Genetic Testing During the Diagnostic Odyssey - Alicia Scocchia, Genetic Counselor, Illumina (Meeting 4 February, 2017)

Meeting Notes

1. Genetic testing looks for variants or changes in the DNA that may or may not be disease causing.
2. Results of genetic testing involve both sequencing and interpretation:
   1. Sequencing: Reading the letters of the DNA and putting them in order
   2. Interpretation: Gathering and reporting evidence about what the letters mean in the context of human disease
3. Not all rare diseases are genetic; although a lot of genetic diseases are rare!
4. There are many different genetic testing options:
   1. Karyotype and microarray tests look at structure of the chromosomes (condensed DNA).
   2. Exome sequencing zooms in to look at smaller variants. Although the exome is estimated to be only 1-2% of the whole genome, variants in exome are thought to be the most common causes of human genetic conditions.
   3. Genome sequencing has the ability to look at the structure of the DNA and smaller variants in the exome and beyond. At this point in time, the interpretation of genome sequencing is a lot like receiving an exome sequencing test + a microarray.
   4. Exome and genome tests which have a primary goal of aiding in the diagnosis of rare disease are most helpful when other members of the family are available to participate in the analyses as well (ex: trio analysis with mom, dad, and child).
   5. Different laboratories/studies will give back different findings, including a clinically significant findings, research candidates, secondary findings, and others. Some laboratories will give back data files, including or VCF (organized raw data, transferrable to most other laboratories) BAM (raw data, only transferrable to laboratories with a comparable workflow). These data files are most helpful to other laboratories which have the processes, software, and expertise in place to re-analyze the data.
5. Genetic testing for use during the diagnostic process is very dynamic process:
   1. Though the science and technology behind genome sequencing has advanced quickly, we are still learning a lot about the significance of variants in the genome every day.
   2. There is dynamic interpretation of results over time as new information on genes and mechanisms of diseases are gathered within the scientific community.
   3. Resequencing is the process of reading the letters in the DNA again. This may or may not require a new sample. We expect the vast majority of a sequence to be the same during resequencing. Resequencing is most helpful to a family when sequencing technology changes and new technology may identify more candidate variants for interpretation.
   4. Reanalysis/reinterpretation is the process of further researching a candidate variant to see if more information is available which supports a change of variant classification. This is most helpful as new various groups contribute more data into the scientific community about gene function and mechanism of diseases.
6. The iHope Program at Illumina partners with clinicians and clinical organizations to offer whole genome sequencing and interpretation at no cost to families. The best way for a family to submit an application is through Rare Genomics Inc. (an iHope clinical partner) online at http://www.raregenomics.org/ihope/.

Resource
"Free Clinical Whole Genome Sequencing to Children with Undiagnosed Genetic Diseases"
http://www.raregenomics.org/ihope/