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Rapid whole-genome sequencing for genetic disease diagnosis in neonatal intensive care units.
MedLine Citation:
PMID:  23035047     Owner:  NLM     Status:  In-Data-Review    
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.
Carol Jean Saunders; Neil Andrew Miller; Sarah Elizabeth Soden; Darrell Lee Dinwiddie; Aaron Noll; Noor Abu Alnadi; Nevene Andraws; Melanie Leann Patterson; Lisa Ann Krivohlavek; Joel Fellis; Sean Humphray; Peter Saffrey; Zoya Kingsbury; Jacqueline Claire Weir; Jason Betley; Russell James Grocock; Elliott Harrison Margulies; Emily Gwendolyn Farrow; Michael Artman; Nicole Pauline Safina; Joshua Erin Petrikin; Kevin Peter Hall; Stephen Francis Kingsmore
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Science translational medicine     Volume:  4     ISSN:  1946-6242     ISO Abbreviation:  Sci Transl Med     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-10-04     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101505086     Medline TA:  Sci Transl Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  154ra135     Citation Subset:  IM    
Center for Pediatric Genomic Medicine, Children's Mercy Hospital, Kansas City, MO 64108, USA.
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