CUSTOMER SPOTLIGHT
KYLE RETTERER

Scaling to the cloud to support
whole-genome sequencing
DRAGEN platform deployed on Microsoft Azure provides
ultrarapid secondary analysis capabilities in the cloud, enabling
adoption of high-throughput whole-genome sequencing
TMIntroduction
GeneDx is a Maryland-based genomic analysis company thatuses next-generation sequencing (NGS) for genetic testing of rarediseases. Kyle Retterer joined GeneDx in 2010 as a bioinformatics engineer, working to establish the company’s infrastructurearound NGS panel testing. GeneDx quickly shifted focus to building
out its whole-exome sequencing (WES) capabilities, recognizing
the advantages WES brought for detecting disease-associatedvariants. Retterer led efforts to take what they had learned fromNGS targeted panels and scale to WES.

PICTUREDKYLE RETTERER, MS, CHIEFTECHNOLOGY OFFICER OF GENEDX"We want to get to a place
where genomics isn't the end of
the journey, it's the beginning."

Exome sequencing continues to grow rapidly for GeneDx, making
the company a market leader. Now the company is building on thatexpertise to introduce scalable whole-genome sequencing (WGS).
“We’re at a point where we can run a genome today for what it cost
us to run an exome several years ago. We expect that at some point
it’s going to flip and become more cost effective to perform WGS
than WES. We’re building our data and interpretation capabilities forthat future, where there will be much more territory that we can interrogate and reinterrogate over time. With WGS we will have comprehensive genome information, instead of these targeted slices”

Moving to WGS with the NovaSeqTM
6000 System
The ability increase sequencing operations has been key toGeneDx’s success. Retterer recalls running targeted panels on theIllumina Genome AnalyzerTM System, “We were able to run maybe
a dozen samples over the course of several days. Today we can

For Research Use Only. Not for use in diagnostic procedures.

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"DRAGEN on Azure enables
people to share data much
more readily because the data
are already sitting in a secure
cloud...Also, the ability toreanalyze older data becomes
more practical...With cloudbased storage, you have all thatdata readily available. It enables
you to do more retrospective
analyses."

Enter the DRAGEN Bio-IT Platform
The DRAGEN Bio-IT Platform uses reconfigurable field-programmable gate array (FPGA) technology to deliver highly accurate,
ultrarapid secondary analysis of NGS data. GeneDx integrated
the DRAGEN Server into its existing on-premise solution to lower
costs and drastically reduce analysis times. The DRAGEN platform
provided more than just the speed. “We liked the simplicity of it.
We also liked the modularity of it. We were able to take DRAGEN
software and plug it into our existing infrastructure and pipelines
relatively seamlessly.”
By incorporating a DRAGEN on-premise solution, GeneDx wasable to build up a significant data center with the ability to handle
the computation and data storage needs that running ~500010,000 exomes per month required. But as GeneDx began theprocess of moving from WES to WGS, the challenge became
obvious to Retterer. “With WGS, you generate about 25× as muchsequencing data per sample as compared to WES. We’ve run over
300,000 exomes to date, about a third of those in the last year. Butif we convert all of our WES to WGS, suddenly our data center hasto grow 20-30 times its current size. The amount of infrastructure
we would need, it’s a bit overwhelming. Our data center would
become bigger than our laboratory. We want to keep with theGeneDx mission; we’re a research and diagnostics company, not adata center.”"You've got to evolve theScaling data infrastructure to the cloudtechnology on all sides. Thewith Microsoft Azure

laboratory technology andthe data technology arecomplimentary pieces."

2 |sequence hundreds of exomes, dozens of genomes, on a single
NovaSeq 6000 System. We’re much higher throughput. We’re able
to investigate more of the genome for more people at a lower costbecause of Illumina sequencing technology.” But scaling up theirsequencing capabilities meant they also needed to increase theirability to manage, analyze, and interpret all that data.

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As GeneDx transitioned from exomes to genomes, Retterer knew
their use of the DRAGEN platform had to scale as well. “You’ve got
to evolve the technology on all sides. The laboratory technology
and the data technology are complementary pieces. I think cloudbased computing and storage are necessary as you adopt WGS at
the scale GeneDx is doing.” DRAGEN on Azure provided GeneDx
the cloud-based computing they needed to scale to WGS, while
delivering the same speed and simplicity they experienced withDRAGEN on-premise for data analysis.

For Research Use Only. Not for use in diagnostic procedures.

In addition to the benefits seen with performing data analysis in
the cloud, Retterer recognizes other impacts DRAGEN on Azure
has on their data management. “One thing that's clear is DRAGEN
on Azure enables people to share data much more readily because
the data are already sitting in a secure cloud. Sharing data withclients or collaborators becomes a bit smoother. Also, the ability toreanalyze older data becomes more practical. We've sequenced
300,000 exomes, but we don't have all 300,000 exomes constantly available on high-performance computer systems on premisebecause that's too expensive. With cloud-based storage, you canhave all that data more readily available. It enables you to do more
retrospective analyses.”

As a bonus, it turned out that migrating to the cloud to leverage
the FPGAs on Azure was more cost efficient for GeneDx thanmaintaining their own high-performance computing center. “TheDRAGEN platform uses these FPGA systems for analysis, and there
are plenty of them in Azure. We’re able to bring a large numberof them online at once, run all of our analysis jobs in parallel, andthen bring them offline. Because the DRAGEN platform is so fast,
we don’t need them for that long, so we can be cost effective withour cloud usage.” That ability to analyze multiple samples simultaneously is another advantage of DRAGEN on Azure. Cloud-based
analysis reduces turnaround times by eliminating the need toqueue up multiple samples for analysis on a single DRAGEN Server
on premise.

"We liked the simplicity of it. We
also liked the modularity of it...
we were able to take DRAGEN
software and plug it into ourexisting infrastructure andpipelines relatively seamlessly."

Security in the cloudAs a research and diagnostics company dealing with personal
genomic data, security is paramount to GeneDx. According toRetterer. “Cloud-based data management can be more secure thanstorage on premise, because you have this larger ecosystem ofsecurity that you can take advantage of, but make sure you designfor that from the start. We’ve worked with a managed cloud service
provider, who specializes in the healthcare space, to help us withthe transition and with securing all of the infrastructure. Whether
you choose to work with a managed cloud service provider or use
services directly through Illumina, it makes sense to get help.”
Retterer sees another area where moving to the cloud offers clear
advantages. “Transitioning to Microsoft Azure removes some of therisk involved in having a large, on-premise data center. We havebuilt-in redundancy and a disaster recovery plan, but with DRAGEN
on Azure, an on-premise disaster won't impact operations to thesame extent.”

For Research Use Only. Not for use in diagnostic procedures.

"The biggest thing is that
DRAGEN on Azure enables
the shift from exomes towhole genomes and thecomplimentary shift to broader
testing of more people."

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Vision for the future
GeneDx is working to integrate genomics into routine health careto improve health for everyone. Historically, GeneDx has become
involved only after a genetics-savvy physician has ordered agenomic analysis, often at the end of a rare disease diagnosticodyssey. The challenge GeneDx is taking on, as Retterer puts it,
is “how do you make genomics something that becomes a routine
part of the healthcare journey for every kid with a developmental
problem or anyone else who could benefit? How do we get themsequenced earlier, so we can get answers back sooner?”
The answer, in part, is a matter of scale. As Retterer says, “Thebiggest thing is that DRAGEN on Azure enables the shift fromexomes to whole genomes, and the complementary shift tobroader testing of more people. It would have been much morechallenging to accomplish that shift from a capital and operational perspective if we were still using an on-premise data center.”
Looking to the future, Retterer believes WGS is key to helping
GeneDx achieve its mission. “We want to get to a place wheregenomics isn’t the end of the journey, it’s the beginning. We
want to shortcut the diagnostic odyssey and give people morecomprehensive answers much earlier in the process, enabling
possible elimination or mitigation of various rare diseases throughemerging therapies.”

Learn more
DRAGEN Bio-IT Platform, illumina.com/products/by-type/informatics-products/dragen-bio-it-platform

DRAGEN on Azure, illumina.github.io/dragen-azure-quickstart/3.9.5/

GeneDx, genedx.com

1.800.809.4566 toll-free (US) | +1.858.202.4566 tel | techsupport@illumina.com | www.illumina.com© 2021 Illumina, Inc. All rights reserved. All trademarks are the property of Illumina, Inc. or their respective owners.
For specific trademark information, see www.illumina.com/company/legal.html.
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