So we'll go ahead and get started with the webinar, and we start with an agenda, which is relatively focused. This is one in a series of webinars that we hope to give on this topic that gets a little bit more clinical and topical as we go on. So the overall plan for today is to show a case study that really just kind of helps you think about the terminologies and alteration discussions that we're having. And then we'll talk about genetic terminology and different types of genetic alterations and modes of inheritance, and then we'll kind of come back to the case study to revisit that and imply it a little bit. So the case study is about a kid named Roger, who's a six-year-old boy brought by his mother because he's struggling in the first grade. His growth has fallen off, and he's the shortest in his class, but he's not super short. He's really just at the borderline at third percentile. He's had one seizure early in his life, and his head circumference is normal, but at the 95th percentile. His mother and father have normal intelligence by report, but his father is unemployed due to generalized weakness and pain.  He's had some initial workup ruling out other short stature causes like thyroid and growth hormone deficiency, and the pediatrician is kind of stumped at this point and wonders if he has an intellectual disability syndrome because of his difficulty in school, even though his appearance is basically pretty normal. So a genetics consultant is engaged and detects mild brachydactyly, which is short fingers, and borderline upper lower segment and arm span to height ratio. So those are ratios that we measure and calculate using a seamstress tape that just has inches or centimeters on it, and then we use a little calculator to do that. And these differences indicate mild limb shortness, and so the genetics consultant thinks it might be a skeletal dysplasia. There we go. All right. So a genetic test is ordered, FGFR3, which is the fibroblast growth factor receptor number three. Gene sequencing is ordered, but the order test sequences only one exon and a specific exon, and it's targeted to detect two variants, C1620C to A, and C1620C to G, and it does not examine other FGFR3 exons, including exon 10, where the fully penetrant pathogenic variant responsible for acondroplasia is located. So the gene test result confirms a heterozygous mutation or variant, P aspera gene 540 lysine. So the aspera gene has changed at position 540 has changed the lysine, and the diagnosis of hypochondriplasia is made. All right. So we're going to just keep this in the back of your mind as we go forward. So the discussion is a bunch of questions, and this is, again, the preview to keep in your mind. So the first question is why do the CDNA variants, and I'm going to get a pointer here, I think. Why do the CDA variants both result in the same protein variant? We'll answer these at the end. How many copies of the hypochondriplasia variant are we found, and is this a dominant or a recessive disorder? How can Roger's diagnosis possibly help his father? Maybe some persons with hypochondriplasia have intellectual disability. What two phenomena explain this? And the doctor could have ordered a complete radiographic survey, including skull, pelvis, AP and lateral spine, legs, arms, hands, instead of a genetic test to diagnose hypochondriplasia. So the question is, can you give three reasons why she might have chosen the genetic test over the radiographic diagnostic approach? And what did she risk by choosing the genetic test instead of the radiographic approach? Okay. So let's talk about the human genome, which is basically a whole bunch of DNA, deoxyribonucleic acid, which is made up of two anti-parallel strands of a sugar phosphate background in the blue, and base pairs that stick out between them and hook together through hydrogen bonding, and the base pairs are specific. So when one base is an adenine, that always pairs with a thymine. When it's a cytosine, it always pairs with a guanine, and so forth. So the human genome is all the genetic material in the nucleus, plus the mitochondrial genome. We'll talk more about that, too. Molecules of DNA that contain the coded instructions for how to build, maintain, and replicate a human being, so they're really kind of the blueprint. DNA is not identical in anyone but identical twins, and it always contains both benign variation and variations that can cause or contribute to disease, and even if they're only recessive diseases, we all have some kind of recessive variance there. And it's really big. It's 3.3 billion base pairs if you include everything. So chromosomes are sort of the packets in which the entire human genome is broken up into. Each chromosome is one strand of really, really long strand of DNA that is rolled up in histones, forming nucleosomes, and then twisted several times to its condensed state during cell division. It's in that condensed state that we recognize that form or that shape of a chromosome, and it has a P-arm, which is the short arm, and a Q-arm, which is the long arm. I always remember that as P for, if you speak French, it's P for petite, which means short and French, so that's how I remember it. And when you order a karyotype, which is shown on the left, you get these chromosome pictures with banded chromosomes, and there are 23 pairs of chromosomes, one pair from mom, one pair from dad, and one pair of sex chromosomes. So 22 pairs of autosomes and one pair of sex chromosomes shown in the blue circle down here, that's the X and the Y, and males, and XX and females. And the chromosomes always have a consistent structure, a consistent banding pattern, and they're balanced. And I think that's a very important point is we're talking about a balanced, a normal person has a balanced amount of genetic material, and that's really important. All right, the gene is kind of the unit of structure that is encoded in the DNA, so you have chromosome, which is one long piece of DNA, and within that you have segments which are functional units called genes, and the gene in eukaryotes and humans and animals and plants and things like that actually has sub-segments which are exons that are interspersed between introns. And exons are kind of the business end because they contain primarily the coding material for the proteins. So when a gene is transcribed and sent out of the nucleus, the RNA that results will have the introns cut out and the eventual mRNA will only consist of the exons. Now I wrote down here that it contains code for proteins. You can have exons early in the gene and late in the gene that don't code for protein portions, but they're important for regulation. Interestingly, I think, is that the gene coding regions, if you add up all the exons in the genome, they're probably only about 1% of the entire genome. So how does this gene get expressed? Some regulatory proteins come along, usually upstream and in the gene and say, okay, this is a gene that needs to be transcribed, it needs to be expressed, it needs to be out there making something that's useful for this particular cell type. And so the DNA is copied to RNA in a process called transcription. And again, the transcription is like a copying process, so that makes sense. And it's done by a protein called or a complex called RNA polymerase and you transcribe the backwards part of the DNA because these are complementary strands and so you get a sense strand of RNA from the anti-sense strand of DNA. And the next step is for that RNA to be exported from the cytoplasm into the, I mean, sorry, I explored it from the nucleus, excuse me, into the cytoplasm and actually into the endoplasm in particular where this huge machine called a ribosome is taking that RNA and the information encoded in the RNA that was copied from the DNA and turning that into proteins and it does that by grabbing these transfer RNAs which have specific amino acids tied to their three base pair code and they match that up with the codon in the mRNA. And then the amino acid is added to this growing polypeptide chain which eventually becomes the protein. So we're translating the code in the mRNA to a protein code and that's sort of described down here in this inset where you have a start codon here and then you have different codons that are coding for different amino acids and we'll talk a little bit more about that. So the codon UAA is the stop codon and that tells the ribosome I'm done, don't add any more amino acids and let me go I'm a free protein now. So if the stop codon doesn't show up or if a mutation or a variation results in a stop codon earlier in the gene then that will result in early termination of the protein chain.  Proteins are really the things that are important in making cells, making them work and they have a lot of different types of functions. They can be structural elements, they can be enzymes that catalyze biochemical reactions and building other things including proteins that are involved in the ribosome and so forth. And they can be proteins that are regulatory factors both inside the out cell and outside the cell. They can be receptors, they can be signaling molecules, they can be hormones, etc., etc. So there's a lot of different ways that proteins can be important but their information is all encoded in the genome. Alright, so let's go on to a little bit different phase where we're talking about some terminology and distinguishing between genotype and phenotype. So genotype is the genetic code that describes an individual. So if I can describe my human genome and say it has these variants in it, that's my genotype and the genotype should include information from both copies of the DNA for any particular gene or region. So I got one copy from mom and one copy from my dad so I have two different copies and they don't always have the same variants, they shouldn't in fact. And so when you describe a genotype you're describing both copies and it's the entire one. Now you can use the word genotype to describe what's going on in a particular gene and then you're talking about what are the two different alleles, what are the two different sort of cassettes that fit into that gene that were inherited from mom and dad. And then phenotype is the physical manifestation of the genotype in an individual. So we may not know the genotype but we can assess the phenotype, that's what a clinical exam or a radiologic exam or some other general laboratory test may be that'll tell us something about the phenotype. So the only diagram that I could find that addresses this is one having to do with fruit flies so forgive me for that. But in this slide the phenotypes are normal wings or wrinkled wings and the only one with the wrinkled wings are the ones that have a homozygous recessive genotype for small W which is basically a loss of function mutation, okay? The heterozygous, those with the genotypes of homozygous normal large W or heterozygous large W, small W all have the same phenotype so you have to understand those differences in how genotype can lead to phenotype. So moving on to more important terminology and that has to do with genetic heterogeneity. Heterogeneity means that things are not all homogenous, they're not all the same. So there are different types of heterogeneity, a legal heterogeneity is disease that results from different variants in the same gene. So a variant is a mutate, what we used to call a mutation we now call a variant so that's an A to C or a deletion or something like that. So allelic heterogeneity means you can get the same disease from various different mutations or variants in the same gene, okay? Locus heterogeneity, locus is which gene are we talking about here? Is this the NF1 gene or is it the NF2 gene for example? So a particular disease can result from variants in different genes and an example of that is dilated cardiomyopathy so you can have a dilated cardiomyopathy in a family and you can't distinguish that phenotypically in one family from another family but it can be caused by different genes. So that's an example of locus heterogeneity. I'm going back to the allelic heterogeneity, an example is hypochondriplasia which is in our case where most but not all patients with hypochondriplasia have one or two or three different variants in that gene but there are at least 54 different alleles that have been associated with hypochondriplasia. Pnetypic heterogeneity means that these manifestations are different in different people. So in the hypochondriplasia case that I mentioned at the beginning, the father is abnormal intelligence and we're going to presume for the moment that the father actually has hypochondriplasia as well and was never diagnosed and he has no intellectual disability but his son does. So here's another term which is sometimes difficult to capture I think it's meeting and that is the expressivity of a gene. So expressivity or expression is used in different manners. So a disease expression is what the detectable disease manifestations are in an affected individual. So usually that means the phenotype. Well you can kind of see if you've done a thorough physical exam. That's the disease expression so that's the disease features that you see. Some people will extend that and say well you have to go to a cellular or molecular level. For example, in sickle cell an individual with the disease may not have a phenotype if they're not having any problems but you may be able to see differences in their hemoglobin or even some sickle cells rolling around their blood and that would be another example of a disease expression if you look deep enough. So variable expressivity is affected persons can show different features or different combinations of features. Just because you have one disease doesn't mean that you're always going to show the same set of features. Some people may show one set of features and other people may show a different set of features and that brings me to patterns because even within families where diseases are inherited there may be variation due to unknown factors despite the fact that it's an inherited gene and gene is all the same in all the members of the family who are affected with that disease. But also among families and that brings up the concept of genotype-phenotype correlation. So different families may be passing along different variants in that gene and so they have a different genotype and that may be responsible for the phenotype. So you can begin to in some disorders you can begin to say well if they have this particular mutation or this particular variant that's causing their disease then they're more likely to have a particular set of features or phenotype than a different variant in that gene. So here's another term which is important to try to understand and that's penetrance. So penetrance refers to the frequency with which people who have the genotype that is typical of that disease will actually express that disease. So there are some conditions like breast cancer predisposition gene where although you have that predisposition gene you only have say an 80 percent chance of getting breast cancer in your lifetime. That's a really high chance but that means that there's 20 percent who don't who in those 20 percent would be called non-penetrant. So complete penetrance is everybody with the pathogenic genotype expresses the disease that's here. Incomplete penetrance is where some but not all will express the disease and a number of sort of patterns that you can see in that one is lifelong. So when you get that genotype at birth you are you know at conception then you may never ever ever get that get that condition okay doesn't matter how old you are or what you're exposed to it's not going to happen in a fraction of people. The next one is age-related penetrance which is for example early onset all-timers genetic all-timers disease where you don't have expression of the disease until you're older right. So you're not penetrant until you're of an age where you start being penetrant if that makes any sense that's age-related penetrance. And there's also environment-dependent penetrance where you're not exposed to the inciting age and for example one of the medications or drugs that has a subpopulation that are particularly susceptible to it for adverse effects you won't be affected so if you're never exposed to that then you're not you're not expressed. So in the context of the case that I presented I'm just going to read this clip from genereviews.org about hypochondriplasia because of evidence that height range and hypochondriplasia may overlap that of normal population individuals with hypochondriplasia may not be recognized as having a skeletal dysplasia they may not get a diagnosis unless an astute physician recognizes their disproportionate short stature that's that short limb bit that I talked about earlier. However there have been no reports of individuals with an FTFR3 mutation without demonstrable radiographic changes compatible with hypochondriplasia or one of the other phenotypes known to be associated with mutations in this GCD. Okay there are at least 13 different phenotypes associated with mutations in FTFR3 so that's one component but the point that's being made here is that if you only look at how tall an individual is you will think that hypochondriplasia has incomplete penetrance. If you look at whether they have disproportionate short stature or their limbs are disproportionate and linked to their to their trunk then you will have a higher penetrance level. If you look with x-ray at whether they have a characteristic radiologic findings then that will be a hundred percent penetrant even in a person with normal stature and really not very impressive short limbs. Okay so I hope that is clear. All right we had talked about this genetic code before so I'm kind of circling back to that and to talk about types of genetic alterations or variants. So I've used the word variant I've used the word mutation a couple of times here and the mutation terminology is on the way out. We tend to use variant or pathogenic variant as our standard terminology now and I'll talk a little bit more about that in a minute. So the this is about the genetic code and this is the standard table of genetic code it is universal wherever there's DNA encoding things this is the genetic code that's used. It relies on a three base pattern which encodes one amino acid or the termination which is stopped in here. Okay it is degenerate which is to say that there are more than one set for a number of amino acids not all but for a number of them there are multiple codon sets that can encode that single amino acid. So for example here you can have a codon which is u, c, u, u, c, c, u, c, a or u, c, g which all will encode series. Okay so you can actually have a mutation or a change in the third position of the codon and not change the amino acid. Right and that's called a synonymous variation. Okay so it doesn't change the amino acid in the protein and so it's much less likely although not certain to cause a problem with that protein. Okay and then they're actually additionally with serine there are additional ones so you can have a difference in the first position and still encode serine as well. All right so what this brings up is the fact that if you have a translation of a protein from messenger RNA is reading frame dependent. So if you shift the reading frame the position of each of these bases in the codon then by having an insertion or deletion of a multiple of anything but three then you can shift the frame and everything after that point is translated into different amino acids because the codons are telling the ribosome to add a different amino acid in that position. So this is what's known as a frameshift variant or frameshift mutation. All right so from at the DNA level so that's kind of the effect of the mutation at the DNA level here are the different things and different ways that you can mess up a gene. So here is a nice base pair of G and C and if the G is the target of a mutagenic event then you can have a deletion over here where the G is missing and you might end up with a frameshift as I just discussed. Okay you can have an insertion where there's an extra base inserted there and A in front of the G and then you obviously because it's paired you get a T on the other strand and you can have a frameshift mutation there for example and then you can just get a substitution where there isn't any new I mean extra base or missing base it's just that the G instead of being G is now an A and then on the opposite strand once you replicate that strand it becomes fixed and the opposite strand will be a T of course. Okay so those are things that can happen right at the small level at the macro level on the chromosomes which these diagrams represent you can have a deletion meaning a segment is that is normally there is missing and you end up with a decreased copy number of those genes that are in that segment can have a duplication meaning and often it's a tandem duplication shown here but it doesn't have to be and you can have an inversion where a segment of DNA is just flipped and the inversions are less likely to cause problems although you're breaking and reconnecting DNA at two points there and if that interrupts a gene or puts the gene in a place it wasn't before with different regulation or fuses two genes together then you can still have a problem. Substitution is where something goes in and replaces something else it's just sort of moving from one chromosome to another and a translocation is another form of moving something from one chromosome to another in this case it's reciprocal the red portion is going on to the chromosome that originally had the green on it and the green portion is going on where the red originally was and the importance of the translocations is whether really whether or not it's balanced if it's an equal swap there's generally very low likelihood of effect although when that gets passed on to the next generation the chromosomes may not pair properly and you may end up with an imbalanced chromosome set in an offspring. Okay so I'm just going to go over that some different types of variants is base of base substitution one base replaces another copy number variants and deletion where you've lost a copy duplication or triplication where you've gained a copy so these are called copy number variants the usual copy number is two except in the mail where you're talking about the X chromosome where the usual number is one and these are called copy number variants or CNVs you'll hear CNV talked about repeat number is important for because it repeats tend to cause mutations or cause deletions duplications through a number of genetic mechanisms and they can be tandem meaning they are both oriented to both repeats are oriented in the same direction they can be flanking meaning that they're on either side of a region the flanking ones are ones that tend to cause deletions like the 22Q11 recurring deletion they can be a direct a direct orientation repeat or an inverted repeat and the size can be you know as large as you want as a whole you know a whole chromosome part of a chromosome down to trinucleotide segments and the trinucleotides are an important class because there's a whole class of genetic disorders such as Huntington's, Fragile X and a number of neurologic disorders which are due to trinucleotide repeat expansions. There are also structural variations rearrangements in the sections of DNA moved around that's in the previous slide as well as translocation I think the really the most important take home lesson from this slide is that all the different types of variation are not detected by single technology so you have to use different laboratory technologies to detect these different types of variations all of which can mess up a gene and cause a disease so if you're using just one technology to try to understand what's gone on in a genetic disease you may be missing something because there may be variations of different types that disrupt that gene that are not detected by the technology that you're using you can hit that small button up there all right this the next two slides really you're trying to connect the interaction of variation with function so a gene or a protein has a function variation in that may have the potential to cause a difference and that difference may depend upon what environment that variation is found in and the function can have several different categories loss of function function for example in recesses or in haplo insufficiency in dominant disorders more function a gain of function a new function is also called a gain of function or no change at all so a benign variant that we wouldn't have known anything about except we sequence somebody's gene or genome now this this slide gets into the importance of dosage in this interaction between function and variation and and the dose if the dose is insufficient to to give you a normal function for that particular gene then it is a loss of function and that again can be you don't have any insufficient meaning you don't have any or insufficient meaning you need two copies worth and you've only got one copy worth and those are recessive and dominant molecular patterns respectively an access of function is usually or a gain of function for example due to a duplication or triplication of a gene or a mutation that causes an activation of a gene that's normally under regulation and those are usually dominant a neomorph is something where there's a new mutation where the mutation causes say an enzyme which used to convert chemical a to chemical b instead of converting chemical a to chemical b it converts chemical c to chemical d now and d happens to be oncogenic for example so that's a neomorph and then if there's just enough then it's benign so that's that's sort of what the balance is about that I was talking about earlier okay modes of inheritance we can figure out modes of inheritance in several way we can infer them from a pedigree or family history tree we can predict them from the functional effect of a pathogenic variant that I was just talking about and we may need in that process to correct for lethality so for example of a dominant disorder is lethal in young life it's not going to be seen in a family in a in a transmitted fashion because it's not transmitted on because the person who hadn't died before they could pass it on and also you need to think about whether it's a germline typical inherited disease pattern or whether it's somatic mutations or variations that are found in tumors so obviously if it's found in a tumor and it's not in the regular DNA of the person then the inheritance pattern is kind of irrelevant okay so the different let's start with them the dominant inheritance pattern and the diagram here is a pedigree or a family health history and the affected individuals are marked by being darkened here and of course boys or squares and girls or females and the oldest generation is at the top youngest generation towards the bottom so the characteristics of dominant inheritance are that affected individuals affect both sexes equally on average and if you know what is going on at the genotype level one of the two alleles of the disease gene is bad in an unaffected individual there's no disease allele so neither copy of the disease gene is bad and since they don't have a bad copy they can't pass it on it doesn't be it isn't transmitted from one generation to the next so for example this guy here isn't affected doesn't have the gene and has all kids who don't have that disorder another characteristic of dominant inheritance is a vertical pattern which means that you see this in multiple generations and and you don't see a lot of generation skipping it's it tends to be passed down from one generation to the next and and on average an affected person will have a 50 50 chance of transmitting it so 50 of the people who are at risk of inheriting the disease will get it on average with autosomal recessive inheritance some people talk about this as having two bad copies of the gene you get one bad copy from mom and one bad copy from dad but from a functional standpoint really the operational definition is that you don't have a normal copy you don't have a backup copy okay that's good that can provide this function that that's missing in the mutated or variant allele okay in an unaffected individual you will have at least one normal copy so that's the criteria for being unaffected is that you have a normal copy of that gene in a carrier the carriers are generally unaffected in recessive disorders and they have a 50 50 chance of transmitting there's a couple of diagrammatic representations of being a carrier and in this slide the dot dot is what is used to represent a carrier for a particular disorder the last characteristic is that both parents of an of of an affected person are carriers or they can be affected but that's pretty rare so this guy down here is the affected person in this pedigree and by definition both of his biologic parents not as adopted parents but as biologic parents are carriers um and so those are the primary characteristics of autosomal recessive inheritance so let's talk about another recessive x-link recessive and remind you that the x chromosome is the strange beast that's present in two copies in females in one copy in males because males have instead this tiny little guy called a y chromosome which is important for making them male so an affected individual with excellent recessive inheritance has no normal copy are generally males because the male with an x passes on only his x to his daughters and the x is mutated or abnormal all of his daughters will be carriers because he passes on his y to make his sons all the sons are unaffected and can't pass on the disorder and here I have it's that males are affected but rarely females and that's a more complex subject we can go to in the q and a if you want to but the important point is you cannot absolutely rule out some x-link recessive disorders expressing themselves in females the unaffected people have at least one normal copy same as an autosomal recess recessive they are the non-carrier males and most females right the carriers are typically unaffected but there can be subtle manifestations in some disorders and and these are the females or males who have an extra backup copy so males with client filter syndrome or x x y all right and these individuals will transmit the females will transmit at a 50-50 ratio the mother of an affected person so remember in in autosomal recessive both parents of affected had to be carriers in x-link recessive the mother is unaffected the mother of an affected is a carrier but not always and that's a real little tricky thing so if it's a benign condition like I have x-linked color blindness right and so I'm always going to inherit that from my mother and my mother's always going to be a carrier for that when the affected males are such that the affected status prevents them from reproducing then the population dynamics results in high frequency of new mutations and so you can predict the mother will have two out of three two out of three of the mothers will be a carrier but one of three out of them won't be so you may actually have to test mother to determine whether or not she's a carrier in x-link recessive disorders all right how about y-link there are some y-link disorders they're quite unusual because most of what's on the y chromosome is junk okay there are there's there's the the male determining region in a few things and then a few genes that are on the very tip of the y chromosome that are also on the very tip of the x chromosome that are called the pseudo autosomal regions because they are copied on on both and act just like autosomes all right mitochondrial inheritance and I think we're getting to the end here is in both sexes are affected there's a lot of variable expression the mitochondria we're talking about inherent inheritance of the small round circle of DNA which is intrinsic to the mitochondria and encodes some of the mitochondrial genes others are encoded in the nucleus of the cell and are migrated into the mitochondria it has also vertical transmission but it's maternal lineage only and never transmitted for males because the mitochondria are only transmitted via the egg never via the sperm and the other way you can notice mitochondrial inheritance is that it the phenotype in deals with the energy intensive organs because the mitochondria mitochondrial deficiency is mitochondria energy producers for the cell and cells that consume a lot of energy are the ones that are going to be sick fastest and then the last sort of pattern of mutation is de novo or new mutation new variation in the family there's no family history in the dominant situation it's not present in DNA of either parent when you go looking and is generally considered to be supporting evidence that the that the variant that is new is it could be pathogenic if it's associated with a disease it's not iron clad but it is supportive evidence so I'm going to come back to the case study and just summarize so Roger is a short slow kiddo with bigger head he has a family history where his father has some weakness and pain and is a bit short he had a genetics consult which found some phenotypic differences in skeletal dysplasia and the genetic test was done that showed that showed a heterozygous variant that predicted a protein difference of aspergine 540 to lysine so we'll go through now the the questions if I can get that click to work why did the cd new variants c 16 20 c to a and c 16 20 c to e both result in the protein same protein variant how many copies of the hypo hypochondroplasia variant to leo were found how can rogers diagnosis help his father only some persons with hypochondroplasia have intellectual disability and why did the doctor choose this particular approach so the answers are that the c dna I'm sorry that these two variants occur at the same position one going from c to a and the other from c to g and as we talked about earlier you can have get aspera gene to lysine by going from c to a or c to g due to the degenerate coson codon in the genetic code how many copies of hypochondroplasia variant to leo were found is this a dominant recessive disorder so there's one variant to leo and one normal leo in the atb p binding segment of the fgfr three tyrosine kinase domain so the test result was heterosagus for the disease associated variant meaning there's one disease associated variant and that's compared with a normal reference sequence hypochondroplasia is a dominant disorder both by inference from pedigrees and by the biologic basis which is a constituents constitutive activation of the receptor tyrosine kinase have gained a function okay how can rogers diagnosis possibly help his father father short and stocky bill suggests that roger may have inherited hypochondroplasia from him a significantly increased incidence of spinal stenosis and bony compression occurs in this disorder so rogers diagnosis might lead to diagnosis and father and detection of and surgery for spinal stenosis so rogers father might recover from his pain and disability which would be a really great thing and this i put this in here as an example of how genetic testing is in some ways in one very important way very different from regular kinds of laboratory testing and that is it has potentially important carry on implications for other family members so its value actually is not just to the patient but to the entire family so the next question was only some persons with hypochondroplasia have intellectual disability and what two phenomena explain this one would be variable expressivity so we did talk about that so that's where one individual with the disorder may have a certain pattern of expression certain pattern of features whereas another individual even the same family may not have the same pattern so that's variable expressivity it makes it difficult sometimes to determine when you take a family history whether whether there's really something going on in the family that's dominant or not because they have different manifestations so for example in a in a in a BRCA family you may have people with breast cancer that but other people with with ovarian cancer only and in the early days we didn't recognize that those were part of the same disorder and so we didn't recognize that they needed to be counted together in terms of a figuring out whether this was a dominant at risk inherited family so the other type thing phenomenon is genotype phenotype correlation and we mentioned that so the particular variant disease associated variant in this case of hypochondroplasia is associated with a higher incidence of intellectual disability not a hundred percent but a higher incidence of an intellectual disability than some other variants that also cause hypochondroplasia all right so the last one was about why did why didn't he or why didn't the doctor order all these x-rays instead and and the answer is that the complete this whole complete radiologic survey is necessary to diagnose hypochondroplasia and the radiation exposure is significant and even then radiologic diagnosis can be difficult and depending on the experience of the radiologist so I'm getting a signal I need to wrap it up so the second point is that gene test is less expensive two to three hundred dollars for a single exon and the tested for variant is associated with intellectual disability so if we find this variant then we believe we've explained his intellectual disability and we don't have to look deeper to try to explain it say well he has a skeletal dysplasia but we haven't still explained his intellectual disability we can probably stop there so that's a that's a plus so I'm going to move on because we need to get to questions and so I'll thank you for your attention and for your patience and we are really interested in your feedback since we're starting this as a pilot and to see how useful this kind of thing is and whether there are changes in the format or the approach that can be useful to you guys and these are just some resources that I used in the case case study development and I'll stop there


I'll now share my screen just one second. Okay. Okay, so basically as Helen mentioned in this very good introduction is what we tried to have in this project as part of STREND2 basically, we tried to organize for experiments in the sense that we tried to see how can we have an experimental introduction of RRI and open science into organizations using the quadruple helix approach. And we had four very good use cases from which two you will see today after I finish this presentation is very short introduction over the experiments. So one of the experiments was focused on completely redesigning the R&D unit by infusing RRI principles. Another one was on photonics and optical monitoring and basically these two will be presented later on today. The third one was on material science and the fourth one on text and data mining as all these main sectors are key sectors for infusing RRI into organizations as it was identified by our skill gap analysis performed in the beginning of this project. Now all the four experiments have followed a standardized approach. So we have something called an experiment organization methodology that you can see here on the screen. So this specific methodology was done in co-creation with the project partners and it is based on various stages starting from an appraisal stage where we try to identify and map on the RRI pillars that each experiment should focus upon as well as to identify internal and external stakeholders and consult them in order to trigger the quadruple helix collaboration. Then we had the design stage where we set the objectives for each experiment and prepared the specific collaborative paradise and approaches that allows the quadruple helix co-creation required to infuse RRI into an ongoing or new research project from those organizations. And then we had the implementation stage that you will see a bit more examples today from the next two presentations how this went and utmost and the most important part of this we had a very detailed and unified measurement and monitoring of the experiment in the sense that we have defined a very detailed list of indicators that allow us to see to what extent RRI and open science was embedded in organizations in organizational streams and to what extent this has triggered institutional change and policy changes inside organizations in terms of ensuring a proper co-creation with the external quadruple helix stakeholders because at the end of the day the whole goal was to see if this embedment is feasible at the end of the day and the answer is yes as you will most likely get access to our comparative and final reports from the experiment and you will see the main lessons learned from this process in the sense that even though in the beginning okay I can say it in a nutshell even though in the beginning there was a lack of major lack of awareness of RRI in these organizations but at the end of the experiments after the two years that we started talking about this type of processes organizations understood the importance and the benefit that RRI does bring to each type of stakeholders and therefore they are taking active means in order to push it forward and to require more funding to help the organizations properly embed and sustain RRI in all of their future operations and it doesn't necessarily have to we don't talk only about universities we talk about associations industry and all type of stakeholders that saw the real benefit of RRI but now without more focus on the theory behind this I would like to move towards the two two demonstrations that we use cases the experiments and I think we will start with the with Raquel right we'll start with the first experiment presented by Raquel focusing on the RRI model so I'll stop sharing my screen


Psych2Go is a digital media organization that raises mental health awareness by presenting psychological topics in a digestible and relatable manner. Please, share our content with those who need it. You know that feeling when your stomach drops, when you ride a roller coaster that's just about to fall over the edge, or feeling your heart beat widely against your ribs so loud you can almost hear it? That's what anxiety feels like, and a lot of people all over the world struggle with it most of their lives. According to a recent survey by the National Institute of Mental Health, it's the most common mental illness with over 40 billion adults in the US alone being diagnosed every year. The American Psychological Association defines anxiety as a future-oriented concern that may lead people to avoid situations that trigger or worsen their distress. Often called the common cold of psychology, along with depression, it's one of the most prevalent and widespread mental health concerns today. Anxiety is an uncomfortable feeling to say the least, but we mustn't let it rent space in our minds, otherwise it can end up taking control over everything, from your thoughts to your attitudes and behaviors. An important first step in overcoming anxiety is acknowledging it and understanding where it's coming from, so if you've been having a hard time figuring it out yourself, here are six of the most common causes of anxiety. One, overthinking, also called rumination in psychological terms. This is when you make a big deal out of everything to the point where every experience and interaction you have starts to seem negative, reading too much into everything from the slightest change in someone's voice to the subtles of facial expressions. It can be enough to drive anyone mad. Sweating the small stuff and never letting anything go can keep you up at night, obsessively thinking about that small mistake you made years ago. Overthinking can make you worry about the most unimportant details and twist everything in your mind into something much, much worse than it actually is. Two, overachieving. While the high of excelling at something can be a wonderful feeling, in the end it's not worth all the anxiety you end up giving yourself in the long run. Overworking yourself and feeling stressed out all the time leads you to becoming more susceptible to anxiety and depression. When you strive for unrealistically high goals, you're only setting yourself up for failure and disappointment. You may feel compelled to busy yourself with work or school all the time and feel guilty about relaxing and having fun. You never feel contented with yourself or what you've achieved because there's always some other mountain you think you need to climb. Three, low self-esteem. In today's day and age, when popularity comes at the price of your privacy, the internet makes it easy for you to feel like you always need to impress everyone. Some people think that their social media presence defines who they are, so the pressure to be accepted and well-liked by others has reached an all-time high. This is probably why having a negative self-image has become one of the most common causes of anxiety everywhere. Insecurity is something that all of us struggle with, but failing to overcome it can cost you a great deal of happiness, energy, and peace of mind. Self-doubt can make the prospect of being judged and criticized by those around you absolutely horrifying. However, caring too much about what other people think and letting this fear rule your life is not healthy. Four, pessimistic thinking. Similar to overthinking, pessimistic thinking is another kind of mind trap most people with anxiety find themselves falling into, a lot of the time. This means you're always worrying about the worst things that could happen in any given situation. Having a negative mindset about yourself, your circumstances, or those around you makes it difficult for you to feel calm because you're forever finding something new to worry about. You can't turn even the smallest inconvenience into a downward spiral of anxiety and depression. It's hard to escape. Five, traumatic events. Every negative experience you may have had in the past plays an important role in shaping your fears and anxieties, even if you don't know it. Our sense of self-preservation is so strong that oftentimes our minds will do everything they can to keep us happy and safe. This can mean avoiding anything that may have previously given us distress or anxiety. In fact, this is one of the most common reasons why we develop phobias. When it comes to anxiety, on the other hand, traumatic events teach us what to fear and be wary of, no matter how irrational it may seem. So if you find yourself feeling anxious for seemingly no reason at all, it might be because you have some deep-seated trauma or lingering issues you still need to resolve. And six, no experiences. Finally, trying new things and stepping out of your comfort zone is another one of the leading causes of anxiety. Certainly, the most positive point on this list. The anxiety you feel here is actually a good sign that you're being brave and making a conscious effort to grow as a person. This kind of anxiety is more of a nervous excitement than a dreadful worry. Change can be scary, especially if it's sudden and stressful, but it's also one of the many constants in life. Learning to embrace change takes a lot of emotional maturity. Of course, the nervousness and worry that accompanies it is only normal. In fact, it can even drive you to do better and try harder if you let it inspire you and remind you of all the possibilities life has to offer. We hope you found this video helpful. Please like and subscribe and keep us alive. As always, thanks for watching.