Rapid Whole Genome Sequencing for Genetic Disease Diagnosis in the NICU

Monogenic diseases are frequent causes of neonatal morbidity and mortality, and disease presentations are often undifferentiated at birth. More than 3,500 monogenic diseases have been characterized, but clinical testing is available for only some of them and many feature clinical and genetic heterogeneity. As such, 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 infants. Sequencing of parents or affected siblings expedited the identification of disease gene 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. Reprinted from Saunders et. al, Rapid Whole-Genome Sequencing for Genetic Disease Diagnosis in Neonatal Intensive Care Units. Sci. Transl. Med. 4, 154ra135 (2012; PMID: 23035047) with permission from AAAS.]]>
To assess the ability to recapitulate known results, whole genome sequencing was performed retrospectively on two infants with molecular diagnoses that had previously been identified by clinical testing. These samples (UDXXXX) were selected from a validation set of 384 samples with known molecular diagnoses for one or more genetic diseases. To assess the potential diagnostic use of WGS, sequencing was prospectively performed on four undiagnosed newborns with clinical presentations that strongly suggested a genetic disorder as well as one affected sibling and their unaffected parents. Seven prospective samples were selected from families with probands that presented in infancy, among 143 individuals without molecular diagnoses who were enrolled between November 2011 and April 2012 for exome or genome sequencing.]]>
2012: The version 1 study release provided SNP data derived from whole genome sequences of n=9 subjects. 2014: The version 2 study release provides SNP data derived from whole genome sequences of n=279 subjects.]]>