I inherited What???You and Your Genes:

The Explosive New World of Genetics

David Finegold, M.D.

DisclosureIn 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.

OverviewBasics of Genetic Testing

Pan-Ethnic Carrier ScreeningWhole Exome Sequencing

Clinician’s Perspective

Genetic TestingOverview

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 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: $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:

~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!