively recruited newborns and infants admitted to the NICU of the Children's Hospital of Eastern Ontario and the Ottawa Hospital, General Campus, who had been referred to the medical genetics or metabolics inpatient consult service and had features suggesting an underlying genetic or metabolic condition. DNA from the newborns and parents was enriched for a panel of clinically relevant genes and sequenced on a MiSeq sequencing platform (Illumina Inc.). The data were interpreted with a standard informatics pipeline and reported to care providers, who assessed the importance of genotype–phenotype correlations. <h3>Results:</h3> Of 20 newborns studied, 8 received a diagnosis on the basis of next-generation sequencing (diagnostic rate 40%). The diagnoses were renal tubular dysgenesis, <i>SCN1A-</i>related encephalopathy syndrome, myotubular myopathy, <i>FTO</i> deficiency syndrome, cranioectodermal dysplasia, congenital myasthenic syndrome, autosomal dominant intellectual disability syndrome type 7 and Denys–Drash syndrome. <h3>Interpretation:</h3> This pilot study highlighted the potential of next-generation sequencing to deliver molecular diagnoses rapidly with a high success rate. With broader use, this approach has the potential to alter health care delivery in the NICU.