Children’s Hospital
Genomics Roundtable

APRIL 13, 2021

Due to the rare occurrence of rare diseases and pediatric cancers, many of their biological details remain unclear. As a result, critical genetic links continue to go unrecognized due to a limited understanding of how certain inherited variants may impact the pathogenesis and progression of rare disease and cancer in children. This information gap not only presents challenges for patient education, but also for diagnosis and treatment plans.

Understanding the hereditary factors underlying rare disease and pediatric cancer equips patients and their families with information that is both educational and actionable. For instance, awareness of a predisposition allows patients to seek appropriate screening and prevention measures, as well as explore conversations surrounding family planning. Most importantly, these insights may aid in selecting the most effective treatment options.

In this roundtable discussion, experienced laboratory directors and clinicians will gather from a variety of institutions leading the charge in pediatric genomics research, including St. Jude Children’s Research Hospital, Children’s Hospital of Colorado, Nationwide Children’s Hospital, and Memorial Sloan Kettering Cancer Center.

Armed with a diverse breadth and depth of expertise in research and clinical diagnostics as well as genetic counseling and clinical care, speakers will share their perspectives on recent developments and current practices within the realm of clinical and research genomics. Additionally, they will describe how artificial intelligence and AI-based tools, including Genomenon’s Mastermind Genomic Search Engine, are streamlining patient care and forwarding the collective effort to advance genomic discovery for rare diseases and cancer in children.

Learning Objectives:

  • Describe key initiatives at selected Children’s and Research hospitals aimed at advancing rare disease diagnosis and care
  • Understand how genomics is influencing the approach to treatment and management in pediatric rare disease and cancer
  • Discuss the role of artificial intelligence technology to optimize diagnosis and healthcare delivery for those with rare disease and pediatric cancer

EXPERT PANELISTS

Amy Treece, MD
Pediatric and Molecular Pathologist, Medical Director of the Precision Diagnostics Laboratory
Children’s Hospital Colorado

Alisa Gaskell, PhD
Co-chair and Scientific Director of Precision Medicine
Children’s Hospital Colorado

Elise Fiala, MS, CGC
Senior Genetic Counselor
Memorial Sloan Kettering Cancer Center

Michael Walsh, MD
Geneticist & Pediatric Oncologist
Memorial Sloan Kettering Cancer Center

Roshini Sarah Abraham, PhD
Professor, Clinical Pathology, Founding Director, Diagnostic Immunology Laboratory, Associate Chief, Academic Affairs
Nationwide Children’s Hospital

Elizabeth Varga, MS, LGC
Director of Clinical Genomics Research and Development Steve and Cindy Rasmussen Institute for Genomic Medicine
Nationwide Children’s Hospital

Kim Nichols, MD
Director of Cancer Predisposition Program
St. Jude Children’s Research Hospital

Jamie Maciaszek, PhD
Clinical Variant Scientist, Department of Pathology
St. Jude Children’s Research Hospital

WEBINAR TRANSCRIPTION:

Good morning, everyone, and welcome to the Children’s Hospital Genomics Roundtable! I’m Garrett Sheets, the content specialist for Genomenon, and I’ll be moderating today’s conversation.
Today, we are excited to host a highly experienced group of panelists from four leading pediatric hospitals, who will share their perspectives on recent developments and current practices within the realm of clinical and research genomics, as well as describe how AI-based tools, including Genomenon’s Mastermind genomic search engine, are streamlining patient care and forwarding the collective effort to advance genomic discovery. They have a lot of great information to share, so I’ll mention a small housekeeping item and then move right into our introductions so that we can get started.
We have a really full agenda today, and for those watching, we want to be able to take all of your questions. If we don’t have time to answer them at the end, we will send them to the panelists after the event and post them on our website. So, without any further ado, I’ll briefly introduce our speakers.

Amy Treece is a pediatric and molecular pathologist, and serves as the medical director of molecular diagnostics laboratory at Children’s Hospital Colorado.
Also from Children’s Colorado is Alisa Gaskell, who is the co-chair and scientific director of precision medicine, with expertise in the development and implementation of next generation sequencing technologies and the analysis of genomic data.
Elise Fiala is a senior genetic counselor at Memorial Sloan-Kettering Cancer Center with a focus on pediatric patient care.
We also have Michael Walsh from Memorial Sloan-Kettering, who is a pediatrician, geneticist, and hematologist-oncologist.
From Nationwide Children’s Hospital, we have Roshini Abraham, the associate chief of academic affairs and founding director of the diagnostic immunology laboratory in the department of pathology and laboratory medicine.
Also from Nationwide is Elizabeth Varga, the director of clinical genomics research and development at the Steve and Cindy Rasmussen Institute for Genomic Medicine.
From St. Jude Children’s Research Hospital is Kim Nichols, a pediatric oncologist and the director of the Cancer Predisposition Program. Her research interests include the molecular mechanisms that provide protection against viral infections and cancer.
Jamie Maciaszek is a clinical variant scientist in the department of pathology at St. Jude children’s hospital. A trained biomedical engineer, her research experience includes the molecular mechanisms of sickle cell disease and pediatric T-cell acute lymphoblastic leukemia.
Finally, Mark Kiel is the founder and CSO of Genomenon, where he supervises the scientific direction of the Mastermind suite of software tools. His research interests include stem cell biology, genomic profiling of hematopoietic malignancies, and clinical bioinformatics. Mark, I’ll open up the floor to you for a moment here. Did you want to say a few words to welcome our panelists?

MARK: Yes, sure, thank you Garrett! I want to welcome all of the panelists — I feel very privileged to have assembled so many folks from the clinical front lines — as well as to welcome our audience members. The very brief introductory remark I want to give is just to say that we at Genomenon really appreciate the time that you’re taking out to attend this discussion. I as a panelist hope to learn much more than I can share in this event. Without further ado, Garrett, I’ll pass it over to you so that we can maximize the conversation time.

GARRETT: Perfect. Thanks, Mark. What a stellar group we have! Now that everyone has been introduced, I want to start a question for the team from Children’s Colorado. Amy, maybe you can speak to this: In terms of genomic health care, what are some would you say are some key initiatives for your organization?

AMY: Yeah, sure! One of the important things to know about Children’s Hospital Colorado is that our approach to genomics currently is very clinically-oriented. One of the big things that our institution is working on is a precision medicine service line, and the goal of the service line is to combine clinical, laboratory, and operational expertise to really help make clinical genomics available to all disciplines. Now that we see genomics really expanding into a lot of subspecialties beyond genetics, we want to make sure that those specialties have the same access to genomics.
With this initiative, there’s a major emphasis on infrastructure to help support patient access to testing, access to counseling, and access to treatment. Our goal is to really have a consolidated approach to issues that cross specialties, so that we don’t see efforts duplicated in various different silos. Under this model, oncology, genetics, and other specialties are all at the same table, discussing their needs and identifying areas where they overlap, particularly in areas of really high priority for the institution. Though this approach is really clinical, the service lines will also focus on how to leverage our clinical data to support research initiatives as well.

GARRETT: Thank you, Amy, for that. Maybe someone from Nationwide — What are some comments on some key initiatives for your organization, and how do they relate to what was just shared?

LIZ: Yeah, I’ll take that one. Very similarly to the objectives at Children’s Colorado, we started the Institute for Genomic Medicine about five years ago at Nationwide Children’s, and the goal is to bring the research and clinical operations together under one umbrella. Instead of being siloed with clinical laboratory testing and a separate research operation, we have the ability to perform research genetic testing — such as whole exome sequencing, as well as some more research-based assays, like RNA sequencing, methylation testing and other specialty tests — within the operation of research, and also confirm that clinically, so that results can be delivered to patients across the institution. Very much like Amy and Children’s Colorado, we are trying to really expand our infrastructure so that it’s not siloed and increasingly incorporated into specialties. One example of that is Roshini operating in immunology, and bringing some of the next generation sequencing technologies into other areas of care.

GARRETT: Thank you, Liz. You mentioned Roshini’s work and immunology. Roshini, could give us kind of an overview about how your work relates to what has been shared?

ROSHINI: So my focus is on inborn errors of immunity. I came to Nationwide Children’s from Mayo Clinic. While I was at Mayo, I developed the targeted gene panels for the inborn errors of immunity, and what I rapidly realized is that we’ve now got over 450 different genetic disorders that fall under the umbrella of inborn errors of immunity. When I started the process several years ago at Mayo, I realized that, with the targeted panels, you need a sort of nimble approach; you need to stay up to date and keep your panels all updated. When I came to Nationwide Children’s, I decided that it would not be reasonable to recreate targeted panels for the inborn errors of immunity because there were commercial reference labs that were doing a far better job, and were probably able to be more nimble and stay current. So we now send targeted gene panels outside, but when it comes to exome or even genome under the research umbrella, then we look within our institution to sort of tease out complex patients with immunological disorders.

GARRETT: Thank you, Roshini. Now that we’ve talked about how these fields affect patients, I think I’d like to shift the conversation to general trends. So I’ll pose the question, and open this up to everyone: How has the approach to diagnosing rare disease and/or pediatric cancer changed in the past five years? How about someone from St. Jude Children’s?

KIM: Sure! Actually, I was going to mention this too in terms of our initiative, so I think this is a good segue. Let me talk briefly about what we have at St. Jude, and then I’ll just talk about how it’s changed. St. Jude, as many of you know, has had a really long history in terms of doing research on genomics and cancer through the Pediatric Cancer Genome Project. Six years ago, I was really fortunate to be recruited to St. Jude to bring on a clinical genomics initiative, where now we can offer all newly diagnosed cancer patients at St. Jude the opportunity to have their tumors evaluated using whole-genome, whole-exome, and RNA sequencing. We can also look at their germline using whole-genome and whole-exome.
That said, we are primarily a cancer institute, studying cancer and other disorders of the blood, so our focus is primarily on the cancer genes and cancer risk genes. But I think that what’s really wonderful about St. Jude is that, in addition to providing this now as a clinical service, the data that’s generated, as long as patients sign for research consent, both the tumor and the germline data gets uploaded through the St. Jude cloud, which is a tremendous research resource for institutions all over the world. I just want people to know that they can access germline and tumor genomic data, free of charge. I think, now, there are probably ten to twenty thousand genomes including both tumor and germline data in the cloud that people can access.
This has had a tremendous impact right on our ability to refine diagnosis of cancers. You can think about leukemia at St. Jude through Charles Mulligan now. What we used to look at under the microscope — I mean, I’ve been doing pediatric oncology for twenty years, and I remember when I started, you looked under the microscope (Mike probably knows this) and you see a lymphoblast, and a lymphoblast was a lymphoblast, and everybody got AOL therapy. Now, thanks to genomic advances, we know that there are multiple subtypes of leukemia, and some of them do better than others. We know we need to adjust therapies based on some of these molecular findings. From a tumor perspective, genomics and precision medicine has made a tremendous impact, particularly for leukemia, but we have a lot of work yet to do for many of the solid tumors, for example, and for some of the brain tumors. We’re just at the tip of the iceberg.

MARK: Kim, we lost your audio, so I’ll try to pick up where you left off. As a metapathologist by training, one of my professors spoke to the obsolescence of the microscope in a similar way to what you talked about. I don’t know if what you mentioned would have to do with its obsolescence, but if it would rather actually be the augmentation with molecular diagnoses. I was struck by how the WHO, the hematopathologic diagnoses in the WHO, were increasingly molecularly predicated. As I was leaving my training, I remember seeing that effect in solid tumors and brain tumors as well. I don’t know how much more that’s flourished since my training, but it was a very encouraging thing for me to see, where the diagnoses become much more molecularly predicated.

GARRETT: Really good discussion! I’m curious to hear, I don’t think we had any feedback from team members at Memorial Sloan-Kettering. Elise, Dr. Walsh, do you have anything to add on to build on what has been shared so far?

MICHAEL: No, I think I would agree with what the others have said. At least to chime in here as well, I think that we are, as Kim said, at the tip of the iceberg. I don’t necessarily foresee any other aspects of diagnosis going anywhere too soon because there’s so much variation of uncertainty that all of the additional information that we’ve relied on, historically, continues to be relevant in different ways. On the germline side, as opposed to maybe just the tumor side, that is probably even more true, as we’re dealing with so much variation of uncertain significance. Being able to phenotype and characterize tumors helps us better understand some of the predispositions as well, and spectrums that go with a lot of the cancer predisposing syndromes. I think we’re we’re still early days with a lot of this stuff. We have moved though, nicely, I think, from some of our original papers from five, six, seven or eight years ago, where we were describing a lot of the genetic predisposition, to more recently, how we’re actually translating this clinically.

AMY: I’d like to quickly add to that. I think something that I’ve seen change here in the past five years is that our genetic counselors on the oncology side are involved from the very beginning of diagnosis of oncology patients. They attend our tumor boards, and these discussions of predispositions happen right at the very beginning of diagnosis, not as an afterthought or a follow-up. So they’re utilizing molecular results as soon as possible to get those patients plugged into predisposition clinics.

KIM: Yeah, I was going to chime in, and this builds on what Mike said: In the old days, twenty years ago, a lot of guidance regarding germline genetic testing was based on basically family history or patient medical phenotype, but now we’re learning that a lot of families don’t have a positive family history, or patients with specific syndromes, Fanconi Anemia as an example, a good proportion of them don’t have clinical manifestations. So, having the ability to do genetic testing a little more broadly has really enhanced our ability to make germline diagnoses.

GARRETT: Okay! So we’ve had a really good conversation about germline variants, we’ve talked about trends that you all have seen in practice over the past five years. I’d like to now kind of look forward, and ask you — to pose again, generally, to everyone, because we had such a great conversation — how do you think this approach to diagnosing rare disease and pediatric cancer will affect things? Over the next five years, what do you see looking forward?

ALISA: I can take that one. Really, this builds on everything that we’ve discussed to date. I think what we will see is merging of fields and breakdown of the silos. It’s very comfortable to think of something as either due to an inherited germline or an acquired mutation, but I think the more we’re seeing and even moving into the transcriptional space, we’re learning so much, and we’re actually seeing that there’s more of a blending. Just as our tests are becoming unbiased, I think we should be approaching the diseases in a very unbiased fashion, and know that we have the expertise, and, based on the molecular profile, we can guide our patients through our system rather than following these very solid paths in the system.

ROSHINI: If I may add to that, in the inborn errors of immunity, I think a particular challenge is the number of new genetic defects we’re adding to the list. We’re at 450 or 460 now, and every two years, there’s an expert panel that gets together to classify all the inborn errors of immunity, and publish those classifications. In January 2020, the biannual classification was published, and then ten months later, we had to have an interim update because we’ve got about 30 new genes added. We can’t wait for another two years to update the classification. I think, for clinicians, it’s exceedingly hard to keep abreast of all these new genetic defects and the phenotypic variability.
Then, of course, clinicians are often faced with the conundrum of these variants of uncertain significance, and trying to find the correlation to the immunological phenotype or trying to do functional validation. In the immunology community, that’s something that we have to really work hard at, and we have a few thoughts and initiatives around that. How do we functionally validate these new variants or new genetic defects? How do we make sure that our community of clinical immunologists, but also hematologists, rheumatologists, anybody who sees patients with these inborn errors of immunity, how do we make sure that they are able to stay abreast of all this new information? So that’s the challenge for the next five years, I think, for us.

KIM: Yes, I absolutely agree. You know, Roshini, I think this goes across all conditions. As you think about it, it’s super exciting, as we discover new genes linked to various diseases, often those reports may be just one or two families that bring these these new genes to light. The problem then is that there’s very little published information about the genes and the genetic variants. So really, as new variants are identified, knowing if these are truly pathogenic or nonpathogenic is very challenging. It’s interesting. As we learn more, the number of questions is exponentially increasing, and we’re really going to have to work together as a community to standardize how we define changes, define conditions, or define phenotypes and put all of our information together to better understand what these new variants are going to mean. So I just wanted to second you very strongly. I think it’s a great time, but a very challenging time.

ELISE: I was just going to say something along the same lines. Better defining the outcomes of screening, now that we’ve brought in so much, has really altered who’s getting predisposition screening. The families who are told that they have LFS today are so different from the families who were told that they had it 15 years ago. It’s a much broader group, and that’s probably true for a lot of conditions, but LFS just stands out in that regard. We have the Toronto paper that showed the outcomes of that original screening, but I just don’t think that the population even looks the same as when they started that study. As the population is constantly evolving, we don’t know the outcome, and that’s only one condition that we really have a controlled study for. So I think that the more and more we’re all growing our surveillance clinics and the more and more people we have in them, the more we need to then publish the outcomes. We can know, did we even make a difference with all of this? What were the findings, what were the false positives, what were the true positives?

JAMIE: I was actually going to use the same exact example as Alisa did, with respect to TP53 and Li-Fraumeni Syndrome. With more and more unbiased testing and unbiased screening, we are seeing people in families that just have one cancer type; they don’t have the full LFS spectrum. In terms of surveillance, is the whole body MRI every six months, or every year really necessary? So there has been some conversation, which I think will inform diagnosis about expanding that phenotype, or having independent Li-Fraumeni and TP53 hereditary cancer phenotypes. As more and more people are have unbiased screening and the phenotypic spectrum expands, that’s going to also influence diagnosis and guidelines.

GARRETT: Mark, I think you were going to say something?

MARK: Yeah, I was just going to build on what Kim and Roshini had brought up, about the functional studies around confirming the pathogenicity of these variants. What Elise and Jamie had talked about, these larger-scale clinical screens and blending those two data sets together — My original question was going to be around functional screening across entire genes, and how much emphasis could be placed in taking a variant of uncertain significance with that functional evidence to suggest that there’s consequences at the protein level. Is there enough evidence from those studies to promote a variant from VUS to “likely pathogenic” within the ACMG framework? I just wonder, again, if it’s outside of a single, very focused paper about those variants; if it’s the result of the screen, is that evidence sufficient for diagnostic purposes? I’m posing this to the group, broadly.

KIM: I don’t have an answer, but I just wanted to say, I think that that’s a super important question. You really need to understand what the function of every specific protein is, right? And some proteins have multiple functions. There are these functional, or quote-unquote, “functional” assays that you can do to look at stability of message or transcriptional assay for a reporter assay for a transcription factor, but a lot of these proteins have multiple functions. I don’t know the answer, but it’s almost a philosophical question. If a transcription factor doesn’t function properly in a reporter assay, is that sufficient to call it a loss-of-function mutation? Honestly, I don’t know the answer. I would love to know what others in in the group think. It’s one piece of evidence but how much weight do you put on that evidence? Is that enough to convince you? And then, of course, there’s 20 odd thousand genes across the genome. We don’t know the functions of all of those. Developing one standardized functional assay that will apply to every gene in the genome is not going to happen. So how are we going to address this? This is something I’ve been contemplating since I moved to St. Jude, and I don’t have an answer, but I would accept any suggestions.

ROSHINI: I agree completely with Kim. Recently, there have been some papers on inborn errors of immunity predisposing to severe COVID disease. Without giving all the information away, because some of it is just about to be published, people have said, “X or Y or maybe 10 other genes — if you’ve got variants in those genes, they predispose to severe manifestations of COVID.” Then they cherry-pick and do certain biochemical analyses, but then they forget to do that with variants in the controls. Reading a paper that has all this information, you start to realize, “well, theoretically, they’ve done some functional validation of their variants, but because they haven’t done it in their controls, how are we to interpret that data?”
So there is one issue, the design of your population genetic studies, and then an additional issue of the functional validation. I agree with Kim. I mean, Kim all knows all too well the challenges with the inborn errors of immunity. We’re like mushrooms in wet grass, you know; we’re just sprouting new genes all the time. I don’t know the answer either. We’re using a hodgepodge of methods and so on, but as we’re getting to gene and variant curation, some of the gaps and holes are becoming glaringly apparent. We’re now finding ourselves soft pedaling or being more cautious about how we’re interpreting and trying to introduce in caveats. I think it is a challenge, because at least from the immune system perspective, we’ve just got too much variety to come up with any facile answers of how to do the functional validation.

MICHAEL: On the cancer side, it’s nice in the sense that we’re learning and being more creative about the way that we integrate the ohmic testing, from both the somatic, germline, transcriptome, methylation testing and trying to understand how we might be able to appreciate a second hit. Splicing might be better interpreted through different assays. On the cancer side there’s a lot of tools that we’re now availing of in a more meaningful way, as we’re getting beyond the initial steps of just describing frequency of variants and and honing in on certain genes in a more meaningful way as we think about them. The functional part will forever be a problem, both for economic reasons and for the way the medical system is set up in terms of our confidence of the rigor behind science, as well as for the mere difficulty of getting certain things published in a timely way. People will use what is being published as evidence, and usually, it’s not more than beyond a couple variants that you can hang your hat on from any given paper, in terms of your confidence for what something may or may not mean. I think that there are some societal or philosophical things that would would have to change gear.

MARK: If I could take that conversation a little bit further and expand it outside of the functional studies, one of the things that I’ve seen with respect to ACMG is more of a disease-specific focus, as opposed to the initially promulgated, very rigid, “this is the way you do the variant interpretation with ACMG,” and now you’re seeing a plethora of disease-specific focused modifications to the ACMG guidelines. Very similarly to what we talked about with respect to functional studies being predicated on disease specificity, I wonder if the group can speak to what changes we’re seeing to get more of a focus on disease-specific context for ACMG, and how that’s going to play out. When the goal of ACMG is to have a framework that can be abided by all, now we’re having these splinterings and ramifications, where it’s requiring increasing specialization within individual disease groups.

MIKE: Yeah, I’ll take a stab at that. In terms of the ACMG, they had a pretty daunting task when this all started. They were in a position where, in many ways, they started off backwards. They just started off with a gene list, and these were genes that you reported back before necessarily defining how you categorize things as “pathogenic” and “likely pathogenic.” It was a need born out of the sequencing that was becoming a mass-scale process. When one dissects the ACMG, you look to see who are representatives of a certain body, and who are medical geneticists that were part of that, and what their disease-specific areas were. You also have to look at what, in a medical genetics clinic, was defined as actionable, or at what areas where there were things needed to be reported back to management, whether it be for a connective tissue disease, or a surgery required for some of the extreme cancer phenotypes, or an arrhythmia might present itself.
As time went on, and that became the reference for people in other disciplines that were not typically card-carrying members of the ACMG to start with, there has been an initial acknowledgment that that was the appropriate place to start; that body has, through ClinGen and other efforts, integrated other colleges and societies. ASH is a perfect example of that, with Lucy Godley and her elite work leading the hematology efforts for classifying variants. An organic outcome of all of this is the additional experts that are being pulled in, and with that process, there’s been a whole lumping and splitting in terms of genes or disease, as well as getting in the more granular space of trying to define variants for all of these things through expert panels. So the ACMG started off with a very broad focus, but with that said, it was still somewhat narrow in terms of the representation. As time has gone by, there’s been a broader scope of folks that have been brought into that, and it’s served as a background for how all this variant curation has evolved.

KIM: I’d be curious, Jamie, what you think about the future as a variant scientist or curator. As it’s become more and more complex, how do you anticipate variant curators or scientists being able to analyze germline data? If every gene has its own rules, how will you keep up with all that?

JAMIE: Yeah, I think that’s going to be one of the biggest challenges. Within the ClinGen efforts, for most of our variant interpretation working groups, the collation of data from the reference labs who have all this internal data has been our most important piece of evidence for variant classification. Of course, as Mike said, some of our groups are using this functional data. In the TP53 working group, there are very well-established functional studies that we trust. In our CDH1 working group, we actually don’t take functional data into consideration, because it has not correlated with patient presentation. So really, the breadth of standardization across all of the genes in the genome to try to figure out what pieces of evidence are useful with respect to variant interpretation is based on the known patient phenotype. So that’s going to be the biggest challenge. The ClinGen efforts are focusing on the highest-profile, the most critical genes, LFS and CDH1, where there’s real surgical and/or surveillance implications. Expanding into those more moderate and lower-penetrance genes and/or variants is going to be very daunting. I’m not sure I answered Kim’s question, but it’s a challenge.

LIZ: If I could just chime in, too, as related to variant science. I think it’s been really interesting to observe the evolution of jobs in the area of genetics. As a genetic counselor, it’s really evolved. I mean, ten years ago, variant science as we know it today really didn’t exist, so I’m still surprised in talking to many of the labs that are hiring variant scientists. They are pulling from PhDs from genetic counselors, kind of converting them, and there’s not really even an organization that I know of for variant scientists in general. Also, with standardizing training, because it’s divided now among pathologists and geneticists — I don’t know if anyone’s really given thought, or Jamie, if that’s started to come up — What will be the standard for training of variant scientists?

JAMIE: I don’t think there is one yet. I mean, we have not discussed it at St. Jude, because our operation in terms of variant scientists is a very small, one to two person operation. But I do think that that’s very important, because reference labs and our children’s hospitals and everything do want standardization for what we are calling variants. I can interpret something completely differently than the person sitting next to me. Right now, I think that there is becoming more of a standardization. A lot of curators are involved with the ClinGen efforts, which definitely does help, having those conversations and seeing how these guidelines are formed. I think it will be important in the future to have a society, or some kind of more formalized training to get everybody on the same page.

MIKE: Yeah, I think that’s a nice point about the educational aspect of this, and almost hinting at a degree that could be had in all of that. When I got started in the space, so to speak, for three years, I just sat and looked at variants, and there was not necessarily any training. The ACMG rules around how to classify variants weren’t there. I had a genetics background from formal education, but it wasn’t specifically around molecular genetics. As this field has emerged, it’s still somewhat gray in terms of who knows what, and what people’s responsibilities are in terms of who should know what. To your point around variant scientists, there are certainly discrepant resumes, so to speak, in terms of who’s doing that. It is a big problem.

ELISE: The other thing parallel to that — The classification system is still “benign” to “pathogenic.” There’s not a formal recognition of moderate- or low-penetrance alleles. I just think that that will have to change at some point. Obviously, all these ClinGen efforts are a start, but it falls on people for the individual gene or the individual lab. Someone might have to write out a paragraph describing the effect of that variant, but that’s really so qualitative for something that should have more of a quantitative basis. We know that it’s so much more complex. Like you were talking about, Kim, all the different functions of a given gene, it is going to be different if all the functions are knocked out, or if one of the three functions is knocked out, it varies so much. It’s hard to have a variant classification system that only reflects a dichotomy of whether a variant is pathogenic or benign. I don’t have a great solution for how to modify that, because it’s so complicated, but it has to be more complex in the formal guidelines than just those two options.

MARK: Yeah, I’ve heard about a movement toward more quantitation of the scoring, as opposed to dichotomization. What I’m seeing in particular in terms of the disease-specific modifications is that there are ways to take these categories of ACMG evidence, even if they’re strong, and downgrade them to “moderate” or upgrade them to “very strong.” That does lend itself, as you said, to a more quantitative approach as opposed to just categorization, but that challenge is standardization. It makes it more complicated to ensure that Interpreter A is interpreting the same variant in the same ways as Interpreter B, even when they’re presented with the same information. I feel like that’s a very large challenge. We’ve talked about this a little bit, with respect to ClinGen and ClinVar. I’m wondering if we as a group can talk about any challenges that ClinGen and ClinVar are facing, or if there are ways that the community can get behind them to break through those challenges.

ALISA: As we’re looking at the challenge in front of us, maybe we need to step back and realize that we have this balance between continuous improvement and learning, and that is led by standardization, but then there are these individual breakthroughs. Every generation brings about 70 to 200 new variants, so to have a very structured, standardized model — the very subject matter that we’re trying to evaluate breaks that norm. So I think that while we need guidelines, you have to look at even mutation in the context of the person and the broader context of the genome. These are the kind of aspects where we as a community often forget that the clinical knowledge and what we’re seeing in front of us is going to be recorded into our EMR. How do we go back and learn from it? Once we realize how to harness that, and then build that into our continuous knowledge, that might be the way forward. Still has challenges

KIM: Yeah, you basically set the stage for exactly what I was going to say. I’m not as involved in ClinGen and ClinVar as I probably should be, I just have too many things going on, but the thing is, it’s really important that the genomic data be looked at in context with the clinical information. In my mind, one of the biggest challenges is bringing those two pieces of information together. You probably know about this, and this gets at what Elise said: There are some variants that are going to have a stronger phenotype than others, and phenotypes are going to vary. How are we going to bring it together?
For Jamie and the variant curator and scientist field, they probably come out from more of a pathology or computational angle. For understanding the clinical component, what’s really important is somehow having constant communication and a way to bring these disparate pieces of information together, so that we can better understand what these variants are going to mean in the future. If there’s an answer for how to combine and continually build on the clinical in a way that helps interpret the genomic, that’s what’s really going to be important moving forward. This is a really challenging but important area. Mike, I’m not sure if you want to build on that, as you’ve been so much more involved in this as a geneticist. I’m just a little old oncologist. What do you think?

MIKE: Yeah, the ClinGen part of it, where it suffers is — well, I shouldn’t say it suffers. I’m chair of the somatic germline integration committee to try to help clarify germline variants utilizing semantic data, and like anything, it’s resources. We all have very good ideas about how to try to take next steps, and then rate limiting steps are getting clean data to integrate and having access to information from different centers. With that said, there is good reason for certain centers to clean their data and have it organized at a particular level. That’s something I’ve appreciated more as time has gone by with the two most recent centers I’ve been with, in the sense that there’s this push. You free the data, free the data, free the data, but you don’t want dirty data. You want things annotated as well as humanly possible, whether that be the clinical part or the molecular part. Ideally, it’s both.
Sharon Plon, who leads ClinGen, she’s the godfather of all this stuff. That’s the way I think of her. She’s very conscientious of all this, and she’s been in this game a long time and has done a tremendous amount in terms of identifying players at different centers that can begin to really move all of this together in a meaningful way. When I mentioned the economic part of it earlier, a lot of it’s economics. Having the additional resources for bioinformatics and so on is always a great limiting step for all of this. Finding the MTAs to share the clean data when it’s available can be a rather drawn out process. Those are just a couple practical things, but they’re things that can actually expedite matters quite a bit, if in place.

LIZ: Mark, I was wondering if you could comment on this. I was just thinking, and I know this is kind of a topic we wanted to discuss, about the role of AI and machine learning here. That’s what I’m hearing a lot of when we’re thinking about the clinical correlation and design of products that can really use the machine learning concept to pull that clinical-phenotypic information together with the molecular. Mark, do you have thoughts, or does anyone else have thoughts on initiatives at their own centers to do that?

MARK: Yeah, I’ll start by saying that, as clinicians, you should always be be armed with evidence. Genomenon does not think of AI as a black box solution to any of these problems. I think that AI is a tool to arm the clinician with the best evidence, and to continue to leave the decision-making in the hands of trained clinicians for all of these nuances that we talked about. In a clinical context, the challenge of these disease-specific diagnoses is just the nature of the complexity of the data. I think of AI as a way to organize evidence for decision support. I don’t know that we, as a community, would ever want to get to a place where AI could be a stand-in for any of these clinical decisions.
Particularly, at Genomenon, we surface information from the medical literature and keep that as up to date as possible, but the idea is always that it be as sensitive as possible and as organized as it can be. Then the ultimate onus of decision making is on the clinicians. I wonder if anybody else is more optimistic about AI taking over? Personally, I’m not. During my training in pathology, I was always very pessimistic about the idea that these tools would replace the human touch.

AMY: I don’t know if that I have the answer to that, but I think one thing this brings up for me is that it’s important to think about how we enter our molecular data into the electronic medical record. With our most recent assays, we were actually able to interface our results directly into the EMR. We now have discrete variants that are searchable, which for us was a huge victory, because now we can actually tie that data to particular patients and particular demographics, but that’s still not perfect either. That’s something we really need to think about — how do we make that better? How do we enter our molecular data into the electronic medical record in a way that makes it useful for all kinds of different things, for interpretation, for submitting data to consortia, for utilizing that data to talk to payers about putting together lists of patients where one test was really impactful? Organizing our data and interfacing that with the electronic medical record is going to be one of the first steps to making AI and decision tools really valuable.

ALISA: If I could add to that — I think, Liz, you mentioned that we need to evaluate the role of clinical labs in this journey and we have to recognize that we’re not at the end. So while we’re entering and interfacing the genomic data that was born out of a subset. I think we mentioned very early on that, as our knowledge is growing, rather than having these very discreet panels, we know that we’re generating a much larger data set. We have the pressures of the payers, and we cannot do exploratory panel research. The lab is actually generating that data. So how do you link that larger body of data with the EMR if you have what I call an unsatisfactory diagnosis? There are boosters in there, can we go back and ping that data in a very streamlined fashion, rather than just pump the brakes, let’s sit down, pull this data set? Can this happen in a more streamlined fashion?

MARK: Alisa, you brought up something that I wanted to touch on. With all this proliferation of new information with modifications to the decision making and these VUS’s in otherwise undiagnosed patients, how does the panel think about the look back challenge, if you have a case that remained undiagnosed? Michael, you’re bringing up this pragmatic challenge, trying to figure out who’s got time for this, who’s got the resources, let alone, how do we communicate this information to the patient? If anybody has ideas about what you’re doing at your institutions to solve this look back challenge of cases that haven’t been diagnosed, but demand a revisitation of that data in light of any published information?

KIM: From our perspective at St. Jude, it really behooves the provider to go back to the lab to ask for a reanalysis. I’m not sure how it works at other places. I’m worried that from a laboratory perspective, it’s going to be too challenging or overwhelming to go back and look at every single case that’s been tested over the prior years. There will be hundreds to thousands of cases. At our institution, it’s been up to the genetic counselor or the provider to ask for review analysis every couple of years as needed, and lo and behold, we’ve come up with new diagnoses as new data has come on board. I’m interested to know if others feel differently, but it’s worked for us. You just have to educate the providers that they will need to reach back out. The question I guess will be economics. I don’t know if it is something that the provider would need to pay for, or if that can be done at a reduced cost or free for service. I think for our patients, the companies that provided the broader sequencing at the time did the re-analysis either for free or for a reduced cost, but I don’t recall. I’d be curious to know what others do or suggest in these cases.

LIZ: One thing that I found helpful when working with Genomenon and interfacing with labs was just learning about their different operations. When you think about some of these tertiary analytic platforms that are now prioritizing variants, as well as other AI-based tools with updated literature, I’m wondering how much can be more AI-based for the look back, or at least presented to the clinician? Like, telling the clinician, “here’s what’s been updated over the last year, here’s the new information about this variant that’s been reported,” which then helps the clinician to triage that look back process. I just think the only way to do it is some kind of automated supplement to that process that preserves the hand element of discernment. I haven’t really come across anyone who’s optimized that process. I’m curious to know if anybody else is aware.

ALISA: I also think that there is a power of the patient. The patient has a voice here as well, and there’s a huge educational component. When we go into surgery, it’s very finite. We know exactly what it is, whereas when they’re entering and getting the genomic testing, this is a journey, and they have to understand that today’s result doesn’t mean that it’s going to be the same tomorrow. Having discussions on multiple levels will help guide us to what that process looks like. As always, just like with our iPhones, some people will say, “track me, I don’t care,” and some people will make sure that everything is well-guarded and put the aluminium hat on their head. So I think we have to be very sensitive to those privacy aspects as well.

ELISE: Yeah, I don’t think we’ve optimized it, either, but I think it is very patient-dependent. The way that we have it, or the way that most people have it, is that the patient has to reach back out to us for clinical updates. If it’s part of a research protocol, like our MSK impact assay, then there could potentially be updates, but only if that patient is signed on to the research protocol. If we find something and then are not able to re-contact the patient, if we can’t track them down and the phones are not in use, then we have a protocol for how to deal with that, but I think everyone’s really nervous to take that responsibility on clinically in addition to the huge workload. It’s just a lot of liability. It’s not a perfect world, where you can find everyone who you could find two and a half years ago.
It is very patient-driven, and that also allows patients to kind of dictate the importance of it, because it’s just not worth our work if they’re not interested or they’re not going to follow up regardless of what we contact them with. There are some patients who really have something, and we know they have something, and they know they have something and we’re all frustrated that we don’t get to it with the first test. Then there are other patients who we send the same testing on, but they probably don’t have a predisposition, and the negative or unlikely VUS’s are reassuring to them. It’s probably fine if those patients don’t recontact us or if they reach out in five years instead of one or two. So we just try to emphasize it to all patients, but we’re not doing anything clinically on our end without them reaching out.

MARK: I wonder in the last few moments if we can build on what Alisa and Elise said about patients and and their intrinsic motivations and their understanding. I’m just wondering how well-educated they are. In light of direct-to-consumer genomics, how receptive are they to these new lines of evidence, and how has that influenced your clinical practice? Or has it not changed at all?

LIZ: As Elise was talking, one thing I was thinking about is health literacy barriers and diversity and access barriers, because it’s incredibly disparate. That’s also a concern of mine, that if it is left to the patient, even though that can be very positive, due to barriers that some patients have over others, that could actually lead to a lot of inequity.

ELISE: Yeah, completely.

KIM: That is obviously a problem, but you know, Liz, I would imagine, even people who don’t necessarily have those barriers could have problems. I don’t know as much about direct-to-consumer testing, but some of those tests are for very specific variants in a gene. If a patient gets a negative test and they think that they don’t have any variants in the gene, they think they’re okay. This just emphasizes, for all you genetic counselors, how critical it is to do genetic testing in the context of genetic counseling. Personally, I feel like it’s a real disservice to do genetic testing without genetic counseling on both pre-test counseling and then post-test counseling. We’re lucky in pediatrics and at St. Jude. Because our patients have cancer, we can see them periodically afterwards to continue to educate the families, but it’s very different perhaps with other diseases and in the real world. The counseling is really critical across the board.

MIKE: Yeah, you often find that providers don’t have a clue about a lot of this, never mind, people trying to explain it to patients.

GROUP: (LAUGHTER, AGREEMENT)

GARRETT: I just want to thank all of our panelists for taking the time to offer your expertise in this roundtable. I think we had a fabulous conversation! It seemed to move itself. You’ve all had a lot of great feedback, and you had some really good conversation chemistry, so I think it was very valuable. I thank you for that. I will close out with this ending slide here.
For everyone watching, thank you for tuning in, and to all of our panelists, thank you for taking the time to offer both your expertise and your time in this roundtable! If you have any questions or would like to discuss your variant interpretation needs, feel free to send an email to our folks at hello@genomenon.com. Additionally, if you don’t already have a Mastermind account, you can create one for free and receive a free trial of Mastermind Pro. Last but not least, your feedback is very important to us, and we’d love to hear your thoughts on today’s webinar. At the conclusion of this event, you’ll be prompted to take a brief survey that will help us as we continue to create a highly valuable customer experience.
With that, thank you so much for your contributions and interactions, everyone! I think we had a great conversation.

good morning everyone and welcome to the children’s hospital genomics round table i’m garrett sheets the content specialist for genominon and i’ll be moderating today’s conversation today we are excited to host a highly experienced group of panelists from four leading pediatric hospitals who will share their perspectives on recent developmentsand current practices within the realm of clinical and research genomics as well as describe how ai-based tools including janomenon’s mastermind genomics search engineare streamlining patient care and forwarding the collective effort to advancegenomic discovery they have a lot of great information to shareso i’ll mention a small housekeeping item and then move right into our introductions so that we can get started we have a really full agenda today and for those watching we want to be able to take all of your questionsif we don’t have time to answer them at the end we will send them to the panelists after the eventand post them on our website so without any further adoi’ll briefly introduce our speakers amy treesis a pediatric and molecular pathologist and serves as the medical director of molecular diagnostics laboratory at children’s hospital coloradoalso from children’s colorado is elisa gaskell who is the co-chairand scientific director of precision medicine with expertise in the developmentand implementation of next generation sequencing technologiesand the analysis of genomic data elise fiolais a senior genetic counselor at memorial sloan kettering cancer center with a focus on pediatric patient care we also have michael walsh from memorial slim kettering who is a pediatrician geneticist and hematologist oncologist from nationwide children’s hospital we have roshini abrahamthe associate chief of academic affairs and founding director of the diagnostic immunology laboratory in the department of pathologyand laboratory medicine also from nationwideis elizabeth varga the director of clinical genomics researchand development at the steve and cindy rasmussen institute for genomic medicine from st jude children’s research hospital is kim nicholsa pediatric oncologist and director of the cancer predisposition program her research interests include the molecular mechanisms that provide protection against viral infections and cancerjamie machasik is a clinical variant scientist in the department of pathology at stjude children’s hospital a trained biomedical engineerher research experience includes the molecular mechanisms of sickle cell diseaseand pediatric t-cell acute lymphoblastic leukemiafinally mark heal is the founder and cso genominonwhere he supervises the scientific direction of the mastermind suite of software toolshis research interests include stem cell biology genomic profiling ofhematopoietic malignanciesand clinical bioinformatics mark i’ll open up the floor to you for a moment heredid you want to say a few words to welcome our panelistsyes sure thank you garrett um i want to welcomeboth the panelists i feel very privileged to have assembledso many folks from the clinical front lines as well as to welcomeour audience members and the very brief um uh introductory mark remarks i want to give is just to say thatwe at genomenon uh really appreciate the time that you’re taking out to attend this discussioni as a panelist hope to learn much more thanthan i speak in this event and without further ado garrett i’llpass it over to you to begin the discussion so that we maximize uh the conversation time perfect thanks markwhat a smaller group we have um and now that everyone has been introduced i want to start with the team from children’s coloradoand amy maybe you can speak to this in terms of genomic health care for your organizationwhat are some would you say are some key initiativesyeah so um one of theimportant things to know about children’s hospital colorado is that our approach to genomics currently is very clinically oriented and so one of the big things that our institution is working on is a precision medicine service lineand the goal of the service line is to combine clinical laboratory and operational expertise to really help make clinical genomics available to all disciplinesand now that we see genomics really expanding into a lot ofspecialties beyond genetics we want to make sure that those specialties have the same access to genomicsand so with this initiative there’s a major emphasis on infrastructure to help support patient access to testingaccess access to counseling and access to treatmentand the goal is to really have a consolidated approach to issues that crossspecialties so that we don’t see efforts duplicated in various different silos and so under this model oncology genetics and other specialties are all at the same tablediscussing their needs and identifying areas that they overlap andin areas of really high priority for the institutionand so through this approach sorry though this approach is really clinical service lines will also focus on how to leverage our clinical data to support research initiatives as wellthank you amy for that um what else maybesomeone from nationwide maybe what are some comments on some key initiatives for your organizationand how do they relate to you know what was just sharedyeah i’ll take that one so very similarly to the objectivesat children’s colorado we started the institute for genomic medicine about five years ago at nationwide children’s and the goal is to bring the research clinical operation togetherunder one umbrella so instead of being siloed with clinical laboratory testing and a separate research operation we have the ability to performresearch genetic testing such as right now whole exome sequencing but also some more research-based assays like rna sequencingmethylation testing and other specialty testswithin the operation of research but alsoconfirm that clinically so that results can be deliveredto patients across the institution and very much like amywe are trying to really expand our infrastructure so that it’s not siloed andincreasingly incorporate intospecialties which one example of that is roshni operating in immunology and kind of bringing some of thenext generation sequencing technologies into other areas of carethank you liz so you mentioned you know roshini’s work and immunology roshini i don’t know if you could give us kind of an overview about you know how your work relates to you know what has been shared so my focus is in being born areas of immunityand where i came to nationwide children’s from mayo clinicand while i was at mayo i developed the targeted gene panelsfor the inborn areas of immunity and what irapidly realized is that we’ve now got over 450different genetic disorders that fall under the umbrellahave been born areas of immunity and when i started the placesseveral years ago at mayo i realized with the targeted panelsyou need to sort a nimble approach you need to stay up to date and you know keep your panelsall updated when i came to nationwide children’s i decided that it would not be reasonable to recreatetargeted panels for the inborn areas of immunitybecause there were commercial reference labs that were doing a far better job andprobably able to be more nimble and stay currentum so we now focus you know we send targeted dream panels outsidebut when it comes to exome or even genome under the research umbrella then we look within our institution to sort of tease out uh complex patients with immunologicalthank disorders roshani so i guess you know we’ve talked about kind of how these affect patients and i think i’d like to shift the conversation to look at you know trends soi’ll pose the question and i’ll i’ll kind of open this up to everyone you know how is the approach to diagnosing rare disease and or pediatric cancer kind of changed in the past five years how about someone um someone from st jude children’ssure um can you hear me okay yes yes so um actually i was i was going to mention too in terms of our initiative so i think this is a good segue um and let me talk briefly about what we have at saint jude and then i’ll just talk about how it’s changed but so saint jude as many of you know you know it’s had a really long history in terms of doing research genomics and cancer through the pediatric cancer genome project andsix years ago i was really fortunate to be recruited to saint jude tobring on you know a clinical genomics initiativewhere now we can offer all newly diagnosed cancer patients at st jude the opportunity to have their tumors evaluated using whole genome whole axon and rna sequencingand we can also look at their germline using whole genome and hall exome i mean that said right we are primarily a cancer institutestudying you know cancer and other disorders of the blood soour focus is primarily on the cancer genes and you knowcancer risk genes um buti think that um you know what’s really wonderful about stjude is that in addition to providing this now as a clinical service the data that’s generated right as long as patients sign or research consent both the tumor and the germline data you know gets uploadedthrough the st cloud which is a tremendous you know research resource for institutions all over the world so i just want people to know that they can access germline and tumor genomic data free of charge and i think now they’re i don’t even know they’re probably including both tumor and germline in the cloud that people can accessso i think this has had a tremendous impact right on our ability to refine diagnosis of cancers right you can think about leukemia at st jude i mean through charles mulligan now what we used to look at under the microscope i mean i’ve been i’ve been doing pediatric oncology for 20 years and i remember when i started right you looked under the microscopemike probably knows this and you know you see a lymphoblast and a lymphoblast was a lymphoblast and everybody got you know al therapybut now thanks to genomic advances i mean there are multiplesubtypes of leukemia and some of them do better than others and we know we need to adjust therapiesbased on some of these molecular findings so i think you know from a tumorperspective genomics and precision medicine has made a tremendous impact particularly in this case for leukemia but we have a lot ofum work yet to do for for many of the solid tumors for example and for some of the brain tumors so i thinkyou know we’re just at the tip of the iceberg so from the tumor perspective yeah i think we lost okayi’ll pick up on where kim we lost your audio but um as a metapathologist by trainingone of one of my professors spoke to the obsolescence of the microscope in the similar way what you talked about i don’t know that would be obsolescence but it would actually bethe augmentation with molecular diagnosesand i was struck by how the who the the humanopathologic diagnosis and the who was increasingly molecularly predicatedand as i was leaving my training seeing that comein solid tubers and brain tumors as well soi don’t know how much more that’s flourished since my training but it was a very encouraging thing for me to see where the diagnosis become much more molecularly predictedreally good discussion i’m curious to hear i don’t think wehad any feedback from uh team members at memorial sloan i don’t know if if elise or um dr walsh if you have anything to addon kind of to build on what has been shared so farno i think i would agree with what the others have said andi um allow at least to chime in here as well um i think that theywe are kind of as kim said at the tip of the iceberg and i don’tforesee necessarily other uh aspects of diagnosis going anywheretoo soon because i think there’s so much variation of uncertaintythat all of theadditional information that we’ve relied on historically continues to be relevant in different ways andon the germline side as opposed to maybe just thethe tumor side that is probably more so trueas we are dealing with so much variation of uncertain significanceand being able to phenotype and characterizetumors uh helps us better understand some of thethe predispositions as well and in the in theum the spectrums that go with a lot of thecancer predisposing syndromes um but yeah i think we’re we’re still early days with a lot of this stuffand um we have moved though nicely i think fromone of our original papers five years six or seven eight years agoto where we were describing a lot of the genetic uh predisposition to more recently how we’rereally actually translating this clinicallyi’d like to quickly add to that i think um you know something that i’ve seen change here in the pastfive years uh is that ourgenetic counselors on the oncology side are involved from the very beginning of diagnosis of oncology patients they attend our tumor boardsand these discussions of predispositions happen right at the verybeginning of diagnosis and not as an afterthought or a follow-upand so they’re utilizing molecular results as soon as possible to get those patients plugged intopredisposition clinicsyeah i was going to chime in one thing i’m sorry about the audio umand this builds on what what mike said i mean in the old dayswhatever 20 years ago a lot of guidance regarding germline genetic testing was based on basically family history um or patient medical phenotype but now we’re learning that a lot of families don’thave a positive family history or patients with specific syndromes fanconi anemia as an example a good proportion of them don’t have clinicalmanifestations sohaving the ability to do genetic testing a little more broadly hasi really think enhanced our ability to make germline diagnosesokay so we’ve had a really good conversation about germline variants we’ve talked about trends that you all have seen in practice over the past five years i’d like to now kind of lookforward um and ask you kind of pose againgenerally to everyone because we had such a great conversation you know just kind of having everyone chime in there how do you think you know this approach to diagnosing you know rare disease and pediatric canceryou know looking forward the next five years what do you seelooking forwardso i can take that one um and really it builds oneverything that we’ve discussed to date that i thinkwhat we will see is merging of fields and breakdownof the silos it’s very comfortable to think of somethingas inherited germline or akind of acquired mutation but i think the more we’reseeing and even moving into the transcriptional space we’re learning so muchand we’re actually seeing that there’s more of a blendingso i i think just as our tests are becoming unbiasedi think we should be approaching the diseases in a very unbiased fashion and just know that we havethe expertise and based on the molecular profileguide our patients through our system rather than having just verysolid paths in to our systemif i may add to that uh in the inborn areas of immunity i think a particular challenge is the number of newgenetic defects we’re adding um to the list you know so we’re at 450 of 416 now and every two years um there’s an expert panel that gets together to classifyall the inborn areas of immunity and they they publish that classification and in january 2020 uhthe biannual classification was published and thenten months later we have to have an interimupdate because we’ve got about 30 new genes addedso we can’t wait for another two years to update the classificationand so i think from for clinicians it’s exceedingly hardto sort of keep abreast of all these new genetic defectsand the phenotypic variability and then of course you know cliniciansoften are faced with the conundrum of these variants of uncertain significance and you know trying to do thecorrelation to the immunological phenotype trying to do functional validationso i think in the immunology community that’s something that we have to really work hard at and we havea few sort of thoughts and initiatives around that you know how do we validate functionally validate and these new variants or new genetic defects and how do wemake sure that our community of clinical immunologies but also hematologist rheumatologist anybody who sees patients with thesein born areas of immunity how do we make sure that theyare able to stay abreast of all this new informationso that’s the challenge for the next five years i think for usyes i absolutely agree you know roshani i think this goes acrossall conditions and you know for many of the new genes and as you think about it it’s super exciting as we discover new geneslinked to various diseases often those may beyou know one or two families that bring these these new genes to light the problem then is that there’s very little published information about the genes and the genetic variants so really knowingas new variants are identified you know are these truly pathogenic or not pathogenicis very challenging so i think you know it’s interesting as we learn more the number of questions is exponentially increasing and you knowwe’re really going to have to work together as a community tostandardize um you know how we define changes define conditions to find phenotypes and you know put all of our information together tobetter understand you know what these new variants are going to mean so i i just second you very strongly i think it’s a great time but a very challenging timemoving forward i wonder if i could ask don’t go aheadoh sorry so i was just gonna say on the same lines thatbetter defining the outcomes of screening now that we’ve brought in so much who’s getting predisposition screening you know the families who are told that they have lfs today is so different from the families who were told that they had it 15 years ago like it’s such a broader group and that’s probably true for a lot of conditions but lfs just stands out in that regard and um you know we have like the toronto paper that showed the outcomes of that screeningbut i just don’t think that the population even looks the same as when they started that study and so as the population is constantly evolving like we don’t know the outcome and that’s only one condition that we really have like a controlled study for soi think the more and more we’re all growing our surveillance clinics um and the more and more people we have in it the more we need to then publish the outcomes of likedid we even make a difference with all of this you know like what was kind of all of this for what were the findings what were the false positives what were the true positives like what um what the outcomes look like i was actually going to use the same exact example of the lease with respect totp53 and lead for meaning syndrome you know with more and moreunbiased testing and unbiased screening we are seeing people thatin families that just have one cancer type they don’t have the full lfs spectrumand i mean in terms of surveillance is the whole body mrievery you know six months every year really necessary so there has been some conversation which i think will inform diagnosis about uh expanding that phenotype or you know havinglife for me and tp53 hereditary cancer phenotype soas more and more people are have unbiased screening in the phenotypic spectrum expands that’s going to also influence diagnosis and guidelines and mark i think you were going to say something yeah i was just going to build on what uh kim and roshini had brought up about thefunctional studies around confirming the pathogenicity of some experience and thenwhat elise and jamie had talked about these you know larger scaleclinical screens and blending those two data sets togethermy original question was going to be around functional screeningacross you know entire genes and how how muchuh emphasis could be placed in taking a variant of uncertain significance um with that functional evidence to suggest that there’s consequences of the protein levelis there enough evidence from those studies to promote a variant from the u.sto likely pathogenic within the acmg framework i just wonderuh again if it’s outside of a single very focused paper about those variants if it’s the result of the screen is that evidence sufficient for um diagnostic purposesand and put it to the group broadly i don’t have an answer but i i just want to say i think that that’s a super important questionand you know if you think about it it means you really need to understand what the function of everyof any different every specific protein is right some proteins have multiple functions and you know there are functional quote functional assays that you can do right to look at message stability of message or atranscriptional assay for a reporter for a reporter essay for a transcription factor but you know a lot of these proteins have multiple functions and i don’t know the answer but it’s a philosophical question you know if if a transcription factor doesn’t function properly in a reporter assay is that sufficient to call it aloss-of-functionmutation and honestly i don’t know the answer umi would love to know what others in in the group think i mean it’s one piece of evidence buthow much weight do you put on that evidence is that enough to convince you andand then of course right there’s 20 odd thousand genes across the genome we don’t know the functions of all of those you know developingone standardized functional assay that will apply to every gene in the genome which is not going to happenso you know how are we going to address this this is something i’ve been contemplating since i moved to saint judeand i don’t have an answer but i would accept any suggestionsi i agree completely with km and i think you know recently there’s been some papers onin born areas of immunity predisposing to severecavity disease and without giving all the information away because some of it is just about to be published but uh you know people have said oh you knowx or y or maybe 10 other genes if you’ve got variants in those genes they predisposeto severe manifestations of cavity and then they cherry they can docertain biochemical analyses but then they forget to do thatwith variance in the controls and then you know yourreading a paper that has all this information and you’re sayingwell theoretically they’ve done some functional validation of their variants but because they haven’t done it in their controls umyou know how are we to interpret that datayou know so there is one issue the design of your population genetic studies and then the issueof the functional validation and i agree with kimi mean uh kim all knows all too well the challenges with the inborn areas of immunity because we’re justyou know like mushrooms in wet grass you know we’re just sprouting new genes all the time and um i i i didn’t know the answer cameeither because you know we’re using uh sort of a hodgepodge of methods and so on but as we’re getting to gene and variant curationsome of the gaps and the holes are becoming glaringly apparentand we’re now finding ourselves sort of soft pedaling or being more cautious about how we’re interpretingand trying to introduce in caveats but yeah i think it is a challenge because at least from the immune system perspective we’ve just gottoo much variety to come up with some sort of facile answers of how to do the functional validationi have to admit i’m also strapped on the cancer side it’s nice in the sense that where i think we’re learning and being more creative about the way that we integrate the ohmic testing uh from both the somatic germline transcriptmethylation testing and trying to understand howwe might be able to appreciate a second hit how howsplicing might be better interpreted throughdifferent assays so i think that on the cancer sidethere’s a lot of tools that we’re now availing of in a more meaningful way as we’re we’regetting beyond the initial steps of just describing frequency andof variance and and honing in on certain genesin a more meaningful way as we think about themthe functional part will forever be a problem both for economic reasons and for the way the medical system is set upin terms of our confidence of the rigor behindscience and for the umyou know the the mere difficulty it is to get certain things published in a timely wayand where where people have will use what is being published as evidence and usually it’s not more than beyond a couple variantsthat you can hang your hat on from any given paper in terms of your confidence for what something may or may not mean so um i think that there aresome societal philosophical things that would wouldhave to change gear get outyeah the storyno problem my son’s usually running around like crazyif i could take that conversation a little bit further and expand it outside of the functional studies one of the things that i’ve seenwith respect to acmg is more of a disease-specific focus as opposed to the initially promulgatedyou know very rigid um this is the way you dothe varying interpretation with acg and now you’re seeing a plethora of disease-specific focused modifications to the acg guidelines so very similar to what we talked about with respect to functional studies being predicated on disease specificityi wonder if the group can speak to what changes we’re seeing to get more of a focus ondisease-specific context for acmg and how that’s going to play outwhen the goal of acmg is to have a framework that can be abided by all now we’re having these you know splinterings and ramifications where it’s requiring increasing specialization within you know individual disease groupsyeah i think i mean i’ll take a stab at that i mean if in terms of the acmg the acmg had a pretty daunting task when this all started of courseclearly and they were in a position where in many ways they started off backwards right they juststarted off with a gene list before they and and genes that you reported back beforenecessarily defining how you define things or pathogenic and likely pathogenicand it wasn’t it was a need it was you know born out ofthe sequencing um that was becoming a mass scale andwhen one dissects the acmg you look to see whoare representatives of that body and who are medical geneticists that werepart of that and what their disease specific areas wereand what in a medical genetics clinic was defined asactionable or in areas where there were things needed to be reported back as it may change to a management whether it be a connective tissue disease or a surgery required for some of the extreme cancer phenotypes oran arrhythmia might present itself so as timei think went on and that became the um the referencefor people in other disciplines oncology what have you that aren’t we’re not typically you knowcard-carrying members of the acmg to start withthere has been uh a an initial um acknowledgment that that was the the appropriate place to startthat body has through clingen and other effortsintegrated other colleges and societies ash is a perfect example of that with lucy godly andher work with her elite work leading the hematology efforts for classifying variantsand kind of a you know organic growth to all of this as there’s there are additional experts that are are being pulled in and with that process there’s been a whole one thing in splitting in terms of thinking about genes thinking about diseaseand then kind of getting in the more granular space of trying to define variants for all of these things through expert panels so i think you know the acmg started off in a very in a veryum what was a broad focus but with that said it was stillsomewhat narrow in terms of the the representation and as time has gone by there’s been um a broader uh scope of folks that have been brought into that with that as a as a backdrop of of of how all this varyingcuration has evolvedi’d be curious jamie what what you think aboutum you know the future as a variant scientist or curator you know as it’s become more and morecomplex you know how do you anticipate in the future variant curators or scientists being able to analyze germline data because if every gene has its own rulesum how will you keep up with all that or how do you imagine it will be yeah well i think that’s going to be one of the biggest challenges and in the within the clinton efforts for most of our very interpretation working groupsreally the collation of data from the reference labswho are doing this you know have all this internal datahas been our most important piece of evidencefor variant classification and you know of course as mike saidthere you know some of our groups are usingthis functional data i mean in the tp53 working group thereare very well established functional studies that we trustin our cdh1 working group there we actually don’t take functional data into considerationbecause it has not correlated with patient presentationso really all of thatthe breadth of standardization across all of the genes in the genome to try to figure out what piecesof evidence are usefulwith respect to very interpretation you know based onthe known patient phenotype so that’s going to be the biggest challenge and it is i mean the clinton efforts are kind of focusing on theum the highest highest profile the most critical geneslfs you know cdh1 where there’s real surgical and or surveillanceimplications butexpanding into those more moderate and lower penetrance genes and or variants is going to be very dauntingi’m not sure i answered kim’s question butit’s a challengewell and i if i could just chime in too as related to variant scienceum i mean i think it’s been really interesting to observe the evolution of jobs in the area of genetics right like as a genetic counselor it’s really evolved andi mean 10 years ago variant science as we know it today really didn’t exist so i’m still surprised in talking to many of the labsthat are hiring variant scientists you know theythey are pulling from phds from genetic counselors kind of converting them and there’s not really even an organization that i know offor variant scientists in general so also standardizingtraining because it’s divided now among pathologists geneticists um i don’t know if anyone’s really given thought or jamie if that started to come up like what will be the standard for training of variant scientists i don’t think so i mean yeah we have not discussed it at stjude because our our operation in terms of variant scientists is veryvery small one to two person operation but i do think that that’s very important you know becausereference labs and our children’s hospitals and everything do want standardization and what we are calling variants and withyou know i can interpret something completely different thanthe person sitting next to me um so right now i thinki think that there is becoming more standardization a lot of curators are involved with the clinton efforts which definitely does help having those conversations and seeing howthese guidelines are formed but i think it will be important in the future to havea society some kind of more formalized trainingum to get everybody on the same page yeah i think that’s a you know a nice point about thethe educational aspect of this and and almost a degreeuh that could be had in all of that um certainly you know goingwhen i got started in the space so to speakfor three years i just sat and looked at variants and there was not necessarily any training the acmg rules around how to classify variants weren’tthere i had a genetics background from you knowformal but wasn’t specifically around molecularand um you know as this field has emerged that it’s it’sin some way still gray in terms of who knows whatand what people’s responsibilities are in the space and in terms ofwho should know what to your point aroundvarious scientists because there are certainly uhdiscrepant resumes so to speak in terms of who’s doing thatand um it’s it is a big problem the other thing kind of in parallel to that isjust the classification system that it still is thebenign to pathogenic you know there’s not a formal recognitionrecognition of moderate penetrance or you know low penetrantalleles and so i just think that that will have to change at some point obviously all these clingen efforts but it justfalls on people for the individual gene or the individual lab oryou might have to write out a paragraph describing the effect of that variant but that’s really so qualitative for something that shouldhave more of a quantitative basis and and we know thatit’s so much more complex you know like kim you’re talking about like all the different functions of a given gene it is going to be different if all the functions are knocked out or one of the three functions is knocked out or you know that’s very so much andi think it’s hard to have a variant classification system that only reflects likea dichotomy if it is pathogenic or benign you knowand so i don’t know the perfect solution like i don’thave a great solution for how to modify that because it’s so complicated but it has to be more complexin the formal guidelines than just those twooptions to have yeah i’ve heard about a movement toward morequantitative quantitation of the scoring as opposed to adichotomization and what i’m seeing in particular in terms of the disease specific modifications isthere’s um ways to take these categories of acmg evidence and even if they’re strong you candowngrade them to moderate or upgrade them to you know very strongand so it that does lend itself as you said at least a more quantitative approach as opposed to justcategorization but thatthat challenge is standardization a great deal and it makes it more complicatedto ensure that you know interpreter a is interpreting the samevariant in the same ways and even when they’re presented with the same information so i feel like that’s a very large challenge and and we’ve talked about this a little bit with respect to clingen and clinvar i’m wondering if we as a group can talk aboutum any any uh challenges that are facing clinton and clinvar in ways that the community can get behind them to you know to break through those challengescan i say somethingwe’re looking at the challenge in front of us maybe we need to step back and justrealize that really we have this balance betweencontinuous improvement and learning and that that is led by standardization but then there are these individual breakthroughsevery generation brings about 70 to 200 new variants so to have a very structured standardizedmodel just the subject matter that we’re trying to evaluate breaks that norm so i i think whilst there needs to be guidelines buteven looking at mutation you have to look at it in the contextof the person and the broader cons and contexts of the genome so i think that thethese are the kind of aspects that and one uh where i do think and it kind of goes into the question where we as a community we oftenforget that the clinical knowledge and what we’re seeing in front of us that is going to be recorded into our emrhow do we go back and learn from it so i i think thatthat once we realized how to harness thatand then build that into our continuous umknowledge that might be the way forward still has challenges yeah besides us you basically have have set the stage for exactly what i was going to say um and i’m not as involved in clinton or clinvar as i probably should be i just have too many things going onbut the thing is i think it’s really important right it’s really important thatthe genomic data be looked atin context with the clinical information andin my mind one of the biggest challenges isbringing those two pieces of information together i mean like you probably know about this and this gets at what elise said i meanthere are some variants that are going to have a stronger phenotype than others and phenotypes are going to vary and how are we going to bring ittogether and for jamie you know in the variant curator or scientist field you know they probably come out from more of a pathology or computational angle but understanding the clinical componentlike i think what’s really important is somehow having constant communication and a way to bring these disparate pieces of information together so that we can better understand what these variants are goingto mean in the future and uh if there’s a you know an answer forhow to to combine and continually build on the clinicalin a way that helps interpret the germline or the sorry the genomic that’s what’sreally going to be important moving forward soi think this is a really challenging but important area mike i’m not sure if you want to build on that i mean you’ve been so much more involved in this as a geneticist i’m just a little old oncologist butyou just didn’t think yeah no i know um you know theuh clingen part of it where it suffers is what should say it suffers i think wherei i’m chair of the somatic uh germline integrationcommittee to try to help us to help clarifygermline variants utilizing somatic data andum you know like anything it’s resources right so wewe all have very good ideas about how to try totake next steps and then rate limiting steps aregetting clean data to integrate and and andhaving um access to information from different centers right so umthe the uh andi with that said there is good reason for certain centers toum clean their data have it you know at a particular level and i think that’s something i’ve appreciatedmore as time has gone by with the the you know the two most recent centers i’ve been atin the sense that um there’s this push you free the data free the data free the databut you don’t want dirty data that’s rightso you want things annotated as well as humanly possiblewhether that be the clinical part or the molecular part and ideally it’s both so um i think clin sharon plan who leads you know she’s the godfather so to speak of all this stuffis yeah that’s the way i think of her um is that is very conscientious of all this and been in this game a long time and i think has done a tremendous amount in terms ofum identifying players at different centers that canbegin to really kind of move all of all of that together in a meaningful way but there are there are um you know therei went back you know i mentioned the economic part of it earlierit’s a lot of it’s economics so having the ability to haveadditional resources for bioinformatics and so on is always agreat limiting step for all of this and and then mtas to to share the clean data when it’s available can be a rather drawn out processso uh those are just a couple practical things butthey’re things that can actually expedite mattersquite a bit if in placei was just thinking um during this conversationjust about the role and i know this is kind of a topic we wanted to discuss of likeai and machine learning because that’s what i’m hearing a lotof when we’re thinking about the clinical correlationand just design of products that can really use the machine learning concept to pull that clinical phenotypic information together with the molecular so i don’t know mark if you have thoughts or other people have thoughts on initiatives at their own centers to do thatyeah i’ll start by saying that you should always be as clinicians be armed with evidenceso i don’t a genomic does notthink of ai as a black box solution to any of these problemsi think that it’s a tool to arm the clinician with the best evidence and to continue to leave thedecision-making in the hands of trained cliniciansfor all of these nuances that we talked about you know clinical context the the challenge of thesedisease-specific diagnosesis just the nature of the complexity of the data and so i very much think of ai as a way toorganize evidence for decision support i don’t know that we’re i don’t know that we as a community ever want to get to a place where ai can be a stand-in for any of these clinical decisions um and so obviously particularly at genomicwe surface information from the medical literature and keep that as up to date as possiblebut the idea is always that it be organized it that it be as sensitive as possible and as organized as it can be but then the ultimate bonus of decision making is on the clinicianso i wonder if anybody else is more optimistic about aiyou know taking over i i i’m not i you knowin my training in pathology um i i was always very pessimistic about the idea that these tools would replace the human touchi think um i don’t know if that i have the answer to that but i think one thing this brings up for me is that it’s important i thinkto think about how we enter our molecular data into the electronic medical recordwith our most recent essays we were actually able to interface our results directly into theemr so that we have discrete variants that are now searchableum which i think for us was a huge celebration in victoryuh because now we can actually tie that data to particular patients and particular demographics but that’s still not perfect either and i think you know that’s something we really need to think about umhow do we make that better how do we enter our molecular data into the electronic medical recordin a way that makes it useful for all kinds of different things for this interpretation forum you know submitting data to consortia to utilizing that data to talk to payers about you knownow i can put together this set of patients where this test was really impactfulso i think organizing our data and interfacing that with the electronic medical record is going to be one of the first steps to making this kind of ai and decision tools really valuable and if i could add to that umit because again um andi can’t i think liz you mentioned that that i think we need to evaluate the roleof clinical labs in thisjourney and we have to recognize that we’re not at the endso whilst we’re entering and interfacing um the genetic and genomic data that that was born out of a subset and i i think we mentionedvery early on that as our knowledge is growingrather than having these very discreet panelswe know that we’re generating a much larger data set and we have the pressures of the payers that we cannot do exploratoryuh panel research but the lab is actually generating that data so how do you link that larger bodyof data with the emr thatif you have what’s i call anunsatisfactory diagnosis so there are boostersin there can we go back andping that data in a very um streamlined fashion rather thanyou know pump the brakes let’s sit down pull this they said pull that daisy set and can it happen in a more streamlined fashionuh alisa you brought up something that i wanted to touch on for sure is the specter ofwith all this you know proliferation of new informationwith modifications to the the decision making and and theseloses in otherwise undiagnosed patients how how does the panel think about the look back challengeof you have a case that remained undiagnosedhow are we going i mean michael you’re bringing up this pragmatic challenge who’s got time for this who’s got the resourceslet alone how do we communicate this information to the patient soif anybody um has ideas aboutwhat what you’re doing at your institutions to solve this look back challengeof cases that haven’t been diagnosed but that kind of demand for the clinical circumstance a revisitation of that data in light of any published informationi mean i think like from at our perspective it’s saying judei mean it really believes the provider um to go back to the lab to ask for a re-analysisi’m not sure how it works at other places i’m worried that from a laboratory perspective it’s going to be too challenging or overwhelming to go back and look at every single case that’s been tested over the prior years there will be hundreds to thousands of casesum you know at our institution it’s been up to the genetic counselor the provider to ask for review analysisevery couple of years you know as needed and lo and behold just like i’m sure for all of you i mean we’ve come up with new diagnoses as new data has come on board i’m going to be interested to know if others feel differently but it’s worked for us but you have to educate the providers that they will need to reach back out i mean the question i guess will beeconomics i mean i don’t know if it is something that the provider would need to pay for again or if that can be done you know at a reduced cost or free for service umyou can’t recall i think for our patients the companies that provided the broader sequencing at the time you know did the re-analysis either for free or for a reduced cost i don’t recall but i’d be curious to know what others do or suggesti mean one thing that i found helpful when working with genomic andinterfacing with labs is just learning about their different operations and when you think about some of these tertiary analytic platforms that are now kind ofprioritizing variants and then also other ai based toolswhere you have updated literature i’m wondering how muchcan be more ai based for the look back or at leastpresent to the clinician like here’s the updated like herein the last year here’s the new information about this variant that’s been reported so that then it helps the clinicianto triage that look back process or you know i i just think the only way to do it is some kind of automated supplement to that processwith still the human element of discernmentbut i don’t i i haven’t really come across anyone who’s optimized that processbut i’m curious to know if anybody else is awarei also think that there is a power of the patients and the patient has a voice hereas well and there’s a huge educational componentum again when we go into surgery it’s a very finitewe know exactly what it is whereas when they’re enteringand getting the genomic testing this is a journey and they have to understand thatyou know today’s result doesn’t mean that it’s going to be the same tomorrow and so having discussions on multiple levels i think will starthelp guiding us to what that process looks like and i and as always they’re just like with our iphone some that people here attract me i don’t care and some peoplewill make sure that everything and the kind of aluminium hat is on their head so i think we have to be very sensitive to those aspects as wellyeah i don’t think we’ve optimized it either but i thinkit is very patient dependent because the way that i mean the way that we have it i think the way that most people have it is that the patient has to kind of reach back out to us for clinical updates if it’s part of a research protocol like our msk impactassay then you know potentially there could be updates but that patient is signed on to the research protocol and so ifyou know if we find something and then are not able to recontact the patient we can’t track them down the phones are not in use then you know we have a protocol for how to deal with that but i think everyone’s really nervous to take that responsibility on clinically like in addition to thehuge workload that that isit’s just a lot of liability it’s not a perfect world where you can find everyone who youcould find two and a half years ago um so i think that it is very patient driven and that also allows patients to kind of dictate the importance of it becauseit’s just not worth our work if they’re not interested they’re not going to follow up regardless of what we contact them withand there’s some patients who really really have something and we know they have something and they know they have something andwe’re all frustrated that we don’t get to it with the first test and then there are other patients who we send the same testing on but they probably don’t have a predisposition andyou know the negative or kind of unlikely vusare reassuring to them and that’s probably fine if they don’t recontact us or you know if they reach out in like five years instead of one or two so we just try to emphasize it to all patients but we’re not doing anything clinically likeon our end without them reaching out i wonder in the last few moments if we can build on whatelisa and elise said about patients and and their intrinsic motivations and their understanding i’m just wondering how how um well educated they are in light of you know direct to consumer genomics how receptive are they to these new lines of evidence and how has that influenced your clinical practice or has it not changed at all i mean as elise was talking one thing i was thinking about is health literacy barriers and justdiversity and access barriers because that’s what my mother looks like incredibly disparateum and so that’s also a concern of mine is thatif it is left to the patient even though that can be very positiveum due to barriers that some patients have overothers that could actually lead to a lot of inequityyeah right completelythink that i mean that is obviously a problem but you know liz i would imagine you know even people who don’t necessarily have those barriers now i don’t know as much about direct to consumer testing butyou know some of those tests are very specific variants in a gene right and they get a negative test and they think that they don’t have any variance in the gene you know they think they’re okay and so i think you know this just emphasizes again for all your genetic counselors i mean how critical it is to do genetic testing in the context of genetic counseling and i mean personally i feel like it’s a real disservice umto do genetic testing without genetic counseling on both pre-test counseling and then post-test counselingum and you know i feel like we’re lucky in pediatrics and at state jude i mean we often can see patient because ours have cancerwe can see them periodically afterwards to continue to educate the families but it’s very different perhaps with other diseases and in the real world so i just think the counseling is really critical across the boardyeah you find often providers don’t have a clue about a lot of thisnever mind people are trying to explain right you arewe have to cancel everyone the tricky spacegarrett i’ll pass it over to you for any closing remarks i was going to say in the interest of time i think you know but i wanted every everyone to have a chance to give you know their final thoughtsi um just want to thank all of our panelists for you know taking the time to offeryour expertise in this round table i think we had a fabulous conversation um it seemed to move itself uh you’ve all had a lot of great feedback and you had some really good goodconversation chemistry so i think it was it was very valuable so i i do thank you for thatso let’s thank you alland um i will go i do have i will close out withour ending slide hereso for everyone watching thank you for tuning in and to all of our panelists thank you for taking the time to offer both your expertise and your time in this round tableif you have any questions or would like to discuss your variant interpretation needsfeel free to send an email to our folks at hello genomenon.comadditionally if you don’t already have a mastermind account you can create one for freeand receive a free trial of mastermind prolast but not least your feedback is very important to usand we’d love to hear your thoughts on today’s webinarat the conclusion of this event you’ll be prompted to take a brief survey that will help us as we continue to create a highly valuable customer experienceso with that thank you so much for your contributions and interactions everyone i think we had a great conversation.