Sunday, 7 October 2012

NGS PubMed Highlights: Researchers sequence and analyze whole genomes of seven infants in about 50 hours!

A team led by Stephen Kingsmore used an Illumina HiSeq 2500 to sequence the genomes of seven babies that died near birth. The 50 hour screening time was not due to sequencing speed, but rather analysis speed.
As discussed in an editorial published on SingularityHUB  "... it took about four and a half hours to prepare the samples and another twenty-five and half hours to sequence the genomes with the HiSeq machine. The remaining 20 hours then was all it took to analyze the entire 3.2 billion base pairs of the genomes and pinpoint causal mutations. They were able to achieve such efficiency by modifying their analysis software to be both automated and smart. Much of what is normally performed manually, like finding a mutation and associating it with a disease, was carried out by software. In addition, the clinical features of the babies were taken into account such that the software focused on genes that were most likely linked to the symptoms, greatly decreasing the analysis workload. And quality was not sacrificed for speed. Retrospectively diagnosing the critical illnesses of five out of seven babies demonstrates that the system could make a huge difference in a clinical setting".

The study was published recently in Science Translational Medicine.

 2012 Oct 3;4(154):154ra135. doi: 10.1126/scitranslmed.3004041.

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.


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 geneticheterogeneity. 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 togenetic and prognostic counseling.

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