Dr. Danny Miller
BBI’s Dr. Danny Miller, in collaboration with other BBI faculty, has used whole-genome sequencing to assess genetic risk of a newborn by 3 hours of life, an unprecedented procedure on such a young infant and an important milestone in advancing precision medicine.
Prior to the sequencing in July, the quickest a whole human genome had been sequenced and analyzed was 8 hours.
“We can use this technology to make clinical decisions rapidly, helping clinicians determine effective treatments, and enlightening parents about their children’s genetic conditions,” said Miller, the principal investigator of the UW School of Medicine Miller Lab. “We are acquiring this important information much more rapidly than ever before.”
Miller noted that while the infant’s whole genome was sequenced only a single gene related to zinc deficiency was analyzed.
“Nonetheless, this approach can be applied broadly to patients of all ages where suspicion of a genetic abnormality is high,” Miller said. “Such precise genetic diagnoses, whether involving an infant three hours young, or a 55-year-old cardiac patient, represent the future of medicine.”
The procedure is explained in a preprint paper posted last month online. Other BBI members listed as co-authors include: Drs. Michael J. Bamshad, Evan Eichler, Christina M. Lockwood, and Andrew B. Stergachis. In addition, three representatives of Oxford Nanopore Technologies participated in the study.
Miller emphasized that Oxford Nanopore sequencing was essential to the success of the sequencing. Nanopore technology is “an ideal platform on which to develop ultra-rapid sequencing approaches because sequencing data from individual DNA molecules are available in near real-time,” he said.
Miller utilizes Nanopore sequencing technology in his ongoing service to BBI members, providing training and technical advice on both targeted and whole genome long read sequencing on the Oxford Nanopore platform and assisting other researchers with their projects.
For that service, he is using, among other machines, a Nanopore PromethION, Oxford Nanopore’s highest-throughput sequencing device, a scalable instrument that runs multiple flow cells independently. To learn more contact him at email@example.com or visit his lab’s website.
In the case of the three-hour old newborn, the child and his older genetic sibling were conceived using donated anonymized embryos from the same biological parents. The older child developed a rash accompanied by increasing irritability at two months of age. It was later determined that the older child suffered from Acrodermatitis enteropathica, a rare genetic disorder caused by the inability to absorb zinc from the intestine.
“The key question the parents wanted answered was, ‘Would our new baby also have this condition?’ They wanted an answer one way or the other, and were very invested in research overall, and genetic testing specifically."
“The key question the parents wanted answered was, ‘Would our new baby also have this condition?’” Miller said. “They wanted an answer one way or the other, and were very invested in research overall, and genetic testing specifically. I met with the parents several times before we conducted the sequencing.”
The child was delivered at the UW Medical Center at just over 39 weeks and weighing nearly 8 pounds. Cord blood was collected at birth, rushed to Miller’s lab, also located in the UW Medical Center complex, and ultra-rapid whole-genome long-read sequencing was performed using 20 Nanopore PromethION flow cells with sequencing libraries prepared by a combination of two commercially available Nanopore kits.
“By optimizing the DNA extraction and library preparation steps paired with targeted analysis, we determined the newborn was neither affected by nor a carrier of the genetic variants,” Miller said. “Here we demonstrated how prior knowledge of familial variants can be used to rapidly evaluate an individual at-risk for a genetic disease.”
So, what are Miller’s next steps in identifying genetic variants?
“We’re looking to conduct a broader study with children in intensive care units,” he said. “I’m exploring a wide range of options at both Seattle Children’s Hospital and the University of Washington, as well as with researchers at other institutions. This project lays the groundwork for the rapid return of actionable information. I am looking forward to returning informative results to the clinical team on an individual that they admitted earlier in the day.”