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Researchers Achieve 26-Hour Rapid Whole-Genome Sequencing In Critically Ill Infants; Fastest Turnaround Time in World; STAT-Seq Test IDs Mutations for 5,300 Genetic Diseases; Edico Data Analysis & Illumina Sequencer Among Keys to Record Speed

A study published on September 30, 2015 in an open-access article in Genome Medicine describes how researchers at Children's Mercy Kansas City, and colleagues, have cut in half the time needed for rapid whole-genome sequencing and genetic diagnosis in critically-ill infants, using a test that is called STAT-Seq. Through a variety of enhancements, the Center for Pediatric Genomic Medicine at Children's Mercy completed the STAT-Seq test in 26 hours compared to 50 hours, improving on a turnaround time that was already the fastest available in the world. The STAT-Seq test can identify mutations across the genome associated with approximately 5,300 known genetic diseases, and in some cases even identify previously unknown genetic diseases. In contrast, standard clinical practice calls for an array of genetic tests to be performed, which are time-consuming, costly and can only test for a limited set of disorders. The Genome Medicine article is titled “A 26-Hour System of Highly Sensitive Whole genome sequencing for emergency management of genetic diseases.” Lead authors of the study were Neil Millerand Emily Farrow, Ph.D., C.G.C., of Children's Mercy Kansas City, and senior author was Stephen Kingsmore, D.Sc., who was previously also at Children’s Mercy, but recently became the inaugural CEO of the Genomics Institute at Rady Children’s Hospital San Diego. "We believe rapid genome sequencing of critically-ill infants with suspected genetic diseases is a breakthrough application for genomic medicine," said Dr. Farrow, Director of Laboratory Operations and a genetic research scientist at the Center for Pediatric Genomic Medicine at Children's Mercy. "We have found STAT-Seq can significantly decrease the time to diagnosis for some of our sickest patients." The symptoms of genetic diseases in infants are often overlapping, making iden a specific diagnosis difficult. Further, infants frequently show only a fraction of the full set of symptoms of genetic diseases, further complicating diagnosis and specific treatment. STAT-Seq bypasses these difficulties by casting the widest net possible in order to rapidly define the underlying cause of the disease.

"Establishing fast, scalable methods is a key step toward making genome sequencing a routine part of healthcare, not only for the diagnosis of genetic disease, but for a wide range of precision medicine applications," said Miller, Director of Informatics and Software Development at the Center for Pediatric Genomic Medicine at Children's Mercy. "This is only possible through collaboration among a uniquely interdisciplinary team of clinical, informatics, laboratory, and genetic counseling experts."

In the retrospective study described in Genome Medicine, blinded DNA samples from infants with known genetic diseases were reanalyzed using various parameters and technologies as a proof of concept.

Significant time savings were achieved with Edico Genome's DRAGEN processor, which sped up data analysis from 22.5 hours to 41 minutes.

To achieve the 26-hour result, the team at the Center for Pediatric Genomic Medicine also developed ultra-rapid run mode on an Illumina HiSeq 2500 sequencing instrument, saving five hours; replaced manual interpretation and reporting process with in-house VIKING software program, saving three hours; and optimized in-house software, RUNES (Rapid Understanding of Nucleotide variant Effect Software), to more quickly detect mutations in gene sequences, saving two hours.

An article by Paul Sisson in The San Diego Union-Tribune (see link below) on this breakthrough reported that senior author Dr. Kingsmore believes that a half-dozen advancements mentioned in the Genome Medicine report can together help make genomic sequencing a reality for thousands of children every year.

Further, the Union-Tribune reported that Dr. Kingsmore said research in Kansas City using the 26-hour test with a small number of patients had primed him for the task of folding whole-genome-based genetic diagnosis into the standard of care at Rady Children’s Hospital, which recently received a $120 million donation from philanthropists Ernest and Evelyn Rady to help push the goal forward.
As noted earlier, Dr. Kingsmore was recently appointed the inaugural CEO of the Genomics Institute at Rady Children’s and moved there from his previous position at Children’s Mercy.

The Union-Tribune quoted Dr. Kingsmore as saying “We’ve not yet put this into production. That’s why I’m here in San Diego, to take this technology and put it into production at scale.”

The Union-Tribune also obtained a comment on the advance from a prominent genetics expert not involved in the work. According to the Tribune, Dr. Hakon Hakonarson, Director of the Center for Applied Genomics at The Children’s Hospital of Philadelphia (CHOP), said the results are unprecedented.

“Dr. Kingsmore deserves very significant credit for what he has done here. He has done what no one else has,” Dr. Hakonarson was quoted as saying by the Union-Tribune.

Children's Mercy is a leader in the development and clinical application of pediatric genomics. In September 2013, Children's Mercy became one of four pilot projects to explore newborn genomics through funding by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the National Human Genome Research Institute (NHGRI), both parts of the National Institutes of Health.

Honored as one of TIME magazine's Top 10 Medical Breakthroughs of 2012, STAT-Seq is being developed at the Center for Pediatric Genomic Medicine at Children's Mercy in collaboration with Illumina, Inc.

[Children's Mercy press release] [Genome Medicine article] [Time Magazine Top 10 Medical Breakthroughs 2012 (STATSeq) article] [Children’s Mercy press release on STAT-Seq as one of Time 2012 Top 10 Medical Breakthroughs] [Illumina web site] [Illumina HiSeq 2500 System]

[The San Diego Union-Tribune article] [Newsweek article] [Popular Science article] [BioIT World article] [Genome Web article]