Rapid Whole-Genome Sequencing for Genetic Disease Diagnosis in Neonatal Intensive Care Units
By Carol J. Saunders, Neil A. Miller, S. Soden, D. Dinwiddie, A. Noll, Noor Abu Alnadi, Nevene Andraws, M. Patterson, L. Krivohlavek, Joel Fellis and 13 more. Science Translational Medicine, 2012
637 citations recorded by the source corpus.
Rapid whole-genome sequencing of neonates can shorten time to genetic disease diagnosis and thus genetic and prognostic counseling. Speed Heals The waiting might not be the hardest part for families receiving a diagnosis in neonatal intensive care units (NICUs), but it can be destructive nonetheless. While they wait on pins and needles for their newborn baby’s diagnosis, parents anguish, nurture false hope, wrestle with feelings of guilt—and all the while, treatment and counseling are delayed. Now, Saunders et al. describe a method that uses whole-genome sequencing (WGS) to achieve a differential diagnosis of genetic disorders in 50 hours rather than the 4 to 6 weeks. Many of the ~3,500 genetic diseases of known cause manifest symptoms during the first 28 days of life, but full clinical symptoms might not be evident in newborns. Genetic screens performed on newborns are rapid, but are designed to unearth only a few genetic disorders, and serial gene sequencing is too slow to be clinically useful. Together, these complicating factors lead to the administration of treatments based on nonspecific or obscure symptoms, which can be unhelpful or dangerous. Often, either death or release from the hospital occurs before the diagnosis is made. The new WGS protocol cuts analysis time by using automated bioinformatic analysis. Using their newly developed protocol, the authors performed retrospective 50-hour WGS to confirm, in two children, known molecular diagnoses that had been made using other methods. Next, prospective WGS revealed a molecular diagnosis of a BRAT1-related syndrome in one newborn; identified the causative mutation in a baby with epidermolysis bullosa; ruled out the presence of defects in candidate genes in a third infants; and, in a pedigree, pinpointed BCL9L as a new recessive gene (HTX6) that gives rise to visceral heterotaxy—the abnormal arrangement of organs in the chest and abdominal cavities. WGS of parents or affected siblings helped to speed up the identification of disease genes in the prospective cases. These findings strengthen the notion that WGS can shorten the differential diagnosis process and quicken to move toward targeted treatment and genetic and prognostic counseling. The authors note that the speed and cost of WGS continues to rise and fall, respectively. However, fast WGS is clinically useful when coupled with fast and affordable methods of analysis. 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.
Subfields: Clinical Biochemistry, Genetics
View Paper: https://www.semanticscholar.org/paper/83622ce5abf7cae424dddadcda69feb8f128acd0
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Citations in the corpus
- The Ensembl Variant Effect Predictor (2016, background): “2014), for patient diagnosis in the clinic and for research on GWAS studies (Leslie et al.; Hou and Zhao 2013; International Multiple Sclerosis Genetics Consortium 2013; Saunders et al. 2012; Wright et al. 2015).”
- Evaluation of CADD Scores in Curated Mismatch Repair Gene Variants Yields a Model for Clinical Validation and Prioritization (2015, neutral): “…diagnostics, which is identifying large numbers of candidate disease-causative variants, ranging from about 250 [Lohmann and Klein, 2014], to 400–700 [Yang et al., 2013], up to a mean of 1,083 [Saunders et al., 2012] variants per exome, depending on which filter steps and stringency are applied.”