 Hi everybody. So my name is Kate Rowan and I'm the Chief of Genomic Medicine at UC Davis, and I've been tasked with the opportunity to talk to you a little bit about what in the world clinical geneticists, who are we, what do we do, what is medical genetics or genomic medicine, and really what is it like day to day boots on the ground of meeting patients, talking to patients, and trying to make a diagnosis. And in the next few minutes, just marking my time here in the next 20 minutes, we're going to talk about a little bit about a grassroots relationship that grew with Kent Lloyd and his group at the mouse biology program at UC Davis and how we're moving forward with what is truly a really great collaboration. So I really want to thank the organizers for this opportunity to speak to you today. So I'm going to give you the punch line right now. You don't even have to wait. So the work that you guys are doing right now creating these mouse models and phenotyping them is critically important to the work we as clinical geneticists do on a day to day basis. So I heard the conversation yesterday about getting your papers published, get your papers published, because we look at those every single day. We are searching and looking on PubMed for genes and variants and stuff like that that we need to learn more about and how it relates and how it could relate to the human condition. So get your papers published. They really do matter. So genomic medicine, I just want to talk a little bit about genomic medicine at UC Davis and the NHGRI defines genomic medicine in a here I quote. It's an emerging medical discipline that involves using genomic information about an individual as part of their clinical care and for example for diagnostic or therapeutic decision-making for the health outcomes and policy implications of that clinical use. So we're it's great to see that genomic medicine is being defined, but I can tell you we have been doing this for a very long time and the fact that you may not know what a clinical geneticist does or what medical genetics is and in how it relates to the medical community that's okay because physicians at our own institution don't even know what clinical geneticists do and some of them don't even know that we exist and so this is having the NHGRI make a public statement about what we do and who we are is really great and it's a great first step. So our mission of genomic medicine at UC Davis is to help improve the quality of life for individuals both children and adults. We see the entire lifespan. Genomic medicine is not just a pediatric subspecialty. We're our own residency program and so a resident can come through after medical school and actually board in clinical genetics. So we see both children and adults and the family members of individuals with genetic disorders through excellent clinical care, through research and scholarly activity and education. We do a lot of education. So again what in the world is a clinical geneticist? Very basic but a lot of physicians don't even know as I mentioned before that we exist. So clinical geneticists are specialized physicians who diagnose and treat patients with inherited or otherwise genetically influenced health issues. So what's a genetically influenced like fetal alcohol syndrome right in utero exposures. They organize screenings for inborn errors. They prescribe therapies. They interact with genetic counselors. Well what's a genetic counselor? Genetic counselors are professionals who have specialized education and genetics and counseling to provide personalized help to patients that they may need to help them make decisions about their genetic and genomic health. Genetic counseling is a super super hot career right now and the fact is genetic counselors are being scooped up by industry and it's really hard for academic centers to hire genetic counselors because we have a much lower pay scale. So this is a typical I'm going to describe for you a very typical genomic medicine or medical genetic division. We are housed within a clinical department and it's typically pediatrics. I transferred to UC Davis from UCSF almost five years ago and when I transferred to UC Davis my job literally was to rip down the division and rebuild it and that's what I did. And so the people that I'm going to describe for your typical geneticist are new hires that I've hired. So I am a physician scientist and the thing is genomic medicine is such a broad field right now. You saw the talks this morning. We have 20,000 genes in our genome. There are about 6,000 Mendelian disorders described and so how do you wrap your head about trying to find out from a phenotype what that genetic lesion is. So I'm a physician scientist. I see patients. I run a lab. I do mouse models, but I don't do knockouts. I actually have my mouse models are activating mutations for Costello syndrome and CFC syndrome. So HRAF and BRAF. Maddie Martin is a biochemical geneticist and actually she sees patients that have very specialized disorders and biochemical derangements. She's also a clinical geneticist. So again, medical geneticists actually specialized because it's such a broad field. Becky Mardisch is a clinical geneticist. She's also biochemical. Her field of expertise is neuro genomics. Chris Herman also a clinical geneticist. She actually specializes in connective tissue disorders, skeletal dysplasias and prenatal genetics and suma shanker that you'll hear from later today on the panel. She's also a clinical geneticist. She specializes in ocular genomics and precision genomics, which I'm going to talk more to you about. And then in your group is typically a genetic counselor. And so we have four fantastic genetic counselors. And again, the field is so broad that even now genetic counselors are specializing in areas. We have Viv, who specializes in neurodevelopmental disorders, autism genomics, precision genomics. Becky specializes in lysosomal storage diseases. And she also sees general genetics patients. Colette specializes in cardiogenomics. And she also is my coordinator for the RAS pathway clinic that I have. And then Ayaka is biochemical genetics and newborn screening. So again, specialized specialized care. In our genomic medicine division, we have lots of different clinics, general genetics clinic, biochemical genetics clinic. I do the NF RAS pathway clinic, connective tissue disorders, cardiovascular lysosomal storage, telegenomics. So Davis is a really big leader in telemedicine, autism genomics, precision genomics clinic, and ocular genomics clinic. Lots of different clinics. Again, at the University of California, ours is a very typical genomic medicine division. And so if you were to go to UC San Diego, or UCLA, or UCSF, again, very similar to what we do at UC Davis. Inpatient, we see about 300 cases a year. Outpatient and these are underestimating. Outpatient, we see about 1000 cases a year. And again, all ages. So when I transferred to UC Davis from UC San Francisco, the one thing that I knew we needed to do was we needed to build precision genomics. Because I honestly, in my lifetime as a clinical geneticist, I never thought we were going to be sequencing the genome. And it happened all of a sudden. And I'm so thrilled because it makes our day to day amazing to be able to sequence the human genome and try to figure out what in the world this means, how can I apply it to the patient? And most of all, how can I help the patient with their health issues? So when I got to UC Davis, my very first recruit was trying to get summa shanker from Emory to come join me at UC Davis and to really run our precision genomics program there and set up a clinic. And so the goal of the precision genomics clinic, I was successful, thank goodness, and she set it up, was to provide answers to families and individuals with suspected genetic conditions that are going through the diagnostic odyssey. And you heard about the diagnostic odyssey already this morning. Genomic medicine is one of those fields of medicine that we are typically the last resort. The patient has gone to cardiology. The patient has gone to immunology. The patient has gone to pulmonary. The patient has seen every medical specialist and has done every single test. And they still don't know what's going on. And so what happens is, oh, well, we don't know what this is. Let's just send them to genetics. So we typically are the last one to see the family or see the patient. And so our goal is to try to end that diagnostic odyssey and to try to figure out what's going on. And so patients that again have a wide range of medical issues throughout their lifespan. This is the patient that comes to see us with the goal of benefiting the patient and the family. We're trying to drive personalized treatment options. We're trying to drive discovery and collaborations and advanced medicine. So when Summa came, what she did was she took a very systematic approach as to what was going on at UC Davis. Again, pretty typical for a University of California division of medical genetics or genomic medicine. So we see about 1300 patients per year, as I said, and let's just round it off to 1000 outpatients. So what Summa did over a year's time is she retrospectively went back, we're housed at the Mind Institute at UC Davis, which stands for the medical investigation of neurodevelopmental disorders. And so a lot of what we see in a lot of our referrals are developmental delay or autism spectrum disorder. And so about a third of those 1000 patients that come to see us on an outpatient basis are developmental delay and autism spectrum, you know, query diagnosis or genomic diagnosis. And so what Summa did was she evaluated the genetic testing approach that we were using. And she wanted to look at the yield for autism spectrum and developmental delay in our division. And so a typical appointment is we gather clinical information, we try to get as much information as we can, because that's part of the phenotyping. So again, what we do is very similar to what you do. We just do it in a reverse order. We phenotype and try to find out what's going on in the genome. You guys create a mouse model, you alter the genome, and then you phenotype. So we gather as much information as we can, we do a very thorough medical physical examination, and we try to phenotype as much as we can. If we can, and if insurance allows, you know, we'll try to get an echocardiogram, we'll get an abdominal ultrasound to look at the liver to kidneys. And the abdomen and anything else we can get our hands on, we'll try to get an eye exam, a hearing evaluation, again, really phenotype that patient in a systematic way. And then based on the phenotype, we want to target the type of testing that we do. We don't just send whole genome on everybody, but that will change. I think there will come a day when we send whole genome on everybody. Right now we try to be very systematic, because insurance just doesn't allow you a visa card and say, do whatever you want. You have to be very systematic in what you're doing. So we are very careful about the genetic tests. And then we take a very systematic approach. This is something that we actually think of, even though this algorithm is not posted on our wall, we will actually think about it and do the best test that we can. So whole genome sequencing has already been mentioned, or this excuse me, whole exome sequencing. This is pretty much the go to that insurance is paying for. But what's really going to change what's the game changer is whole genome sequencing, this will predominate. This is what's going to be our go to test for the future. And I just want to very parenthetically mention that there's a project in California where MediCal, which is the Medicaid for the rest of the country, they're actually paying $2 million to sequence a project of about 100 patients right in the newborn period to see if we can stop that diagnostic odyssey in the newborn period. So that's actually launching right now. So getting back to Summa, what she saw was about 300 referrals. I'm going to go through this quickly. 300 referrals of which 86% of those referrals were recommended new genetic testing or additional genetic testing. And of the of the of those 300 patients, they're about 255 of those 255. There was a subset of genetic testing that was actually performed or additional genetic testing. The here's the bottom line is that of all the genetic testing that was done, more than half of the genetic testing produced variants of unknown significance, either a variant in genome sequencing, genome sequencing, or or a variant in a gene that we don't even know what the gene does. And so the thing is half of what we identify is unknown. And so there are guidelines from our college on how to approach this. And we go through that we approach it in the very systematic way. And the other thing that we do is we use all these databases just like what the laboratories used to try to help us figure out what that gene does. And so we do use these databases. And the thing that I also want to mention is we do use PubMed to look at mouse models, if mouse models have been produced to also help us glean information about the gene or about the variant that we might be querying. And so with this, and in collaboration with Kent Lloyd, is we know that animal modeling biochemical testing of a variant or of a gene truly is the gold standard of functional studies. And so we hooked up with the mouse program at UC Davis to look and discuss our variants of unknown significance, our genes of unknown significance, genes of interest for phenotyping to see if we can come together and create a mouse models or mouse models for these genes or variants to really identify what's going on. So over the last year, Summa, who has only about 30% clinic time, this is one person in just a year's time at 30% effort, she's already identified 70 V us's, you know, and so this is how many V us's we come across on a day to day basis. And that is a lot. So I just want to give you a couple of examples of what we see in the clinic, and how we approach this. So here's a family that came in with the diagnostic odyssey. We were the last individuals that that this family saw. This is an eight year old brother, a six year old sister, they immigrated from Syria with the family. They were very dysmorphic to cranial facial dysmorphic features, short stature, they were failure to thrive. Both had a history of global developmental delay. They weren't talking, they weren't walking. They had an intellectual disability with seizures. They had really bad behavioral issues. And their diagnosis was cerebral palsy, a diagnosis we cannot stand, because that means no one knows what's going on. So one thing that we do is genetic counselor does a pedigree. And as you can see, probably the most important thing, they're three sibs, two are affected. This is a consanguinous mating. Okay, so we're probably looking at an onosomal recessive issue here. So a chromosomal microarray was already done before they came to us. There were multiple runs of homozygosity. There was a panel done a panel testing for Angelman and Rett's Phena syndrome that was negative congenital disorders of glycosylation was ruled out that was negative. But summa sent an exome and found a homozygous variant of unknown significance in the DPH5 gene, which is also of unknown significance. So this is the diphtamide biosynthesis gene. What we do know is that it's really important in diphtamide synthesis pathway, and it's very well conserved across multiple different species from archaebacteria to man. So this is an example of a perfect, perfect gene that would be an excellent candidate for a mouse model. The gene's not described, and it causes a severe childhood onset neurodevelopmental disorder. So this is a gene that's going into the pipeline at UC Davis. So here's another case, typical case of what we see that walks through the door, and we don't know really what's going on. So this is a four year old who presented with vision issues since 18 months of age. An MRI of the brain and spine showed cerebellar and a supertentereal white matter multifocal changes with restricted diffusion and dorsal column signal abnormalities. In other words, a bad brain. So there was an EMG done, and it was consistent with a demyelinating polyneuropathy. So an exome analysis was done, and it revealed two missense VUSs in the AAR-S2 gene. So two different missense mutations, and the missense mutations were found to be in trance because thank goodness we had the parents. So sending a trio is really good. It's good medicine if you can, because then you can figure out what came from whom. Okay. And so the AAR-S2 gene encodes mitochondrial tRNA synthetase, and it's really important for mitochondrial translation. So very important kind of a housekeeping, housekeeping gene. And so looking at the comp database, this knockout was available. And the mouse phenotype showed that it was a preweening lethal, and there was a cardiomyopathy involved. And so based on these findings, Summa went, Oh, gosh, okay, I need to go back and look at my patient and do an echocardiogram. So here we took mouse data, and we applied it back into the clinic. Very important. So that's why I'm saying get your papers published, because we use it. So here's another case, as I wrap up, as my time is almost up. Here is a case where a child presented with visual problems. This is the picture of the back of the eye. And the kiddo had distinct facial features, a pronounced broad forehead, the eyes were wide space, down slanting palpebral fissures, a prominent chin, and the retina exam and looking at the back of the eye, the kid had an abnormal macula. So what was identified was an exon deletion of VCAN. And VCAN is a gene that encodes VersaCAN, which is a large extracellular matrix, chondroitin sulfate, proteoglycan, and it's really important in a variety of human tissues. The VCAN mouse model is not available. And so creating a mouse model of VCAN will study not only what VCAN does, but if there's other systems that are involved, that are involved in the phenotype. And so, again, working with the mouse biology program to create a mouse model would be really important for this gene. So that's pretty much what I said, because I'm running out of time. So this is a case where we take something from the clinic, we go back into the lab for mouse biology, mouse modeling, and then bring it back to the clinic. And again, we as clinical geneticists actually do this all the time. And I think getting your word out there, having a booth as what was going to be done at ASHG and other national genetics meetings, again, helps get the word out there that you guys are open for business and genotyping and phenotyping. And so I'm going to circle back to the bottom line now that the 20 minutes is up. The work that you do in creating mouse models and phenotyping them is critically important. And the work the clinical geneticists do on a day-to-day basis. So again, get those papers published, because we use them and they really matter. And I'm on time. Catherine, have you published this stuff yet? It would help us if you published that stuff.