title: Rapid whole-genome sequencing for genetic disease diagnosis in neonatal intensive care units.
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.
authors.affiliation: Center for Pediatric Genomic Medicine, Department of Pediatrics, Children's Mercy Hospital, School of Medicine, University of Missouri-Kansas City, Kansas City, MO 64108, USA.
authors.forename: Carol Jean
authors.initials: CJ
authors.lastname: Saunders
authors.forename: Neil Andrew
authors.initials: NA
authors.lastname: Miller
authors.forename: Sarah Elizabeth
authors.initials: SE
authors.lastname: Soden
authors.forename: Darrell Lee
authors.initials: DL
authors.lastname: Dinwiddie
authors.forename: Aaron
authors.initials: A
authors.lastname: Noll
authors.forename: Noor Abu
authors.initials: NA
authors.lastname: Alnadi
authors.forename: Nevene
authors.initials: N
authors.lastname: Andraws
authors.forename: Melanie LeAnn
authors.initials: ML
authors.lastname: Patterson
authors.forename: Lisa Ann
authors.initials: LA
authors.lastname: Krivohlavek
authors.forename: Joel
authors.initials: J
authors.lastname: Fellis
authors.forename: Sean
authors.initials: S
authors.lastname: Humphray
authors.forename: Peter
authors.initials: P
authors.lastname: Saffrey
authors.forename: Zoya
authors.initials: Z
authors.lastname: Kingsbury
authors.forename: Jacqueline Claire
authors.initials: JC
authors.lastname: Weir
authors.forename: Jason
authors.initials: J
authors.lastname: Betley
authors.forename: Russell James
authors.initials: RJ
authors.lastname: Grocock
authors.forename: Elliott Harrison
authors.initials: EH
authors.lastname: Margulies
authors.forename: Emily Gwendolyn
authors.initials: EG
authors.lastname: Farrow
authors.forename: Michael
authors.initials: M
authors.lastname: Artman
authors.forename: Nicole Pauline
authors.initials: NP
authors.lastname: Safina
authors.forename: Joshua Erin
authors.initials: JE
authors.lastname: Petrikin
authors.forename: Kevin Peter
authors.initials: KP
authors.lastname: Hall
authors.forename: Stephen Francis
authors.initials: SF
authors.lastname: Kingsmore
mesh_terms: D000072259:Connexin 26; D017630:Connexins; D030342:Genetic Diseases, Inborn / Q000235:genetics*; D015894:Genome, Human / Q000235:genetics*; D006801:Humans; D007231:Infant, Newborn; D007363:Intensive Care Units, Neonatal; D012189:Retrospective Studies; D017422:Sequence Analysis, DNA / Q000379:methods*
chemical_list: D017630:Connexins; C000607042:GJB2 protein, human; D000072259:Connexin 26