Rapid Whole-Genome Sequencing for Genetic Disease Diagnosis in Neonatal Intensive Care Units

Center for Pediatric Genomic Medicine, Children's Mercy Hospital, Kansas City, MO 64108, USA.
Science translational medicine (Impact Factor: 15.84). 10/2012; 4(154):154ra135. DOI: 10.1126/scitranslmed.3004041
Source: PubMed


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.

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Available from: Stephen F Kingsmore, Jan 04, 2014
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    • "In recent years, high throughput sequencing has generated thousands of new genomes from various species across the tree of life and millions of genetic variants. Especially in the field of human genetics, targeted or whole exome and genome sequencing are becoming standard assays (Ng et al., 2010; Ng et al., 2009; Saunders et al., 2012) to identify causal single-nucleotide variations (SNVs) as well as short insertions/deletions (indels) "
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    Full-text · Article · Mar 2015 · PeerJ
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    • "WGS, and whole-exome sequencing, have already been used to provide genetic diagnoses that inform clinical care (Worthey et al., 2011; Bainbridge et al., 2011; Rios et al., 2010). These early successes in individual patients prompted expanded studies to investigate a more general use of WGS in clinical settings (Saunders et al., 2012). Indeed the growing adoption of WGS in the clinic and the potential to positively impact patient care contributed, at least in part, to the UK100K Project, an effort by the Department of Health (United Kingdom) to provide highcoverage WGS for clinical interpretation in 100,000 participants focusing initially on rare diseases, cancer and infectious disease (www. "
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    ABSTRACT: Despite the potential of whole-genome sequencing (WGS) to improve patient diagnosis and care, the empirical value of WGS in the cancer genetics clinic is unknown. We performed WGS on members of two cohorts of cancer genetics patients: those with BRCA1/2 mutations (n = 176) and those without (n = 82). Initial analysis of potentially pathogenic variants (PPVs, defined as nonsynonymous variants with allele frequency < 1% in ESP6500) in 163 clinically-relevant genes suggested that WGS will provide useful clinical results. This is despite the fact that a majority of PPVs were novel missense variants likely to be classified as variants of unknown significance (VUS). Furthermore, previously reported pathogenic missense variants did not always associate with their predicted diseases in our patients. This suggests that the clinical use of WGS will require large-scale efforts to consolidate WGS and patient data to improve accuracy of interpretation of rare variants. While loss-of-function (LoF) variants represented only a small fraction of PPVs, WGS identified additional cancer risk LoF PPVs in patients with known BRCA1/2 mutations and led to cancer risk diagnoses in 21% of non-BRCA cancer genetics patients after expanding our analysis to 3209 ClinVar genes. These data illustrate how WGS can be used to improve our ability to discover patients' cancer genetic risks.
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    • "The International Rare Disease Research Consortium (IRDiRC) has been established to bring together researchers and organizations investing in rare disease research in order to achieve two main objectives by the year 2020, namely to deliver 200 new therapies for rare diseases and the means to diagnose most rare diseases ( In future, it may be feasible to examine the natural history of disease in each patient, and look for changes in the 'slope' following treatment in n= 1 trials [51] "
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