March 8th-12th was the annual Annual Clinical Genetics Meeting, this year in Tampa, Florida. Amongst other things, attending gives a great opportunity to develop a sense of how genetics is impacting medicine today. Below is a round-up of what stood out for me.
We heard from ACMG’s President, Jerry Feldman, that Medical Genetics as a specialty in need of urgent change. We’ve all heard about the shortage of genetic counselors, but ~50% of Medical Genetic residency positions go unfilled. He stated “Patient volume will support the future of our specialty”.
Demonstrating the value of genetic services needs to be a top priority, and there have been few concerted aggregation efforts so far. Geisinger’s Mark Williams, shared his experience with payors, including a conversation in which a payor suddenly got much more keen on whole exome sequencing when they realized you could diagnose Lynch syndrome, i.e. when they saw the prevention dollars.
In general, there was a huge focus on healthy babies.
Traditionally, carrier screening was intended to identify couples at risk of having a child with a severe disease. But last year, ACMG made a statement http://journals.lww.com/greenjournal/Citation/2015/03000/Expanded_Carrier_Screening_in_Reproductive.20.aspx, that the purpose should be to provide information to adults to “optimize pregnancy outcomes”. Whereas previously we were looking at diseases with minimal treatment options, now we also look at cases where something can be “done” with the information. The Counsyl team used the example of MCAD, which in 5% of cases causes death within 72 hours of birth, but which is readily treated by diet.
The traditional uses of pre-implantation genetic diagnosis (PGD) are to diagnose and prevent disease, and to select the healthiest embryos for disease. But we heard from Melissa Brisman, who is a lawyer specializing in setting up surrogacy arrangements, that the reality today is that PGD is used for family balancing, for sex selection, and for selecting certain desirable traits. This is all happening within an area that no US politician wants to risk legislating in.
Non-invasive prenatal testing (NIPT), which relies on fetal DNA detected in the mother’s blood, first became available in late 2011 and can reliably detect chromosomal abnormalities (it can now also detect copy number variants as small as 7MB, though clinical guidelines recommend against this screen). Abnormal NIPT results prompt an amniocentesis or CVS, but something that complicates results is learning something unexpected about the mother. Diani Bianchi from Tufts recalled a colleague joking that NIPT can lead to a Non-Intentional Pre-symptomatic Tumor Diagnosis. She stressed the importance of pre-test counseling including the potential for maternal findings.
Whole exome sequencing of fetuses with ultrasound abnormalities is now offered by several labs. For example, at Baylor they have a 2-3 week turnaround time, and a 35% diagnostic rate. Most of the time the information is used for management post delivery.
What about revealing genetic information of an un-born child to its parents? Historically, the ideal was to defer testing for adult onset conditions until adulthood, but a position paper from the ACMG and others in 2013 said “It may be ethically acceptable to proceed with predictive genetic testing to resolve disabling parental anxiety”. http://pediatrics.aappublications.org/content/131/3/620
Genetic sequencing can give you a fairly good idea of how related the parents are. ACMG guidelines recommend reporting as a secondary finding if it looks likely that are one or two degrees of relationship apart (i.e., first cousins or closer), but stress that speculation of specific parental relationships is heavily discouraged.
After Angelina Jolie’s decision for an elective double mastectomy in 2013, demand for BRCA1/2 testing doubled, and has not declined since. How to cope with increased demand in a world where getting a genetic counseling appointment can take months? Counsyl’s approach has been to try an online platform, with most negative results being released online with accompanying videos, and remaining results (all positives and some negatives) results being released over the phone. Genetic counselors are available via a chat feature, with average wait time less than two hours. They see a future where positive results could also be released in this fashion, the comment “Patients often aren’t as fragile as we think they are” drew applause.
Variant Interpretation was a hot topic, unsurprisingly as this was the first meeting following the release of the ACMG/AMP guidelines for classifying variants (released May 2015). Part of the motivation for establishing clearer guidelines was the high discordance rate noted in classifications across, and sometimes even within, laboratories. (Though this discordance was challenged by Stephan Lincoln from Invitae, who showed 99+% concordance for BRCA1/2 variants.) The general feeling seemed to be “its super helpful to have guidelines, and it will help greatly in having a common vocabulary BUT they sometimes need tweaking”. Various groups have proposed modifications. For example, Baylor have added on six extra criteria of their own, and a project out of ClinGen, in an interpretation effort of MYH7, have dropped one criterion, added some, and modified others.
With testing moving beyond single gene and into large panels of genes, gene level curation was almost as talked about as variant interpretation. ClinGen have a “semi-quantitative” approach for assessing the link between a gene and a disease. Remarkably few genes on commonly available panels end up with “strong” or even “moderate” scores on this scale. If the criteria are made stricter, and case-control evidence made necessary, the numbers drop off yet more.
Amid the general frustration with reports containing “variants of uncertain significance”, a major downside of whole exome or genome sequencing, there were a couple of interesting perspectives on returning results. Kate Forman, a genetic counselor at UNC Chapel Hill, shared her perspective that parents sometimes view these tests as a “last hurrah”, after which they can feel like they’ve done their due diligence, and can focus on treatment (though they know they can have the test re-done in the future, and they hold out hope for scientific advances that will provide clarification). Birgit Funke, from HMS, said her rule of thumb is “would I report this in a prenatal setting? (where there’s a chance the parents will abort based on the information)”.
In a whole session dedicated to Utilization Maximization, the mantra was “the right test for the right patient at the right time”. Melissa Bennett, form the payor side, said that 20-50% of genetic tests ordered are unnecessary. Mary Beth Dinulos shared her experience at Dartmouth Children’s, where a combination of bringing testing in house, negotiating pricing with diagnostic labs, and developing a testing utilization management team have saved millions. One way Genetic counselors provide value is by quality checking which tests physicians order.
I realize the above covers rather little novel science, and I think that is a fair reflection of the talks at the conference. One thing that piqued my interest from Cynthia Morton’s Harvard lab was the use of “Topological Associated Domains” (TADs) in variant interpretation. TADs are large scale, conserved, 3D genetic structures (se e.g. http://www.nature.com/nature/journal/v515/n7527/full/nature13986.html). Their disruption can lead to “rewiring the genome”.