Transcript Magee Symposium March 8 slides.

I inherited What???
You and Your Genes:
The Explosive New World
of Genetics
David Finegold, M.D.
Disclosure
In relation to this presentation, I declare
the following real or perceived conflicts
of interest:
 I am employed by GeneDx, a commercial
genetic testing laboratory that performs
whole exome sequencing.
 GeneDx is a wholly owned subsidiary of
BioReference Laboratories, a publicly
traded company.
Overview
 Basics of Genetic Testing
Pan-Ethnic Carrier Screening
Whole Exome Sequencing
 Clinician’s Perspective
Genetic Testing
Overview
Types of Genetic Testing
Pan-ethnic Carrier Screening
Pan Ethnic Panels
 Labcorp/Integrated Genetics: Inheritest
 430 mutations in 87 genes
 not including SMA
 Counsyl: The Counsyl Test/Family Prep Screen
 398 mutations in 102 genes
 includes SMA + Fragile X
 GenPath*: Inherigen Plus
 733 mutations in 167 genes
 includes SMA + Fragile X
*Disclaimer: GenPath is also a subsidiary of BioReference Laboratories.
Advances in Genomic Medicine
 Definition of Genomic Medicine

use of genetic information to improve health outcomes
 Rapid advances in genomic technologies, such as
next generation sequencing and whole exome
sequencing has led to
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dramatically lowered cost of genetic testing
dramatically increased amount of genetic data
dramatically increased need for analysis and
interpretation
What is WES?
 Whole Exome Sequencing
 Targets the protein coding regions of the
human genome: ~180,000 exons in
~20,000 genes (30Mb)
 Coding regions of interest are targeted and
“captured” for massively parallel
sequencing (NextGen technology)
 Generates a huge amount of data which
needs to first be filtered by bioinformatics
and then analyzed by both bioinformatics
and humans
Why WES and not WGS?
 Whole Exome vs. Genome Sequencing
 Exome = <2% of the entire genome
 However, ~85% of known disease-causing mutations
are located in the exome
 Cost-effective alternative to WGS
 Costs are now less for WES than to sequence just a
few genes. Institutional bill prices at GeneDx:
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$9000 for trio (31% diagnostic rate)
$5000 for singleton (24-28% diagnostic rate)
$3000 for slice for singleton
(http://www.genedx.com/xomedx-slice-tool/)
 Much of the non-coding portion of the genome is
still poorly understood
WES Limitations
 Not technically possible to capture and sequence the
entire exome at present.
 Coverage:
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~90-95% of the targeted region of an individual’s exome will
be assessed with WES with at least 10x coverage
NEW: With the Clinical Research Exome (CRE), the ~4500
known disease-causing genes are enriched to ~99% coverage
 There may be some genes or portions of genes that are
not amenable to capture, sequencing, and alignment
 Certain types of sequence variations are difficult to identify
using WES (i.e. repeat expansions, deletions, duplications)
 The scientific knowledge available about the function of all
genes in the human genome is incomplete at this time.

WES may identify the presence of a variant in the exome
sequence of an individual, which will not be recognized as
the cause of his/her disease due to insufficient knowledge
about the gene and its function.
A Clinician’s
Perspective
Summary
Resources
Thank you!