Child Study Center Grand Rounds 10.26.2021

October 29, 2021

The Power of Gene Discovery for Patients and Their Families - Informing Science and Families

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00:00So good afternoon, afternoon
00:02again and welcome to grand Rounds.
00:06It's great to see so many of you
00:08joining us on zoom remotely.
00:09I hope that there's at least one or two of
00:12you in sunnier climes than here in New Haven.
00:15The only way that I can describe the weather
00:17here in New Haven is a little bit Irish,
00:18so I'm feeling very at home.
00:21And now when we launched this
00:23new series of grand rounds,
00:25we talked about the importance
00:27of building bridges,
00:28building bridges across research.
00:30Programs and clinical programs
00:32within our department,
00:33but also building bridges across
00:36different departments.
00:37Here at Yale,
00:38and I think that's really exemplified
00:40by our next to grand rounds speakers.
00:43So next week we'll hear from Doctor
00:46Marietta Vasquez who will talk to
00:48us about her work to address and
00:50combat structural racism in academic
00:53medicine and medical education.
00:55And today it is our great privilege
00:57to welcome another speaker from
00:59the Department of Pediatrics.
01:01Doctor most difficult who will
01:03speak to us today and Doctor Copas
01:06work really merges his fantastic
01:08and important work in the pediatric
01:11intensive care unit with critically
01:14ill children with some really
01:16elegant molecular biology and that
01:18molecular biology is done in the
01:21service of his patience and his
01:23families who are seeking answers
01:25at a time of a lot of stress and
01:28where their children are being
01:30born and suffering with congenital
01:32malformations and doctor Coco.
01:34Elegant molecular work really tries to
01:36find an answer to why these children
01:39are born with these congenital
01:41malformations and really to try and
01:43determine have medicine can help.
01:46So with that I would ask you to
01:48please join me in welcoming Dr.
01:49Moustapha Coca to grand rounds
01:51into job study center.
01:56Alright. Mask off.
02:01Thanks Karen for that very nice
02:03introduction and and the invitation
02:05to come here to talk to you today.
02:08You hear me OK, Yep, alright,
02:11so let's get started.
02:16OK, uh, no I don't have any.
02:18Well, I have one conflict.
02:19It's not at all relevant to the talk
02:21that I'm going to give today. See here.
02:24OK, so this is the outline of my talk.
02:27I I'd like to introduce the child
02:30with critical illness and our
02:32our efforts to sort of identify.
02:36Genetic changes gene changes in the
02:38genome that might address why these
02:40children have critical illness,
02:41so we'll talk about genomic testing
02:43and the different kinds of genomic
02:44testing that we could do at Yale,
02:46both clinically and in the research realm
02:48and and we'll talk about our program,
02:50called the Pediatric Genomics Discovery
02:52Program, really a translational research,
02:55basic science and clinical translational
02:58program in order to understand the
03:01causes of children critical illness.
03:04Uh, then it then that that's
03:05the first part of the talk,
03:07and then I'll talk about 3 short stories,
03:09which include basic science,
03:11and I've chosen these three
03:14stories more for their.
03:15I think clinical relevance,
03:17and in the way they informed our
03:20work with patients as opposed
03:22to basic science discoveries.
03:23So I hope that you'll find
03:26them very interesting and and.
03:28And for us it's been really powerful
03:30because they've been so after the
03:32results that we've gotten from them have
03:34been so applicable to patient care.
03:36OK,
03:36so you know this is this is the
03:38kind of care that we provide in in
03:40pediatric critical care.
03:41You can see there's this tiny baby
03:44surrounded by enormous amount of machinery.
03:47And what we find now is that you
03:49know a huge cause of the reasons why
03:51children are coming to the pediatric
03:54ICU into my clinical care is because
03:56they have variations in their DNA that
03:59can lead to errors and development.
04:01So certainly that includes birth defects
04:03such as congenital heart disease,
04:05but there are so many different kinds
04:06of birth defects that are out there and
04:09and and as well as seizures or shock.
04:11I mean there's just a host of different
04:13reasons why they may present to the
04:15ICU and present with such illness.
04:17If they require really lifesaving measures.
04:21So what I'd like to say to you,
04:22maybe one of the key take home message
04:25messages today is that the huge impact of
04:28of these rare life threatening disorders so.
04:31If you really combine rare disorders,
04:34rare genetic disorders,
04:35it's really a huge percentage of
04:37the population that are affected.
04:39In fact, if you just consider birth defects,
04:42this now is the number one cause
04:43of infant mortality in the US,
04:45and so it's.
04:46It's really a huge effort.
04:47And really,
04:48what what these all are is a is a huge
04:51constellation of many rare disorders and
04:54rare disorders are challenging because
04:56one they're difficult to diagnose.
04:59And they're difficult to diagnosis.
05:01So oftentimes what we do is
05:02give them very uninformative,
05:04descriptive diagnosis, right?
05:05So in the context,
05:06congenital heart disease,
05:07we might say that the child
05:09has tetralogy of flow,
05:10which is sort of an explanation
05:11of the Phoenix,
05:12or is a description of the
05:14phenotype that you see,
05:15but really doesn't tell us
05:16molecularly what's going on.
05:17Same thing with the term seizures, right?
05:19I mean the child is having convulsions,
05:21but we don't understand molecularly
05:23why that's occurring.
05:24And So what we really want
05:26to understand is what's
05:27really wrong, and that's important
05:28for prognosis, right? Because?
05:30Oftentimes we take all children
05:32with tetralogy of flow and lump
05:34them together when in fact
05:35they present quite differently.
05:37Uh, or they can have a outcome
05:39that's quite different and so really
05:42understanding that molecularly is important.
05:44And then finally,
05:45one of the challenges that we have
05:46with rare disorders is that families
05:48often feel very isolated and desperate
05:50for answers and and they can't get
05:51them as critical care physicians.
05:53These these patients present with unexpected.
05:57Clinical courses and and and and
06:00so we don't know how to manage
06:02them in the best way possible,
06:04which is very frustrating to the clinician.
06:06But you can imagine the terror that
06:08leads to the family so many of them are
06:11asking why did this happen and will
06:13my next child be affected in in in?
06:15These can be really challenging questions
06:16to answer if you don't know what's
06:18going on molecular and so one of our
06:20exciting things that have happened
06:21in the last ten years is that next
06:23generation DNA sequencing has come
06:25through and we have now the opportunity to.
06:28Potentially asked the
06:29question what's going on?
06:31OK, so to that end we have created a hill.
06:35The pediatric Genomics Discovery program,
06:37which is a translational research program.
06:39We're particularly interested in rare
06:41disorders that lead to unexplained
06:43critical illness and and a lot of
06:45those patients have birth defects,
06:47but we've actually branched out to
06:48a number of other disorders as well,
06:49such as seizures or shock, for example,
06:52that presents that we can't explain
06:54by an infection,
06:56and then we leverage next
06:57generation technologies,
06:58particularly whole exome sequencing.
07:00To identify candidate genes
07:02that might explain the disorder.
07:05And often then we also launched
07:07right into the lab to do basic
07:09science research and see if we
07:11can understand the path,
07:13the pathology or the the the the
07:17the molecular biology that's
07:19that's leading to the illness.
07:21So we have a couple of different
07:23aspects of the program.
07:24First, we have patient oriented care,
07:26so we have a collaborative outpatient
07:28clinic with the Department of Genetics.
07:30They're here right now.
07:32Consultations from the outside.
07:37We also have a basic
07:38science research that we do,
07:40so we certainly do a research oriented
07:42bioinformatic analysis and then we
07:44ourselves actually do a number of
07:46experiments in my lab as well as
07:49collaborative efforts with Yale
07:50investigators and outside researchers
07:52in order to investigate the molecular
07:54mechanisms that lead to disease.
07:56And ideally, then we return these
07:58results to families and and referring
08:00providers and all of this work
08:02is sort of coordinated through an
08:04exciting meeting that we have.
08:06Which we called Genomics board.
08:07So this is a multidisciplinary
08:09meeting where we invite clinicians.
08:12And the by informatics team as well as
08:14the basic science scientist to all present.
08:17It is at one meeting.
08:20Which requires a lot of coordination.
08:22But then at that meeting we all
08:24discussed the results as well as the
08:26clinical presentation that we've found
08:28to be extremely powerful for all groups.
08:30The clinicians are excited
08:32to see basic research done.
08:33The basic scientists are excited
08:36about seeing a clinical opportunity
08:38to connect with and so this is
08:40actually been a really powerful
08:42force for continuing our research.
08:43And so this is that's been an important
08:46lesson to connect these people together.
08:48And then importantly,
08:49we return results to families
08:50in referring providers,
08:51even if their research results and
08:54and that that has been exciting.
08:55And we've been surprised that it's been,
08:58it's been met with some concerns
09:00which we've pushed through there.
09:03We think it's really important to
09:05consider families and patients is
09:07as participants in the research.
09:09And so we, we,
09:10we work hard to engage them as well.
09:13OK,
09:13so I just want to take one or
09:14two minutes to talk about next
09:16generation sequencing.
09:16The kind of sequencing
09:17that we can do at Yale.
09:18So one of the things that really
09:20a sequencer today is no different
09:21than any other sequencer,
09:22except that it's massively parallel.
09:24So instead of having one sequencer
09:27running and generating sequence,
09:28you have a machine that produces millions
09:31of sequences all at the same time,
09:33and that has made it possible to do
09:35sequencing at really remarkable cost,
09:37so you know we now at Yale have
09:40a number of clinical sequencing.
09:43Efforts that we have.
09:44So for example, in the PICU and NICU.
09:46We are doing a rapid whole genome
09:49sequencing where we can identify
09:51patient and produce genome sequence
09:54and results within five days in that
09:57can often we usually have a clinical
09:59requirement that's that's necessary
10:01that includes Courier servicing, alerting,
10:03Yale Center for Genomic Analysis,
10:05and rush sequencing to really
10:06push this as fast as possible so
10:09that it could be immediately.
10:12Return back to the clinic.
10:15We also have clinical whole exome sequencing
10:17where we just sequence the exons right
10:19as opposed to whole genome sequencing.
10:21Here, sequencing just the exons and
10:23there were trying to stab establish
10:24causes of genetic disease and one of
10:26the challenges whenever you do clinical
10:28Hawks and sequencing is you're often
10:30finding variants of unknown significance
10:32and this is a big challenge and one of
10:34the things that we do on a research
10:36side is try to convert variants of
10:38unknown significance to significance
10:39right to do scientific studies in
10:41order to investigate them and and
10:43that again is another basis.
10:44For the pediatric generalists very program,
10:46it's something we'll talk about today.
10:50OK, so you know we have exciting way forward.
10:53This is sort of the path that we've
10:55created for the pediatric Genomic
10:57Discovery program where we have
10:58my colleagues Tsakani and Lauren
11:00Jeffries who are reviewing children's
11:03diseases and Monica Constantino,
11:04who collects DNA and consents families.
11:09DNA is then sent to Yale Center for Genome
11:11Analysis and Wage in who is our bar.
11:13Informatician wizard analyzes that DNA
11:15and then returns results to all of us.
11:19And then my team.
11:20He also works to do basic science
11:23research to try to identify molecular.
11:27So sort of bring those molecular
11:28changes to the lab to try to understand
11:31the impact of those variants,
11:32and then you know soccer in his team.
11:35Go back to return any of those
11:36results back to the family,
11:38and so it's actually become a very
11:39exciting team and and we'd love for
11:41you guys to participate as well.
11:42So if you have patients that you
11:43think could benefit from our program,
11:45we'd love to hear from you and I'll give
11:47you those contact information in a minute.
11:50OK,
11:50so let me now start with three different
11:54stories that I'd like to tell you about.
11:57In in,
11:57in each of these stories are they
12:00clearly have clinical impact and and in
12:02each case I'd I'd like to point out the
12:05reasons for why I'm presenting them today,
12:07so one of them is about
12:09a gene called Dell G5.
12:10In that case,
12:11we had a clear need for the bench
12:13in in studying those variants,
12:15but we then have another gene called a RS2,
12:18where we actually could lead to
12:20an intervention.
12:21Actually, that the family initiated,
12:23which was extremely exciting,
12:24and then our full I'll tell you about.
12:27A story where I actually have one of
12:29the rare times where we actually have
12:32the story as it comes particularly
12:35straight from the mom and her
12:37how it's been impactful for her?
12:39So those are the three stories
12:41we'll talk about today.
12:43OK,
12:43so this is how often are
12:45our genomics board starts?
12:46We start with the case so there's
12:48a fetus with multiple anomalies
12:50that have been presented to us
12:52from the maternal fetal medicine
12:54group that there's a 21 week.
12:56I just just just stational
12:57age fetus that has extra
12:59dakhli and club feed.
13:00You could see the X rays here that
13:02show that there's missing digits.
13:04The child also has a VSD and
13:06extremely cystic kidney,
13:07so these are the kidneys here and
13:09you can see this one is extremely
13:11cystic with all these cysts here.
13:13And so when sequencing this child,
13:14we actually found a de Novo mutation
13:17in DL G5 and so DL G5 has never
13:20been associated with disease before
13:22and so we were curious as to what
13:25that de Novo mutation really meant.
13:27And and and one of the things that has
13:29been shown in the literature is that
13:31Dell G5 may have a role in in Syria,
13:33although that's not been well worked out,
13:35and so, you know,
13:36looking at these phenotypes,
13:38polycystic kidney disease, limb defects,
13:41we certainly were thinking that there
13:43might be a defect in cilia signaling.
13:46And so we promptly went to frogs.
13:48So in my lab we use frogs as a model system.
13:52So frogs are extremely efficient
13:54for studying a gene function,
13:56and that's mainly because we can generate
13:59frog embryos in the 10s of thousands a day.
14:02So we can just basically,
14:04frogs were, oddly enough,
14:06the first pregnancy test.
14:08So if you take HCG and
14:09inject them into frogs,
14:11you get eggs the next the next day,
14:13and so we can produce eggs in the
14:15thousands whenever we need them.
14:16And then by doing in vitro fertilization,
14:18get hundreds of synchronized embryos.
14:21And so in this case will inject a
14:23DLG 5 morpholino antisense oligo
14:26that blocks protein translation
14:28and ask the question what happens.
14:30So it's also exciting about frogs,
14:32is that they're extremely fast,
14:34so you can go from a cleavage stage
14:36embryo that's just been fertilized and
14:37then two or three days you can have a
14:40tadpole that has a functioning kidney
14:41and ask the question in this case,
14:43what has happened to the kidney?
14:45Here's the kidney tubule here.
14:47In purple is is the Floyd in standing
14:49that shows the tubule of the kidney.
14:51This is right where the glomerulus is,
14:53and acetylated tubulin marks the silliest.
14:55So all this this this screen inside the
14:58tubular actually cilia that are in the.
15:00In the lumen of this tubule,
15:02and when we knocked down DLG five,
15:04you could see that indeed we can
15:06start forming cysts just like
15:07we did for the patient,
15:08and the effect you also see a
15:10rather dramatic loss of cilia,
15:11suggesting that you know indeed
15:14this could be a silly opathy that
15:16is happening in the patient,
15:17and that the cystic part of the kidney
15:20is something that we can very readily
15:23recapitulate in the frog embryo.
15:25Now one of the exciting things
15:26about this kind of research is
15:28the opportunity for collaboration.
15:29Now,
15:30what we've identified is a single
15:31patient with a denovo mutation in DL,
15:33G5, and,
15:34and while it's exciting to see that in
15:36this frog model we can recapitulate
15:39the polycystic kidney disease.
15:41One of the challenges is always
15:42is what it you
15:43know. Is this also potentially
15:45just irrelevant right?
15:46Is it just something finding and?
15:47And maybe this doesn't really matter
15:49to the patient and so one of the
15:50things we can use is this tool called
15:52gene matcher which is a website
15:54that connects researchers that and
15:55what they do is they basically enter
15:57the gene that they're interested in
15:59because they have a patient and then
16:01once you everyone enters a gene,
16:03that sort of sends emails to
16:04everyone saying hey,
16:05would you guys like to connect and
16:07so we did that and we identified
16:09a number of additional patients.
16:11Uh, including one patient that has a huge,
16:14so your ureter probable junction,
16:17obstruction hydronephrosis so kidney defects.
16:20Also us maybe a particularly abnormal foot.
16:25We also found patients that has
16:27steroid resistant product syndrome and
16:29increased ventricles on ahead and and
16:31then two patients at hydrocephalus,
16:32which is this disease where you have
16:34swelling in the brain because the
16:36CSF circulation is not normal and
16:38all of them had mutations in DL,
16:40G5 in fact and of course when we
16:42first saw this we're thought what
16:44in the world does this mean right?
16:46I mean clearly there's kidney abnormalities
16:48but then also hydrocephalus and in
16:51fact the researchers before us were
16:54the paint had patients with this huge.
16:56Construction hydrocephalus.
16:57In it they actually thought they
16:58had nothing to do with one another,
17:00and that maybe there is something
17:01else going on.
17:02But when we also had the hydrocephalus.
17:04Sorry, the polycystic kidney disease.
17:07Then it became more clear that maybe
17:09all of these phenotypes might be
17:10reflective in the fact that you
17:12have a silly a defect.
17:14Because in all cases have been shown to
17:16be important for all of these freedom types,
17:19so so we actually thought that maybe
17:22this was connecting and and and it
17:24led to some some questions next,
17:26which was, you know what?
17:27What's going on with all these different
17:29variants that we were identified?
17:31So the variant that we found in our
17:34patient was this Arch 249 missense mutation.
17:36There was also a termination codon
17:39and and the other thing is that you
17:40could see is that our our patients
17:42seem to have the most of European type.
17:44Really, you know.
17:45Is a fetus was presenting while
17:46many of these other patients were
17:48were not quite so severe.
17:49So what's going on there?
17:51And so we had some key questions
17:53there with we thought that the we
17:56could answer in the laboratory.
17:58One of which is that we could clearly
18:00see a kidney phenotype in Xenopus.
18:02The question is,
18:03could we see a hydrocephalus phenotype
18:05'cause this was something else that we saw?
18:07And then you know the severity of
18:09the symptoms seemed quite different.
18:10Ours had cystic kidneys and severely maletis.
18:14Others had hydrocephalus and others,
18:16yet had nephrotic syndrome or or
18:18UPJ obstruction which is really sort
18:20of a difference.
18:21And so we wondered if what we
18:24really need to do is see if these
18:26variants of unknown significance right
18:28which all of these were characterized
18:30at this point might also give us some
18:33insight as to the severity of the phenotype
18:35and so this is sort of the genotype.
18:37Phenotype correlation that
18:38people are looking for,
18:40and we thought we would do some some
18:42investigation into what's going on there.
18:44But first, let's look at this hydrocephalus.
18:46You know, could we actually see
18:48hydrocephalus in our frog model?
18:49And to do that we took advantage
18:51to some of the tools that my
18:54colleague ending in Denise developed.
18:56Which is this this tool,
18:57called optical coherence tomography.
18:59So hydrocephalus is is an abnormal
19:02collection of fluid in the brain.
19:04There's a,
19:05there's a ventricular system that
19:07circulates CSF through the brain,
19:09and when that gets clogged,
19:11the CSF can accumulate and can lead to brain
19:14compression actually can lead to severe.
19:16It can be life threatening.
19:18And so one of the questions is,
19:19could we visualize ventricles in the
19:21brain of the frog and we use this
19:23tool called Oct which is is like CT
19:26scans except rather than using X rays,
19:28it uses light. And so here's a tadpole.
19:31You can see the eyes here.
19:33This is the brain here.
19:34Here's the gut.
19:35And then the tail as it extends posteriorly.
19:37So this is sort of a dorsal view
19:39and you can see when we do OC T you
19:40can actually make sections through
19:42the brain and you can see the entire
19:44ventricular system as this space
19:47here where CSF fluid is accumulated
19:50and if you now take a section you
19:53know along the midline here.
19:54That's what this section is.
19:56So here's the forebrain.
19:57Here's the hindbrain.
19:58This is the brain itself,
20:00and you could see this.
20:00Ventricular system and it's very
20:02cool about this is that while it
20:05can give us sections like a CT scan,
20:07the embryo is like in a CT scan,
20:09completely alive and so we can
20:12actually visualize CSF circulation.
20:14So here's a movie again,
20:15here's the forebrain at the tadpole.
20:17I'm sorry.
20:18Here's the forebrain of the tadpole.
20:19Here's the hindbrain.
20:20You can see the whole CSF ventricle
20:23system here at certain room or a
20:25section sort of going right through
20:27that middle and you can actually
20:29see that there's fluid flow that's
20:30occurring because of the cilia.
20:32That are driving these these small
20:34particles and moving through the circulation.
20:37So really we can really see not only
20:39the size of the ventricles with
20:41CSF circulation and actually we
20:43can even do particle tracking and
20:46calculate velocities of that as well.
20:49And so then the question of course
20:51is do we get hydrocephalus and
20:52so when we knock down DLG five?
20:55You can see that in our control embryos,
20:57the ventricles or a one size,
20:58and they're considerably larger.
21:00And we quantitative this and you can
21:03clearly see that our frog embryos
21:05that are depleted of DLG 5 do indeed
21:08have enlarged ventricles suggestive
21:09of the hydrocephalus that we see in.
21:11In the patients that we enrolled.
21:15OK, so then the second question
21:16is what about these variants of
21:18unknown significance and the
21:19differential phenotypes that we saw.
21:21You know, can we make some sense of that?
21:23So remember, these are all
21:24the different variants.
21:25This is the one that we saw in.
21:26These are the different
21:27ones that are are seen I.
21:29I think these two are more seem to have a
21:33more striking phenotype like hydrocephalus,
21:34while this one was the most mild phenotype.
21:38And what we wanted to do is test
21:39these variants and see if they
21:41had also impact in our system and
21:42one of the things that we can do.
21:44That's pretty cool in frogs is
21:45that we can fertilize embryos and
21:47inject things at the one cell stage.
21:49If we do that,
21:51the whole embryo has a depletion of dog 5.
21:55Then what we can do is wait at the two
21:58cell stage because of the two cell
22:00stage we can inject drug five RNA.
22:02So the human morning expecting
22:04that one side of the embryo will
22:07rescue while the other side will
22:09be depleted of the LG five and then
22:12use that depleted side that rescued
22:14side compared to the depleted side
22:16and actually make a ratio.
22:18So here you can see that what we're
22:21measuring is the kidney tubule diameter.
22:24And we're measuring one side
22:26versus the other.
22:27So here you can see that normally if we
22:29just inject DLG 5 morpholino and a mock RNA.
22:32So GFP for example,
22:34the the ratio is about 1,
22:36right?
22:36So that the depleted sides basically
22:39on both sides are not rescued.
22:41But if we inject DLG frog morpholino
22:43and then on one side injected
22:45DLG 5 M human M RNA,
22:46you can see that we get a rescue
22:48right the the size of that tubulin
22:50on the rescued side on the side
22:52with where we've injected human
22:54DLG five is actually quite smaller,
22:56and so the ratio becomes less than one.
22:59On the other hand,
23:00if we take this Arch 166 histidine marker,
23:02you see that there is no rescue
23:04that's occurred suggesting that this
23:06variant actually is detrimental to function,
23:09and so maybe that would suggest that This
23:11is why this this patient has hydrocephalus,
23:14for example.
23:15In fact, it was very striking.
23:17Is is these patients were homozygous for
23:19the variant and so that made sense that
23:21they had a loss of function of the LG 5.
23:23But we're more our patient was de Novo,
23:24so it had one copy that was abnormal.
23:26One copy that was normal and
23:28in fact you could see that.
23:29When we deplete,
23:30when we use this variant in our assay,
23:33it actually harms the size of the tubule,
23:36right?
23:36The tubule actually gets more dilated
23:39by overexpressing this variant
23:41completely opposite of the rescue.
23:43Really suggesting that it could
23:46have a dominant effect in the sense
23:49that this this this this sorry,
23:51this variant,
23:52even if it's in a in a region
23:54that is is not a known domain.
23:56It actually really harms
23:58the function of the protein.
23:59Literally giving it a what we call
24:02a dominant negative phenotype.
24:03And then interesting, this last variant,
24:05which sorry, this is a typo.
24:07It should really be this glycine 1509.
24:09Leucine actually has relatively
24:11mild loss of function.
24:13You could almost see that it kind of rescues,
24:15really suggesting that maybe this
24:17variant is not so a strikingly harmed,
24:21and in fact that makes sense,
24:22because that these this variant
24:24was identified in those patients
24:25that had the mildest phenotype.
24:26So again,
24:27this is the kind of assay that
24:29you can do that can really help
24:30you connect the Geno types that
24:32we're seeing with the phenotypes.
24:33And so that was that was exciting
24:35to us and really sort of highlighted
24:37the importance of of bringing
24:39this work into the lab.
24:43OK, so one of the things I'd like to
24:45summarize at this point is that we do
24:48have clinical genetic testing at Yale
24:49and like it is in many places and that
24:52could be used to a clinical diagnosis.
24:55And there's a lot of types
24:56of genomics that we can use.
24:57So if there's a patient with real
24:59critical illness that we need
25:00to make a diagnosis quickly,
25:01there is the option for rapid
25:04whole genome sequencing,
25:05which you know it's more expensive for sure,
25:07but we can then also do clinical
25:09exome sequencing and and and
25:11this kind of information.
25:12Can get right into the medical record.
25:15Then one of the things we can
25:16do is that if in these sorts
25:17of strategies were identified,
25:18variants of unknown significance,
25:20we can try to discover that
25:21significance by going into the lab
25:23and and that's where our pediatric
25:24genomics Discovery program is working.
25:26Very hard to do.
25:28This is the power of animal model testing.
25:30It allows us to understand the biology
25:33and tested the US is for a phenotype,
25:35genotype correlation and just to see
25:37if they are actually dysfunctional.
25:40Now one of the other things that was
25:42interesting to do is because we then
25:44identified as cilia phenotype in our fetus,
25:47the family decided to terminate that
25:49based on the severity of the phenotype.
25:52But we took some of those tissues and
25:55asked the question can we see defects
25:57in cilia and those fetal tissues,
25:59and in fact we did.
26:00We definitely saw lots of silly and the
26:02key I don't have time to show you that data,
26:04but we did.
26:05But interestingly we saw totally
26:07normal silly in the trachea.
26:09Suggesting that this gene clearly has
26:12effects on certain cilia and not other cilia,
26:15and so again this is an Ave that
26:17we're now starting to investigate.
26:19What?
26:19What is this silly a predilection
26:21for DLG 5 and and and that then,
26:24is really the launch of a basic
26:26science study.
26:27And importantly,
26:28we can return these research
26:29results to the patients.
26:30You can imagine for this family
26:32that we saw here at de Novo
26:33mutations really would suggest that
26:35it's pretty unlikely that they'd
26:36have this phenotype again.
26:38Of course, you never say never in genetics,
26:40but it's really powerful to know.
26:44OK time yeah. OK, good so uh next talk.
26:50I'd like to talk about a RST which
26:52actually led to an exciting intervention
26:54that was really driven by the family.
26:56So there's a young couple
26:58that plans to have children.
27:00Mom has some fertility issues,
27:02so you can see that she lost two pregnancies.
27:06Then the child that we first met had
27:09some polyhydramnios at 35 weeks and
27:12some fluid around her pregnancy and
27:16then was born at term after a C-section.
27:19In the delivery room,
27:20the baby immediately had severe hypoxia
27:23and was promptly intubated and ventilated.
27:26But despite all of their
27:27efforts at resuscitation,
27:28the baby died within an hour.
27:30Really sort of a severe effect,
27:33and in fact, on autopsy.
27:34It was really unremarkable except
27:36for the striking finding that
27:38there were very hypoplastic lungs.
27:41Normally the weight of the lung should
27:43be about 53 grams at birth and these
27:45were only 14 grams or very hypoplastic.
27:48They had a second pregnancy and
27:50had a healthy girl and then hoping
27:52to expand their family further.
27:54They had another baby that unfortunately
27:56passed away so that third pregnancy
27:58was smooth until birth again.
28:00You can see that the baby boy
28:02had severe hypoxia,
28:04was then intubated and ventilated
28:05again was unable to be resuscitated
28:07and again they could see pulmonary
28:09hyperplasia and this is the X ray.
28:11You can see that there's just literally
28:13no lung tissue there, and an autopsy.
28:15You can see the heart normally,
28:17but where you should see.
28:18His lungs, it's just empty, right?
28:21There's no lungs there.
28:24And so we did exon sequencing and
28:28identified a variant in error 2.
28:30These are quite rare.
28:32Not not entirely missing
28:34from the populations.
28:36But you could see that father was
28:38heterozygous for this variant.
28:39Mom was Heteros Igas and his and the
28:41affected brother of the program that
28:43we studied was also carrying both.
28:44So his compound heterozygotes for
28:46this error is too and I think to
28:49look at the pet and importantly the
28:51affected brother was also hit but his
28:53his healthy sister was heterozygous.
28:55So really the genetics make sense.
28:57It looks like this.
28:58So the mother and father are
29:00heterozygous for these two variants.
29:03Both affected children are compound.
29:06Compound heterozygous while the
29:08healthy child healthy girl is is is
29:11is has the same genotype as mom.
29:16So, uh, you know the family
29:17very much wanted to have a, uh,
29:20expand and have more children.
29:22And so, uh, we started wondering how
29:25relevant this arrasta mutation was.
29:28So RS2 is a protein that's involved
29:31in mitochondrial protein synthesis.
29:33It's a T RNA synthesis.
29:35And we know mitochondrial diseases can
29:37certainly cause brain, skeletal muscle,
29:39heart and kidney defects,
29:40but no one had really identified
29:42them in pulmonary hypoplasia.
29:44And remember,
29:44all of the other organs were normal,
29:46and so we weren't sure what to
29:48make of that for this family.
29:52And in fact, uh, uh,
29:55most of the there was a few reports
29:56on areas to the suggested that
29:58the maybe the pulmonary hypoplasia
29:59was due to cardiomegaly.
30:01But again,
30:01in in this in the patient that we saw,
30:03there wasn't any evidence of cardiomegaly.
30:06And in fact,
30:06the variants that we've seen
30:08are present in the population.
30:09There was another report with
30:11exactly the same variance.
30:12This R.
30:13592 W in in this frameshift,
30:16in an infant that died but from
30:19cardiomyopathy without pulmonary hyperplasia,
30:20and so trying to get at the
30:22relevance of these variants for
30:23the family was a bit tough.
30:25But then two siblings with Arrows 2
30:27variants were also published that did
30:29have primary pulmonary hypertension,
30:31and so this was very reassuring to us.
30:33Then maybe these errors 2
30:36variants are relevant.
30:37And so we wanted.
30:38So we communicated all these results to the
30:40family and wondered where to go from here.
30:42Well,
30:42one of the things.
30:42Of course we can do is we recognize
30:45that mitochondrial genes have very
30:46highly pleiotropic phenotypes,
30:47partly because of the inheritance.
30:50And this is always the challenge
30:51of rare diseases in small numbers.
30:53So we discussed these research
30:54with jobs with the family.
30:56And they were extremely grateful.
30:59I also had a strong desire to
31:01expand their family and they
31:02were planning to have another
31:04child anyway because they have us
31:07incredible health care system.
31:08They actually convinced their
31:09health care system to do pre
31:11implantation genomics so they
31:13actually did in vitro fertilization,
31:15identified those embryos that
31:17were wild type ferreras too,
31:19and just implanted those embryos.
31:22And have to admit that was
31:23a bit terrifying for us.
31:24'cause you know,
31:25there's just so few patients with this,
31:28we weren't sure if there S2 was really.
31:32Causative gene here.
31:33And so we counseled them and said look,
31:36you know we could be wrong you
31:38could have wild type for us too
31:41but still have the disease and they
31:43understood that and and said look,
31:45we're going to have another child
31:46anyway and we feel this is important
31:48information we're not willing
31:49to take a chance otherwise.
31:50Our chance is one in four anyway.
31:53And so we hope that this would improve
31:55our chances and so knowing that we
31:57were reassured and then happily.
31:59Uh, this is my hip, a sort of OK picture.
32:03You can see that there's a
32:05beautiful baby girl there,
32:06and so it was really
32:07exciting to see the family
32:08be able to take advantage of of
32:10some knowledge that we gave and and
32:13hopefully that led to this healthy baby.
32:15And instead of the sort of the
32:17challenges that they had previously.
32:21OK, so the summary of Part 2 is that genetic
32:24testing can be extremely powerful, right?
32:26And the ability to make a molecular diagnosis
32:29immediately opens up the things that you
32:31can do and opportunities for management and
32:34and I think that's that's really important.
32:37It also is important to return research
32:39results, and we really view patients
32:41as participants in the research,
32:42not subjects, and so that's challenging.
32:46In fact, we've faced some criticism from some
32:48of our colleagues that returning research.
32:51Results is challenging and and
32:53can be confusing to patients and
32:56so many people don't do it.
32:59Or we felt that it's really critical
33:00to return those results, because,
33:02again, we sort of view these
33:04patients as partners in research.
33:06And so we work hard to make sure that
33:09their information is is returned to them.
33:12It's particularly important because
33:13these are rare disorders, right?
33:15And so you know,
33:16it's not like there's a large
33:17cohort of these patients that they
33:19can use that kind of information,
33:20and so returning results.
33:21In these rare cases,
33:22is really powerful.
33:25OK, so in the last story here in the
33:28last 1015 minutes I hope to finish.
33:30I'll tell you about a last gene and
33:32this is exciting for me to share
33:34with you because we actually have an
33:36opportunity to talk to or hear from
33:38the mother of the patient involved.
33:41OK, so case three is lung disease
33:44in a toddler, right?
33:45So there's a young boy,
33:47so this is the patient that was
33:49referred to us who died in 18
33:51months from severe lung disease and
33:53and and without any cause was on
33:55actually on his way to get his lung
33:57transplanted and then passed away.
33:59He had an older sister who died from
34:02a similar mysterious lung disease at
34:0426 months and and and had an older
34:07brother who was nine year old and perfect.
34:10Perfectly well.
34:11What's striking about this story?
34:12Story is.
34:13When our patient died,
34:15mom was pregnant with another baby and
34:17so you can imagine what she must be thinking.
34:19I've just lost two children
34:21at 18 and 26 months of age.
34:24What's going to happen to this baby right?
34:26And so it's it's really a striking
34:29story and and what's also powerful
34:31is that when this child Sister died,
34:34the parents were told they would
34:35never have another child with
34:37this terrible disease.
34:38And of course,
34:39whenever you say that you're always wrong
34:41and so one should always be careful.
34:43And so, of course.
34:44They had another child that passed away
34:46and now you can imagine her terror on
34:48what's going to happen to her 4th pregnancy.
34:51So we did xom sequencing.
34:54We identified a variance
34:56compound heterozygosity,
34:57again for norful.
34:59It's a nuclear preliminary
35:00recognition factor,
35:01like I have no idea how this could
35:04possibly affect a lung disease,
35:06and this is something that
35:07we're now investigating,
35:08but you could see that again.
35:12He became a very strong candidate
35:14because if we look at the family
35:15you can see that mom is heteros.
35:17I guess Dad is heterozygous for this gene.
35:19The brother has the same genotype,
35:21his mom and his hetero zigas.
35:23But both children that passed away
35:25are compound heterozygotes for this
35:27and so I have what we think are
35:30dysfunctional proteins and so of
35:31course the question now is is what's
35:33happening with this unborn child and
35:34and one of the things that I want to
35:36make clear here is that this is one
35:38of those unique situations we can
35:40actually put names to these pedigrees and.
35:42I think it's really important
35:44to understand that these aren't
35:45just squares and circles,
35:46but they're people.
35:48And so the unborn child was named Stone and
35:51I'm happy to report that he was wild type,
35:55and so that was really exciting
35:56for the family and and actually,
35:58he's now few years old and big is a bull.
36:07So, so I'm going to play a video,
36:10so one of the things that happened
36:12is after this case was presented.
36:14I was invited by Diana Bianchi who's the
36:18division head of the NICHD at the NIH
36:22to present at the voice of a patient
36:25which is at their Council meeting.
36:27They present the case and then
36:29bring the patient family there as
36:31well to sort of talk about sort of.
36:34Give them a perspective of what the goals
36:36of the NICHD it's really to help patients,
36:40and so this is.
36:41This is exciting because you know this.
36:42This is actually available to anyone.
36:44On video, and I think,
36:47well I think and and Kendra haifley the
36:49mother of these children will will will,
36:51will talked about her experience.
36:54I think you'll find it extremely powerful.
36:56I'm going to play for it,
36:56play it for you in just a minute
36:59and I think it's rare because
37:00we actually have a video,
37:02but it's not really rare.
37:04And what Kendra is going to
37:05describe to you is something that
37:07many of these families feel.
37:08And there's some points that are
37:10worth pointing out here is that the
37:12diagnostic odyssey that multiple tests.
37:14No answers, referrals, multiple hospitals.
37:16She's gone everywhere to try
37:18to diagnose her children.
37:20The severity of the illness has led
37:22to severe desperation, isolation,
37:24feeling of completely alone.
37:26In fact, you know,
37:27I think you'll find that mom
37:29becomes an expert.
37:30She'll tell you how she
37:31managed her is the oscillator.
37:33I mean,
37:33you know there's many critical
37:35care fellows that joined critical
37:36care that know less about a
37:38ventilator than this mother.
37:40And then there's this incredible
37:41guilt that she feels right, I think.
37:43And that's the part that breaks.
37:44My heart is it somehow she feels
37:46that she's supposed to protect
37:48her child and she's failed and
37:50that's why her child's got sick.
37:52And so I think by providing a genetic
37:54reason we can really kind of address that.
37:57And that's so knowledge of self
38:00is extremely powerful there.
38:03And,
38:03you know,
38:03as being one of these critical care
38:05physicians who sometimes face these children,
38:06I'm not going to deny that it
38:08is powerful for us as well,
38:09because we'd lots of time see
38:11these kids and try to take care of
38:13them and are just completely at
38:14the loss as to what is going on.
38:16And so to provide a a genetic
38:18molecular diagnosis that might
38:20help us is it's really important.
38:22OK, so let me end this.
38:26Here's the video started off.
38:30Please let my name
38:31is Kendra Haifley and I'm just one
38:34of many faces of rare diseases.
38:37I always dreamt of being a mother.
38:40I am the mother to Rome.
38:44I would call the doctors and beg them
38:46to listen, begged them to get her in.
38:49We added lay 6 and had a
38:51heart Cath on the calendar,
38:52but I knew something wasn't right.
38:55Isabel's concentrator malfunctioned
38:56while I was packing to head to children
38:59one morning and she turned blue.
39:01I made sure I had enough oxygen to
39:03get her through the 45 minute drive.
39:06In the ER, as Isabel was
39:07switched to Wall air,
39:08her stats dropped to 58 and
39:10again she turned blue.
39:12I kept begging for anyone to do something.
39:15Find out what is wrong with my daughter.
39:18The next morning I had no idea.
39:22As I was kissing her and
39:24telling her I loved her,
39:26I meant she was going to be OK that
39:27it was going to be the last time
39:29that I would hold my daughter at life.
39:31I never want to let her go.
39:35Isabel did have pulmonary hypertension,
39:37but it was due to her incredibly sick
39:39lungs lungs, so sick that they were
39:41struggling to inflate and oxygenate.
39:43He told me he believed Isabel
39:45would require lung transplant and
39:46that we needed to consider getting
39:48her into a transplant center.
39:49Ourworld immediately shifted.
39:52Isabel was placed on the
39:54oscillating ventilator and had
39:56incredibly high CO2 levels.
39:57I immediately went into shock.
40:00After a trip to the hospital
40:01across the street to get my
40:03stress vomiting under control,
40:04I started researching everything I could.
40:06Everyone was perplexed. Day 12.
40:09We took a turn for the worse.
40:11Is the most P, CO2 and her blood was 212.
40:15ECMO became our life.
40:16Our doctors work to get us accepted
40:17into a transplant facility and we
40:19waited on as well to tell us when
40:21she was ready to come off ECMO.
40:22After 21 days she was ready and she
40:25did great on the conventional vent.
40:27We got accepted to Texas children.
40:29We felt optimistic and hopeful.
40:31New lungs were just weeks away and Isabel
40:33would be able to breathe freely once again.
40:36Transport with Smith.
40:37Isabel was showing beautiful blood
40:39gases and we were able to grab Damon.
40:42My husband had traveled commercial
40:43from the hospital lobby to join us.
40:45As we entered the hospital.
40:47Within minutes,
40:48Texas children was working to transfer
40:50as well to their machines and for some
40:52reason they decided to handbag her
40:54instead of transferring her directly
40:56to the same vent settings as in Omaha.
40:58The 275 pound male nurse not
41:00knowing Isabelle saw her Brady
41:02due to a vagal response,
41:04and he jumped on her to perform CPR.
41:07Isabelle's aorta was torn.
41:11I immediately went out of body and
41:13after 30 minutes our nurse Angel
41:15touched my arm and told me I could
41:17still hold her while she was warm and
41:19I could ask them to stop at any time.
41:22I asked the doctor in charge
41:24how long it had been.
41:25And then I asked them to stop.
41:28And then I asked them to leave
41:29the room so that my nurses could
41:30help me clean up my daughter.
41:33That night my daughter became
41:35a star amongst the heavens.
41:39She was two years, two months, two days.
41:44We held on hope knowing Isabel was our
41:46guiding light and knowing we didn't want
41:47other families to go through our pain.
41:49We started the Warrior Princess
41:51Foundation in honor of her.
41:52Our goal was to advocate for rare
41:54disease research and also to help
41:56families struggling with rare disease.
41:57That February raised over $8000,
42:00which we gifted to for families
42:01to use as they wish.
42:02Knowing the financial struggles
42:03of rare disease having almost
42:05lost everything ourselves.
42:07Just days before I found out I
42:09was carrying our sweet Silas.
42:11The struggles of family faces after losing
42:13a child are unnatural and immeasurable.
42:15We grieved differently,
42:16and we grew apart and
42:18together at the same time.
42:19I knew throwing in the towel was
42:21not an option and I would fight
42:22for my marriage to my husband.
42:24There were days that my husband
42:25struggled so deeply that I believe the
42:27only reason he survived was because he
42:29didn't want to hurt our oldest son.
42:31We wondered why he hadn't gotten sick.
42:34Through meeting with our doctors,
42:35we were assured we could have
42:37100,000 more kids and I would
42:39never have a sick child again.
42:40This wasn't genetic.
42:42This was just a fluke in nature.
42:46Sweet Silas arrived and loved Cuddles,
42:48which were therapeutic and welcomed.
42:50He reminded us of his sweet sister at times.
42:53He was also silly and love Dragons and books.
42:56The days were filled with hope
42:58and it felt like we were healing.
43:00After his first bout with
43:02hypoxemia during an illness,
43:03I requested a console at Colorado
43:04children to meet with one of the
43:06world's leading specialists in
43:07children's interstitial lung disease.
43:09We had an appointment scheduled
43:10less than a month away.
43:11Silas caught RSV and we drove
43:13immediately to children where he
43:15was stayed for the next 14 days
43:16before convincing them to let us
43:18leave on oxygen to head to Colorado.
43:19It couldn't be a coincidence.
43:22This was too similar to Isabel
43:24and happening just months apart
43:26from her first illness.
43:27Stylus had a CT bronk with
43:29lavage and echo done.
43:30He did not have interstitial lung disease.
43:33We were so relieved.
43:34We plan to keep silence on
43:36oxygen to help him grow.
43:38We came home and almost immediately Silas
43:40is need for oxygen continued to increase.
43:43I was confident in my ability to
43:44care for Silas on oxygen with a cold,
43:46but this didn't feel right.
43:48I was told Silas's Echo had been
43:49slightly off when we were there,
43:51so maybe we should have that checked.
43:53I took Silas to children's and once
43:54we were admitted, Silas had an echo.
43:57The pressures in his heart were 90.
44:00Normal is 25 and under.
44:02Silas had pulmonary hypertension.
44:03We decided to attempt attempt at
44:05different way of ventilating and
44:07the moment Bipap was attempted,
44:09stylist turned Gray and his eyes
44:11rolled into the back of his head.
44:13My sister was with me when Silas coded soon.
44:15My whole family was there.
44:16Damon was immediately on a flight home
44:18and once again the nightmare began.
44:20Only this time I was eight months pregnant.
44:23Silas ended up on the oscillating ventilator,
44:25one of the most nauseating
44:27sounds triggering past trauma.
44:28From Isabel stay, I worked daily on PT with
44:31Silas while we searched and researched,
44:33and although we had an incredible
44:35team of doctors working with us,
44:36no one had ever seen anything like our kids.
44:38We were once again alone
44:41on this unknown island.
44:43Some doctors gave up hope you could
44:45see the pity on some of their faces.
44:47After weeks on the ventilator,
44:48I requested a trach and GJ tube
44:51stylist deserved quality of life,
44:52and if we ever had a chance of
44:53bringing him home, this was it.
44:55Our desire for full healing was still there.
44:58We always held on to hope,
44:59but I always stood by quality over quantity.
45:03Silas had surgery and was so brave.
45:06I took over his care.
45:07I looked at every blood gas and every
45:10blood panel. I watched the trends.
45:14I was the expert. I was also in labor.
45:184th Baby first time.
45:19The night before had been a rough one.
45:22Little to no sleep.
45:23CO2 creeping up sometimes
45:25incredibly high that changes.
45:27He woke around four and we read and
45:29he grabbed my face and laughed and
45:32we had the most incredible hour.
45:34And I knew what this meeting was.
45:36I told our team that even if
45:37Silas were to get better and we
45:39were able to transfer to shop,
45:40I would have to decide at that time
45:43if it was for him or if it was for me.
45:46I would not put him through trauma
45:48to extend his life if it didn't
45:50improve his quality.
45:51I told the doctors I was going to
45:53be headed to Lincoln to have a baby
45:54and it was arranged so that I could
45:56watch through a video monitor.
45:57My sweet baby boy while I brought
45:59his brother into the world,
46:01I arrived at the hospital at five
46:03and delivered stone at 9 via.
46:05C-section.
46:06Roman, our oldest son,
46:07came and met his brother,
46:09and he told me how Silas would
46:10love him so much and he couldn't
46:12wait for them to meet.
46:13I was devastated and elated.
46:17I remember this scream Roman let
46:18out when we sat on the couch the
46:20night we arrived home from Houston
46:21and he asked where is Isabel?
46:23Did she get her new lungs fully expecting
46:25her to be running around upstairs?
46:29We told them she had died.
46:32And the screen was unworldly
46:34followed by sobbing.
46:35He had lost his best friend and
46:37his baby sister, and here I was,
46:39holding his little brother,
46:40knowing his little brother might not make it.
46:43The next morning I received a call
46:46that Silas Hemoglobin was down to 5.
46:48I knew what that meant.
46:49He needed a blood transfusion.
46:51The last one had resulted in tralia
46:53transfusion related acute lung injury,
46:55which sets us back and LED to him coding.
46:57But I knew he would die without it.
47:00By friends more like my brother, the man
47:03who cared for Isabel for 21 days on ECMO.
47:05Justin started the transfusion.
47:07A couple hours, then I got the call.
47:09Things weren't going well.
47:11I called my pede and my midwife
47:12and both told me I could leave.
47:14They would give me meds and
47:16Get Me Out of there.
47:17By 5:00 PM that evening I was back in Omaha
47:20less than 19 hours from having surgery.
47:23I was bringing my son to meet his brother.
47:25The first and last time.
47:27I was exhausted and destroyed
47:29and so tired and so happy.
47:31It's so sad.
47:38Roman and Silas made hand
47:40molds and we all read books.
47:42When we were ready to let him
47:43gracefully and peacefully pass,
47:44Roman held him first.
47:46They laid together for hours
47:47and Roman slept one last time,
47:49holding his baby brother his best friend.
47:53Then it was time for Dad.
47:55They laid and snuggled and I knew
47:56he needed to hold him as he passed.
47:58So I just loved onsite listened
48:00stone and Roman in demon as we
48:02waited until he took his final breath
48:04and his heart had its final beat.
48:06He was 19 months old.
48:08One of our intensivists with a
48:10passion for research stopped us
48:11and asked if we would sign papers
48:13to send or genetics to you.
48:14I said absolutely and we all signed.
48:17He promised no matter what
48:19we would hear the results.
48:20Yale would share any results with us.
48:24The next year was a blur.
48:25It was painful and joyous.
48:27Wondering how long we had with
48:28our new baby and worried our
48:29oldest would someday fall ill.
48:31And then we got a call.
48:33Yale had found something.
48:35Did I want to know? Yes now?
48:39My husband and I both carry
48:41different mutations in the same gene.
48:43Isabelle and Silas received both.
48:45Roman carries mine.
48:47Stone carries neither.
48:50Did we wanna video conference and hear
48:52from the research team that was possible?
48:54Yes, please answers tell me everything.
48:58A video conference was scheduled
48:59and all at once. I wasn't alone.
49:01I found someone who cared as much as I
49:04did about finding an answer as to why
49:06my children got sick, why they died,
49:08but what's more is they want to
49:10understand their disease process.
49:12They want to know more.
49:14They want to know if there is a treatment.
49:16So do I. They want to know and they will,
49:20and they became our beacon of hope.
49:22This news was life changing.
49:25After so many years of trauma and tragedy,
49:27we could finally actually breathe.
49:30The thing we so desperately
49:31wanted for our babies.
49:33The joy and excitement Roman expressed
49:34when he found out his littlest brother
49:36wasn't going to get sick and die,
49:38and neither was he inspired him to
49:40donate his 10th birthday to raising
49:42over $1000 for Yale's research team.
49:45We are dealing with real
49:47and intimate information.
49:49We had two of four children known
49:51in the world with this disease.
49:54But I am just one of millions of people
49:57around the world affected by rare disease.
49:59Just because the disease is rare doesn't
50:01mean it's not common to have one.
50:03We need a clinical research infrastructure
50:05that allows these rare diseases to
50:07be found so that we can treat and
50:09understand the disease process.
50:11It is vital the scientists share
50:13this information with the affected
50:15families because we deserve to know.
50:17We deserve some Peace of Mind
50:19and we deserve some answers.
50:21That is what Yale's program does.
50:23What are family experience was
50:25painful and traumatic five years ago
50:27yields pediatric genomics Discovery
50:29program wasn't in existence.
50:31Had this program been around
50:32when we lost our daughter,
50:34we would have had the opportunity to
50:35find what caused Israel to get sick.
50:37It could have helped us understand
50:39what was happening,
50:40how to move forward for family planning and
50:43additional research and treatment options.
50:45PDP is the pinnacle of research and medicine.
50:48They not only search for a diagnosis but
50:50also a way to treat the disease the way
50:53they have changed our lives is immeasurable.
50:55They gave us back in innocence and freedom.
50:57We had taken from us.
50:59They are the hope for the future.
51:01My children.
51:02Are lucky and that my husband and I
51:05are educated and live comfortably.
51:07We had a community that surrounded
51:08and supported us so we didn't lose
51:10our home and could pay to properly
51:12place our children to rest.
51:14We had resources and the ability
51:15to advocate for our children and
51:17to understand what was going on.
51:19This is not true for many Americans or
51:22any family with a medically fragile child.
51:25Yale's mission to find answers and to
51:27be a resource to the families needs to
51:29be marketed so that families can have
51:30the help they are so desperately seeking.
51:48OK, so it's very hard to
51:51follow anything after that,
51:54so I think I think the points
51:56there are are pretty clear.
51:58Is it is to the desperation these
52:00families have and the impact that we can
52:03have by studying these rare disorders.
52:06So I'd like to finish at that point.
52:09And and really ask you guys to to join
52:11us that you know if if any of you have
52:15patients that you could benefit from
52:17genome sequencing or or exon sequencing.
52:19All you have to do is email peeds
52:21discovery at yale.edu and we'll
52:23be happy to get back to you.
52:24We see we see a wide variety of phenotypes,
52:27structural birth defects,
52:28we've been doing, metabolic diseases,
52:30unexplained critical illness,
52:31seizures and developmental delay.
52:32So I I think there's a lot of possibilities
52:35and I think we haven't yet explored all
52:37of the possibilities and I have no doubt.
52:39That you guys have collections
52:41of patients or even one or two
52:44patients that if we could help,
52:46we'd be.
52:47We'd be happy to participate and
52:50collaborate with you to do so.
52:52I'm very thankful to the patients
52:54and families who are the
52:55inspiration for all of our work.
52:57We've gotten support from a
52:58number of different groups,
52:59including the hospital,
53:00the Yale Medicine, and School of Medicine.
53:02In order to create this program,
53:04we're always grateful for our
53:05funding sources and the people
53:07who have done all the work.
53:09I think I'll stop there and
53:11I'll happy to take questions.
53:19Let's see, how do you do? Is it in the chat?
53:23Thanks so much Mr.
53:24Uhm there's already a couple of comments
53:26that have come in from Carla Stover.
53:28He says thank you so much.
53:29That was a powerful story.
53:30She told thank you and her for sharing
53:32with us and and the office and saying yes,
53:35thank you so powerful.
53:37And indeed that is an incredibly
53:39moving and powerful video.
53:41And I think some of the points that
53:43you've raised about the you know,
53:44the the the Odyssey that these
53:45families go on is really something
53:47that I think is is shared by a
53:49number of the patients and families
53:50that are seen by our clinical
53:52colleagues absolutely center.
53:53And do you have any questions
53:55in the room or on zoom?
53:57Please raise your hands or
53:58pop them into the chat.
54:09So while people are collecting there,
54:11Oh yeah, go ahead, go ahead.
54:13Just wait for the microphone.
54:17Thank you so much. That was a very
54:19powerful thank you for the presentation.
54:23I just have a question.
54:24Do you know what is the state of
54:27the the diagnosis odysseys for this
54:29disease is and I know that these
54:32diseases are very heterogeneous, right?
54:34But what can be done to at least like
54:38shorten or alleviate the diagnostics?
54:42Odysseys, yeah, so that's a good question.
54:45I don't. I don't know if everyone
54:46could hear that one of the questions.
54:47This is that you know,
54:49perhaps part of the challenge
54:50for some of these rare diseases
54:52is the diagnostic odyssey,
54:54which can be very desperate for families.
54:56And is there a way to shorten them?
54:58You know, to me to me,
55:00I think one of the ways to shorten
55:03the diagnostic odyssey is certainly
55:05to implement exome sequencing or
55:08genome sequencing much earlier,
55:10and I think you know.
55:13Genome sequencing,
55:13like any other test is is it
55:16requires some expertise to interpret.
55:19But the one challenge with it is
55:21that it's always evolving, right?
55:23So, like you know,
55:24we've had we've had cases where it
55:26was very hard to make a diagnosis
55:28and then a year later there was
55:30a whole cohort of patients that
55:32were identified that allows us
55:33to make a diagnosis right,
55:35and so that the evolution of it is is very
55:37fast and really requires continuous updating.
55:40So to me,
55:41there's no question that this is
55:43a very powerful diagnostic tool.
55:45EXO more genome sequencing.
55:47The question is implementing it is.
55:49Is as quickly as possible,
55:51and to recognize that it's not.
55:52It's far from perfect right now,
55:55but you know,
55:56for example,
55:56we sometimes say that we can get
55:59diagnosis in about 30 to 40% of
56:01the patients that we see through
56:02extreme seeking or genome sequencing,
56:04even after they've had a huge
56:06battery of other diagnostic tests.
56:08And to me some people say, well,
56:10that's 70% that you didn't diagnose,
56:12but I would say that's 30% that we
56:14can diagnose that we're undiagnosable.
56:16So to me, that's already infinitely better.
56:21And Mr. Could you talk a
56:23little bit about the. The
56:25role of genetic counseling
56:26in the pediatric genomic
56:27Discovery program right so so genetic
56:30counseling is is really critical.
56:32I think you know one of the things we had.
56:34One of the challenges is that what
56:37what we're often doing is returning
56:39research results to patients you know.
56:42So I think genetic counseling is tough
56:44when you have a clinical diagnosis
56:46right when you have enormous amounts
56:48of evidence defining a diseases as
56:51causative for the patients phenotype.
56:53But when you have a research result?
56:55Uh, you need to very carefully
56:58temper expectations.
56:59Saying that you know research can be wrong.
57:02It is not definitive, right?
57:05I mean, you know, we might, you know,
57:07we, it may not be reproducible.
57:09'cause this is the first patient that
57:10we're seeing with this diagnosis,
57:12and so we have.
57:13We're always very careful to
57:15explain to families that research
57:17results are not perfect,
57:18but that recognize that this, of course,
57:21if you don't start with research,
57:22you won't actually make it
57:23to a clinical diagnosis,
57:24and so this is an important first step.
57:27Uhm,
57:27and so I think the genetic counseling
57:29part is is really critical and and it
57:31requires a different kind of genetic
57:33counseling 'cause we need to make sure
57:36that the people who are doing this
57:38kind of counseling recognized that
57:39it's it's a research result which
57:41adds another layer of complexity.
57:46My supper weird just at time now,
57:48but as you can see the comments rolling in,
57:50everyone is just commenting on more
57:51powerful and important work you're doing.
57:53So please join me once
57:54again attacking Dr. Coker
57:55for a fantastic dog. It's.
58:00Thanks again for the invitation.
58:03If people would like to email me,
58:04I'd be happy to continue this
58:07conversation in the future.