Rapid Phenotype-Driven Gene Sequencing with the NeoSeq Panel: A Diagnostic Tool for Critically Ill Newborns with Suspected Genetic Disease

Abstract

New genomic sequencing techniques have shown considerable promise in the field of neonatology, increasing the diagnostic rate and reducing time to diagnosis. However, several obstacles have hindered the incorporation of this technology into routine clinical practice. We prospectively evaluated the diagnostic rate and diagnostic turnaround time achieved in newborns with suspected genetic diseases using a rapid phenotype-driven gene panel (NeoSeq) containing 1870 genes implicated in congenital malformations and neurological and metabolic disorders of early onset (<2 months of age). Of the 33 newborns recruited, a genomic diagnosis was established for 13 (39.4%) patients (median diagnostic turnaround time, 7.5 days), resulting in clinical management changes in 10 (76.9%) patients. An analysis of 12 previous prospective massive sequencing studies (whole genome (WGS), whole exome (WES), and clinical exome (CES) sequencing) in newborns admitted to neonatal intensive care units (NICUs) with suspected genetic disorders revealed a comparable median diagnostic rate (37.2%), but a higher median diagnostic turnaround time (22.3 days) than that obtained with NeoSeq. Our phenotype-driven gene panel, which is specific for genetic diseases in critically ill newborns is an affordable alternative to WGS and WES that offers comparable diagnostic efficacy, supporting its implementation as a first-tier genetic test in NICUs.

Using the Sankey diagram to visualize article features on the topics of whole-exome sequencing (WES) and whole-genome sequencing (WGS) since 2012: Bibliometric analysis

“…Further advances are required to make precision, personalized, and predictive Medicine into reality. [ 1 ]…”

“…The incorporation of sequencing techniques has been rapidly launched into health care, [ 1 ] partially attributed to the decreasing costs and clinical utility experience given to clinical settings and some to whole-exome sequencing (WES) and whole-genome sequencing (WGS), which are anticipated to replace conventional genetic tests, such as gene panels and chromosomal microarray analysis. [ 2 ]…”

“…[ 7 , 8 ] Timely and specific diagnosis of newborns can have critical implications for health and wellbeing for the remainder of an infant’s life. [ 1 ]…”

Molecular Genetic Screening of Neonatal Intensive Care Units: Hyperbilirubinemia as an Example

“…However, there has been no study on large-scale genome sequencing screening so far. With the promotion of neonatal genome screening project, the patients from NICU constitute a suitable population as in Neoseq, 37 Newbie Seq, 3 NC NEXUS, 4 BabySeq. 9 A high incidence of genetic disorders is often found in this population, and so is a high false-positive rate of TMS screening.…”

The genetics of mitochondrial disease: dissecting mitochondrial pathology using multi‐omic pipelines

“…A recent study sequenced a custom panel of 1870 genes associated with early‐onset metabolic, neurological or dysmorphic presentations to critically ill children and their parents, achieving a diagnostic yield of 40%, with an average turnaround time of 7.5 days. Whilst these cases were not specifically enriched for suspected ‘mitochondrial disease’ cases, the fact that almost half of the diagnoses (5/13 diagnoses) involved mitochondrial proteins supports its utility for this patient group [ 27 ].…”