Genomic Approach for Rare and Undiagnosed Diseases

April 30, 2021

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00:00It's my great pleasure to now
00:03introduce our next speaker,
00:04Doctor Yunk Lijiang.
00:05Doctor Zhang is a professor of genetics,
00:08neuroscience, and Pediatrics,
00:09as well as a chief of medical genetics.
00:13He joined Yale in 2019 from Duke at Duke.
00:16He was a key member of the NIH
00:19Undiagnosed Disease Network and
00:20his research interests are genomics
00:23of rare diseases and modeling.
00:25The neurodevelopmental disorders
00:26using functional approaches.
00:27The floor is now yours Doctor Young.
00:36Thank you Nicole for kind introduction on.
00:39I'm taking about 15 minutes.
00:41You can introduce you kind of
00:44class backed off the genomic spoj.
00:50You got everyone's same page.
00:54Then I have no conflict, and indeed,
00:57and the undiagnosed disease, a rare disease.
01:00Bilateral mean is easy to understand,
01:03but in I actually indeed have
01:05us very specific and terminology
01:07to describe this term,
01:09which is basically sweet term.
01:11It's a real previous can lung disease,
01:14has won the SEC.
01:16It's knew yet to be discribed disorder,
01:19but presumably Israel to the
01:21server could be common disease,
01:23but it's rare atypical presentation.
01:26Which of these is EU DNS and
01:28Nicosia loaded 2 hours apart?
01:30Up with the the team before I
01:33left the Duke forward disease.
01:35Of course this is oftentimes the
01:38policy definition in the US,
01:40which is often drug act in 1983 as
01:43it described as less than 200,000
01:45people or one in 1500 in the US,
01:48will qualify as a real disease.
01:51Roughly,
01:51we know about 7000 rare disease
01:53are known and destination you.
01:56One discovered over the time.
01:59Individual rare disease is real,
02:01however, as a group is now well,
02:03one in a 10 or estimated 25
02:06million US are living in the US
02:08are living with real disease.
02:10You can see that number is
02:13pretty pretty challenge.
02:14Summit register maybe diagnosis
02:16or undiagnosed for both.
02:19The reason they got the janome
02:21assists almost an estimated 80% of
02:23undiagnosed disease or rare disease.
02:25Have a genetic etiology so I'll think
02:27about so called the same page on that one.
02:31So,
02:31and I indeed have many,
02:33many program intramural extramural
02:34program dedicated for rare disease,
02:36just list some here.
02:38I'm Luckily I was Luckily as part of
02:41the UDN before left a year left of you.
02:45As you probably also know that the
02:47sellers and the parents of private,
02:50industrial or philanthropy sponsor
02:52efforts and our foundation is
02:54oftentimes real disease specific.
02:55In the US in the world,
02:58the partner between NIH program
03:00and Parents Group.
03:01Indeed,
03:02it's become very powerful force to
03:05promoting the research for rare disease.
03:08Of course,
03:08in the history in the year that for
03:11real disease or undiagnosed disease research,
03:14definition,
03:14outstanding and just highlight a few summer.
03:17Probably you know that Lee Rosenberg
03:19and was the former chair of the
03:22Department of Human Genetics.
03:23Also Dean of the School of Medicine.
03:26He highlighted one lecture,
03:27said for children and yield
03:29making awful human geneticists.
03:31I would argue probably making the grade
03:34of Human Genetics in our country on history.
03:37An awesome notice have very many
03:39many other notable fellow from
03:41the year Training program.
03:43Just to list a few on here and I
03:45don't have to say anything further.
03:48For most recent one,
03:49like Clifton also make a huge
03:51contribution for real disease for sure.
03:55So it's kind of problematic
03:57at medical education.
03:58Often time we're saying making a medical
04:00diagnosis is the art of medicine.
04:03Sometimes can be quite easy,
04:04such as like this if you encounter a
04:07patient in the clinic like this presentation,
04:10you will say,
04:11OK,
04:11I know what it is.
04:13If you got some training.
04:15However, they often that's not very easy.
04:18We often time car diagnostic
04:19Odyssey for real disease.
04:21This is a slide I took from alumina.
04:24Kind of modified a little bit.
04:26And that shows you the challenge
04:29before the next generation sequencing
04:31technology available on average,
04:34the real disease diagnosed taking
04:36about five years and kind of
04:39looking for a different position,
04:41an average final which diagnosis,
04:44diagnosis oftentimes
04:45also misdiagnosis at end.
04:48So therefore,
04:49which the new generation sequencing
04:51now really look at the possibility
04:54comma ending the diagnostic Odyssey
04:56by global efforts for this one or
04:59in the US government also pushed
05:01for the policy or or two supporting
05:04this effort study in 2019 that
05:07HR4144 on passing the House but
05:09not yet in the Senate and renamed
05:12in the 2020 called ending the
05:14Diagnostic obviously act hopeful.
05:16We got this one pass.
05:18We really would benefit a four million
05:21offer where disease patient family.
05:23So really,
05:24not on the next generation
05:26sequencing and Internet diagnosing,
05:28the clinics are restarting
05:30roughly earlier for 2000.
05:32Can a 2011 yell definitely Distaff
05:35Latinist efforts which shows this
05:37publication lot about Rick Lifton?
05:39Here he was the former chair in the
05:42Department and shows at the same time
05:45is asking another group from Seattle,
05:48WA and publish almost the same
05:51time just to demonstrate.
05:53The whole exon capture and sequencing has
05:56significant value or effectively can use.
05:59It can be used in the real
06:02disease diagnosis in the clinic.
06:04So,
06:05uh,
06:05some of you probably know and
06:08Baylor Genetics consider powerhouse
06:10for medical genetic diagnosis.
06:12Last for decades and then in the
06:152011 and two years after initial
06:18researchers are the demonstration.
06:21Yeah, Baylor considered the first offer.
06:24The whole exome testing in
06:27the clinic and about 2019.
06:30Baylor also introduced the whole exon.
06:32Of course, that's the place I was trained as.
06:35Happy for that kind of advancement.
06:38And then, on the other hand,
06:40I should also try to make an argument.
06:43Yield does deserve a huge credit
06:45for this particular area,
06:46or even consider the same level
06:48which you can shows here under
06:51leadership of Alan Bell Net,
06:53which you can see here,
06:54offer the first whole exon in
06:57the December of 2011.
06:58Literally, it's one month after Baylor.
07:00Introduce the whole exon in a clinic,
07:03which is your second in the
07:06country and similarly in the 2019.
07:09A couple months later,
07:10year offered rapid whole genome
07:13sequencing in New Haven Hospital.
07:15Patient any liver flavor to
07:17that which is Apple.
07:18There was the chair of the genetics
07:22at Baylor when I took it off for
07:25a year and he was telling me,
07:28well when I moved to the.
07:31A Mailer stunning genetics the year is
07:33the model I've tried to replicate it.
07:36That's worse than the siding here.
07:38Code here.
07:39When he received the victim
07:41Acustica Leadership Award 2017,
07:42which is kind of interesting
07:44flavor for this story.
07:46I just got a 2 slide to show what our
07:50medical journals. Glad you can offer
07:53for patient care or diagnostic.
07:55Purpose so this is a a
07:58leadership without laughter.
07:59It directed by Alan Bell and way Jonah here.
08:03Just highlight a few or we offer.
08:06Here is a critical access,
08:08you know, start in 2011.
08:10We offer both inpatient outpatient
08:12impatient regardless insurance.
08:13Your health will cover it's very
08:16generous asanka keys and many others.
08:18General support for this effort.
08:20The Russia case and the whole exon
08:24lab reporting within 7 to 12 days.
08:27The regular is 2 months time to
08:29reporting out the result totally.
08:32Lab has performed about more than
08:3410,000 whole exon case and the
08:37lab also contributed generation
08:39project for the reporting.
08:41On 2019, we introduce rap.
08:43The whole genome sequencing is a few in
08:46the country and we offer the critical.
08:49Your patient in the NICU and PICU in
08:52the New Haven Children Hospital and
08:54the turn around time is 3 and five
08:57days with our support from why SGA.
09:00The total number so far we performed is 19.
09:04I was touching out later for
09:06the detail and one of the also
09:09significant strengths and the lab
09:12drackett inform me it's in our
09:14lab DNA diagrams diagnostic lab.
09:17We are often customer testing,
09:19customized testing,
09:20including origin interesting.
09:21The team is awaiting to discuss
09:23a walking with the clinical team
09:26for any specialty or subspecialty
09:28for design and validation.
09:31Which is very significant for this type
09:33are often a diagnostic testing purpose.
09:36There's a lot of strengths are listed
09:38here for experienced laboratory team.
09:40Easy ordering from epic and we have
09:43a team clinical team assisting
09:44you for the complicated case.
09:47The Russian service available 7227
09:49to 12 days for the whole exon
09:51is impatient and we offer the
09:54printer testing and I sort of the
09:56child OneNote four and ask for
09:58generation project for the raw data.
10:01Here are we offer if the order
10:04and provide interesting data.
10:05Raw data hold Gina,
10:07who acts on laptop with able
10:09to accommodate to that.
10:11We also got a huge support for ICJ
10:13II laboratory is it's a side of
10:16genetic laboratory is directed by
10:18pending Lee and very quickly they
10:20offer the traditional karyotyping
10:22and fish and in 2006 and they often
10:25genome wide copy number analysis
10:27by Michael Away which is regular.
10:30Taking one 2-3 weeks time.
10:32Performing more than 7000 cases for
10:34both prenatal and adult pediatric population.
10:36Again,
10:36they're very experienced team.
10:38It's very easy to ordering.
10:40The team is assistant for you
10:42for interpretation and then you
10:44can order Rush rush service.
10:46If you need,
10:47just contact the lab and they will
10:50help you out for the patient care.
10:53Stop for rest of the time.
10:55I'm gonna just as you probably
10:56heard from the tax partner.
10:58Kind of interesting case.
10:59I'm going to show you a few
11:02more case how the genetic.
11:04May lead into the different type of the,
11:06so the revolution from the clinical
11:08care and then the details on the
11:10clinical Side Story is not important.
11:13You pretty much you can't
11:14just come look at the title.
11:16So the point I want to make it to show
11:19you the success opportunity and also
11:21challenge was still facing for using
11:23the application for the whole exon.
11:25Hoje no, in the clinical 7
11:27so this case number one.
11:29It's very quickly.
11:30It's a 30 week and SJ in
11:32the Premier baby with this.
11:34With their short Lambda
11:36and abnormal rib cage.
11:38And this sort of quiet kind of
11:41significant recipe support and also
11:42when incubated ventilators are and
11:44had a difficult to win ventilator.
11:47So here's the initial actually at birth,
11:49which you can see here.
11:51Let me see if I can get my.
11:56Pointer so this is a normal X Ray and
12:00this is the patients actually on the
12:03left side and this is the one in the
12:07middle which is tactical from textbook
12:09which initially actually report about
12:12radiologist say OK this is very similar.
12:14The patient based similar
12:16to a one known condition,
12:18comma center, foreca displeasure.
12:20It's a skeletal dysplasias,
12:21oftentimes caused by FGFR receptor mutation
12:24disease often time considerably so.
12:26Post Natal reappearing natively so the
12:29whole exon was done and the quickly getting
12:33report initial report and no mutation
12:35FGFR 3 that pretty much accounted for,
12:38now confirmed for the clinical
12:40impression by an X Ray.
12:42And indeed we find a homozygous mutation
12:45for a splice inside mutation foreign Eugene.
12:48Can IMPP L1 gene,
12:50it's extremely rare condition.
12:52You can see the earlier frequency.
12:54It's very very low.
12:56But this gene mutation homozygous terroir.
12:59Stage cost another different
13:01scatter displeasure,
13:03and this one indeed clinically.
13:07The symbol for the silverback
13:10Assire Friedrich.
13:11Centerfire before your displeasure,
13:12but the patient often times survive,
13:15and the prognosis is very
13:17different for this one.
13:19Fun are MPPL optimal
13:21displeasure on presentation.
13:22They often time after past and you
13:26need to stage.
13:27This is viable.
13:28Well,
13:29we wish the treatment particular
13:31as a treatment available by by
13:34phosphonate infusion can increase
13:36the bone health and good mobility.
13:39So indeed this initial diagnosis by genetics,
13:42changing management and also potentially
13:45for the prognosis for the future.
13:48The second it's a I want to
13:50show you it's my own case.
13:52Other cases are shared by Doctor
13:54Phalen other my other colleague here.
13:57It's the final ideological
13:59diagnosis that's waiting 20 years.
14:02So this is a 26 year old female
14:04present to my clinic last summer
14:07which continue onset of a seizure
14:10and cognition deley and she had a
14:12history of our Department delay or
14:15intellectual disability was evaluated
14:17in the genetics Connect 20 years ago
14:19by my colleague and yell at that time,
14:22as you know,
14:23is very limited genetic testing
14:25available and no 'cause it was fun
14:27because it's a new problem then the
14:30physician appreciate physician not refer
14:32back to the generic say hey help it again.
14:36See if you understand why these
14:38patients suddenly have sort of
14:41deterioration or other on you symptoms.
14:43So we indeed who acts on the outpatient
14:47setting identify exonic dilution
14:49for 27 or 30 in than Eugene Comma,
14:52USP 96 is X linked gene,
14:55and usually it's a show dominant.
14:57Therefore you will see the female has
15:01a significant presentation and the gene
15:03is encoding our Du broken eighting.
15:06Enzyme in surpass way shows here.
15:09This is you population are passed away
15:11from E1E2E3 for putting degradation but
15:14USPX is on the Du population answer.
15:17Of course this is a relatively new
15:20condition was first reported 2014
15:23and by the Spider 2021 is only
15:26totals 38 case report but we are
15:29very convincing convinced that their
15:31leases are cause for her condition.
15:34But that took almost 20 years.
15:36We finally. Check it out.
15:39The next one is, as you probably know,
15:41and we are primary practice in
15:44pediatric hospital, but we indeed see
15:46that all the patient different age.
15:48This is the one case and the case number 3.
15:51The whole Axon allowed to the funding.
15:54Of course for adults.
15:56Which cancer, which is 70 years
15:5971 years old man and which showed
16:02the cancer to 64 and then which?
16:06History of the uterine fibroids and then
16:09also has a skin layer myomeres and also
16:12found a colon polyps but unknown type.
16:16Lots of the scheme funding for
16:18Leiomyoma in an interesting
16:20family history on as shows here,
16:22which is clearly suggesting
16:24genetic contributed.
16:25Further genetic cancer risk for sure.
16:27This is the proband here and 71 years old,
16:31crazy and to the clinic.
16:33I'm glad and then the physician
16:36ordered how excellent.
16:37But initial, who acts on testing,
16:40looking small mutation point
16:42mutation in India was negative.
16:44Then the further looking for detail.
16:46Indeed who accent identify a 2.3
16:49mega base confirmed by Michael Ray
16:51later about seeing at 9 Gene was
16:54a diluted in the comments on one
16:57Q 4 sweet region among all nine
17:00gene at one particular gene in
17:03the film erator Hardrick how tasty
17:05Lincoln FHT in is the Omen Gin?
17:09In the literature we know Homosassa
17:11mutation interesting 'cause they Sevier
17:13in your Natal and stuff allopathy.
17:15But ahead was expectation is to contribute
17:19leiomyoma and renal cell cancer risk.
17:23Interesting Lee,
17:23for this contiguous dilution.
17:25It's very,
17:26very rare in the literature.
17:29So this is a.
17:31It's also interesting to notice
17:32this gene is in the TCA cycle and
17:35the key enzyme in the TCA cycle,
17:38which is a contributor to condition in
17:41the heavens eggs versus the homozygous.
17:44The next one is very quickly,
17:47so see you often.
17:48Time is clearly challenge and
17:50your physicians,
17:51persistent efforts or technical
17:53improvement can lead into diagnosis,
17:55which shows you know re analysis here,
17:58which is 9 years older,
18:002018 with the Autism no diagnosis
18:03industry will come back.
18:04Return with the whole exome reanalysis
18:07will indeed find the cause for
18:10her for his autism diagnosis.
18:13So very quickly it's gonna last the
18:16case which I want to share with you,
18:19which is interesting.
18:20Which is us that's the case I learn
18:23from Duke as part of a genomic
18:26sequencing program is 15 months old.
18:28Girl shows you progressive neurological
18:30deterioration can occur on set was
18:33to try out of many men in treatment.
18:35And this including this or cortico steroid,
18:38Ivy IG and no significant
18:41improvement was considered.
18:42Chemotherapy by neurology and
18:44the families insisted say, OK,
18:46you need to figure out what's
18:48the radiologist.
18:49Let me present to us asking help
18:52for the genetic evaluation.
18:54Indeed, this is a very quick a whole accent.
18:5711 days and we come from the
19:00mutation in the one off the vitamin
19:03B2 transporter and in the weeks
19:06three we offer that high dose
19:08to offer up for
19:10even treatment. Here's the outcome.
19:13Quickly I can see it.
19:16Show the video.
19:20Oh, I cannot see the videos now working.
19:29Oh, I'm unfortunate videos not working.
19:33Erica, can you help it? Look at video.
19:39So basically, for week after treatment,
19:41I wish you can see the video
19:43is a strikingly improvement.
19:45Even only four weeks with high
19:47dose of vitamin B2 treatment
19:49for this particular case,
19:51let's move on to the next slide.