Diane Allingham-Hawkins, PhD, FCCMG, FACMG, Senior Director, Genetic Test Evaluation Program
Friday, March 28, was the last full day of sessions for the 2014 ACMG meeting. Friday’s sessions included a very interesting plenary session regarding sharing data from genome testing in order to aid interpretation of results. There are two major challenges when analyzing data from whole genome sequencing (WGS), whole exome sequencing (WES) or microarray analysis: the sheer volume of data obtained in the analysis and the interpretation of variants of unknown clinical significance (VUS). Consequently, there are now a number of initiatives for sharing data and standardizing interpretation—a sort of “crowd sourcing” approach to genomic analysis. ClinGen is a Clinical Genome Resource that has established a consortium of genomic researchers to establish standards for variant interpretation, data gathering, and sharing through the database ClinVar and defining and reporting the association between genetic variation and disease.
Probably the most entertaining session at ACMG is the Diagnostic Dilemmas session held on Friday evening. Each year, geneticists from around the world bring their toughest cases for discussion. After a brief description of the patient and laboratory findings to date, the audience is invited to share suggestions regarding diagnosis and/or further testing options. You can imagine how lively the discussion is with several hundred clinical and laboratory geneticists and genetic counselors providing their input. I always learn a great deal in these sessions and, more importantly, many diagnoses are suggested or even made during the session!
The three major takeaways for me from the ACMG 2014 meeting were:
- Non-invasive prenatal testing (NIPT) for common fetal chromosome abnormalities is being widely used in obstetrical care. Nearly all of the validation of these tests has been done for the most common prenatal chromosome abnormality, Down syndrome (trisomy 21). The tests are not nearly as well validated for the other chromosomes included in the test (chromosomes 13, 18, X, and Y) yet they are still being used in clinical care. Much work is still needed to understand all of the risks, benefits, and limitations of using these tests in the care of pregnant patients.
- Whole exome sequencing (WES) is being widely applied in a variety of settings. Much of this work is still considered research, although there is an increasing tendency for use in clinical care. For example, Baylor College of Medicine reported that they receive 180 to 200 samples a month for WES. Interpretation of these results in order to provide meaningful information to patients and their physicians is complex and fraught with uncertainty. The added controversy of “incidental” or “secondary” findings—those that are unrelated to the reason for referral but that may be clinically significant to the patient or their family—increases the complexity of interpretation, reporting, and genetic counseling.
- Public sharing of data from WGS and WES studies is critically important to further our collective understanding of the interpretation and clinical significance of genetic variants. As one speaker put it, it is likely that every single nucleotide in the human genome will turn out to be variable so we really need the collective wisdom of all researchers, laboratorians, and clinicians to ensure that standards are defined and maintained and interpretation is consistent across laboratories.
The ACMG annual meeting is a wonderful opportunity to learn about emerging and controversial issues in genetics and I am thrilled that I was able to participate this year and to provide updates via these blog posts.