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 Clinician’s Perspective 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 -Not sequencing. Still looking at founder mutations on chips -Not all created equally. Vary by both number of genes tested, and mutations within each gene that are screened. -Counsyl offers a sequencing option as well, but could then miss some founder mutations *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 XomeDxSlice captures and sequences the whole exome, but analysis is targeted to a limited and specific phenotype-driven gene list.

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. -GeneDx average coverage is 100x consistent with the recommendation from the ACMG -Problems: Pseudogenes, deep intronic changes, complex ins/del/dups, CNVs -Currently with WES, we have greater than 90% sensitivity for detecting deletions when more than two exons are deleted.

A Clinician’s Perspective

Summary

Resources

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