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

María José De Castro,Enrique Salguero,Alejandro Pérez-Muñuzuri,Sofía Barbosa-Gouveia,Olalla López-Suárez,María-Luz Couce,Emiliano González-Vioque,Segundo Rite

doi:10.3390/jcm9082362

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.

Highlights

While genetic disease is suspected in over 50% of the children who are admitted to neonatal intensive care units (NICUs) and die during the first year of life, diagnosis is confirmed in only 20%–30% of cases, often post-mortem [1,2]
We evaluated the utility of rapid selective gene panel trio sequencing in critically ill newborns with suspected genetic disorders
Between the period of January 2018 and December 2019, 51 newborns were admitted to the NICU with a suspected diagnosis of genetic disease

Summary

Introduction

While genetic disease is suspected in over 50% of the children who are admitted to neonatal intensive care units (NICUs) and die during the first year of life, diagnosis is confirmed in only 20%–30% of cases, often post-mortem [1,2]. Technological advances in gene sequencing have enabled rapid reading of any part of the genome at an affordable price [8,9]. Integration and interpretation of the data produced by genomic sequencing is a key obstacle to the incorporation of these strategies into clinical routine practice [24,25]. Phenotype-based filtering and prioritization could greatly facilitate the interpretation of genetic variants detected by genome sequencing [26,27]

Methods

Results

Conclusion