Learn how advances in biomedicine hold the potential to revolutionize drug development, drug treatments, and disease prevention: where are we now, and what does the future hold? This course will present short primers in genetics and mechanisms underlying variability in drug responses. A series of case studies will be used to illustrate principles of how genetics are being brought to bear on refining diagnoses and on personalizing treatment in rare and common diseases. The ethical and operational issues around how to implement large scale genomic sequencing in clinical practice will be addressed. After completing this course, learners will understand 1. The ways in which genetic variants can contribute to human disease susceptibility 2. How to choose among drug therapies based on genetic factors 3. That the functional consequences of the vast majority of genetic variants discovered by modern sequencing are unknown. This course is targeted primarily at physicians 5+ years out of training. Other healthcare providers, medical/health sciences students, and members of the public may also be interested. Course launches January 15, 2016. * The information presented in “Case Studies in Personalized Medicine” is offered for educational and informational purposes only, and should not be construed as personal medical advice. If you have questions or concerns about a medical matter, please consult your doctor or other professional healthcare provider.
Long QT Syndromes, Part 2
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来自 Vanderbilt University 的课程
Case Studies in Personalized Medicine
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从本节课中
UNIT 3: CASE STUDIES IN PERSONALIZED MEDICINE, PART 1
In Module 5 we will begin to discuss specific cases as these apply to personalized medicine. We will first look very closely at a case of familial hypercholesterolemia as we investigate how we use genomic medicine to move from a rare disease to a common medication, using genomics to find new drug targets, and a discussion of the side effects of statin therapy. In Module 6 we will look at a collection of "high risk pharmacogenetics"cases that illustrate adverse reactions due to drug metabolism and variable drug responses.
与讲师见面
Dan Roden, M.D.Professor of Medicine and Pharmacology
Assistant Vice Chancellor for Personalized Medicine
[MUSIC]
We're going to continue our exploration of the Long QT syndrome and
its implications for things like variable penetrance in this module.
We started with this family and ended the last module with the disclosure that
the affected sister has a mutation that results
in deletion of three nucleotides, one amino acid, in the gene KCNQ1,
which is one of the major disease chains in the Long QT Syndrome.
The inference is that she has reduced potassium occurrence and
that accounts for longer QT intervals in here compared to normal people.
I want to start this part by talking a little bit about the problem of
drug induced Long QT syndrome.
So, so far I've talked about the congenital syndrome,
congenital Long QT syndrome caused by rare variants or
mutations in ion channel genes and genes that control their function.
This is an article from the Wall Street Journal in 1999 describing how
the drug company Glaxo was withdrawing an antibiotic named Rexor.
And the reason they were withdrawing the antibiotic was not because of skin rash or
anything like that but because occasionally patients receiving this drug
would develop long QT intervals and an abnormal rhythm called torsade de pointes.
Torsade de pointesis actually a very fast ventricular tachycardia that's
polymorphic that actually is the cause of the abnormal rhythms or
fainting or death in the congenital long QT syndrome as well.
So this is what we call a phenocopy.
Patients who develop,
who get a drug, appear to behave as though they have the congenital syndrome but
they by and large were not known to have the congenital syndrome.
So that's a a phenocopy of the congenital disease and
drug-induced torsade de pointes is one of the rare serious adverse drug effects that
I spoke about in one of the earlier modules.
And you can see on the lower right hand panel,
that's an example of drug induced torsades de pointes.
And in fact, I know exactly what patient that came from because
I'll tell you about the patient now.
This is a 78-year old man, who has coronary artery disease and has 13
years status post coronary artery bypass grafting and has congestive heart failure.
He was given a drug called dofetillide which is actually
a blocker of a potassium current called IKr.
And mutations that result in decreased IKr are one cause of the congenital long QT
syndrome.
So the fetillide in this particular case appears to phenocopy the congenital
long QT syndrome because patient two days after starting dofetilide
developed drug induced arrhythmia that looks, that is torsade de pointes and
looks like somebody with a congenital long QT syndrome.
He's a little old to be presenting for the first time with a congenital syndrome.
But he doesn't, and he has no family history of anything suggesting
the congenital long QT syndrome.
But we, as part of a research project that we have ongoing in our laboratories,
got DNA from this individual and looked for variance in ion channel change and
to our surprise, he actually has a variant that results in not a change in IKr,
but a change in the other potassium current, IKs.
We didn't find it in lots and lots of control individuals, and so
our assumption is that this man has a very mild form of
the congenital long QT syndrome that remained asymptomatic for 78 years.
That's about 2 billion heartbeats, but
then when he got a drug that interfered with the function of the second potassium
channel, he developed this abnormal rhythm.
So many patients, as I said in the previous module, particularly with
the KCNQ1 variants, the LQT1 variants, many patients will be asymptomatic.
And one of the things that brings out a tendency to have arrhythmias is exposure
to drugs that block IKr.
Now, we're still working on understanding
exactly how many patients who have drug induced arrhythmias have this scenario.
It turns out a minority, probably, have classic congenital long QT Syndrome and
there are other risk factors that were just working to understand.
But, this is a nice story of how the combination with drug and
the genetic background combined to produce an abnormal phenotype type in this
case in abnormal rhythm.
This is another example that I think to tell a story,
this is a 28 year old woman, who I encountered.
Because when she was 16 she had a cardiac arrest and
received an implanted defibrillators.
The diagnoses of the congenital long QT syndrome was made at the time.
She also has a very strong family history of sudden death and
interestingly epilepsy.
Again, we think many of those maybe related to abnormal rhythms and
two cousins who also have implanted defibrillators.
So we look at her electrocardiogram and her QT interval is actually quite long.
It's very long, it's 523 milliseconds which is way, way out there.
And marks her as a person at markedly increase risk.
We do genetic testing, and I must say,
the guess was that you would have a variant she would have LQT2.
That's based on what her electrocardiogram looks like.
But as I told you in the last module, that's sort of an intellectual exercise
that we go through, we rely on the genetic testing.
And the genetic testing in her revealed that she actually has two mutations.
She's what we call a compound heterozygote.
She has a mutation in the KCNH2 gene, which is the LQT2 disease gene,
and gives the characteristic electrocardiogram that she has.
She also has a mutation in KCNQ1.
It's uncertain which of these causes the disease in her, and
the suspicion has to be that it's the combination of the two.
Between 5 and 10% of patients with severe long QT syndrome
have more than one mutation as is the case in this person.
And in fact it turns out that if you look at large numbers of patients,
these are data from the so called long QT registry which has collected
literally thousands of patients and their families with congenital long QT syndrome
over the last 20 years has been exploring the relationship
between genetics and clinical events in a variety of settings.
This is one of many many examples that they have published and
it just shows the event rate among subjects with more then one mutation
is much much higher then the event rate among subjects who have a single mutation.
All of them have the congenital long QT syndrome.
And of course,
you have to ask whether there's a relationship with the QT interval itself,
the more mutations you have, the longer the QT, the greater the risk.
So that's one story, this is the 28 year old woman's sister.
Her QT interval is completely normal,
completely normal and yet she is a mutation carrier.
So either this mutation doesn't do anything to cause the congenital long
QT syndrome or she has, she's one of those individuals who has.
Reduced penetrance in other people who have the mutation could in fact
could have long QT intervals, or it takes the combination of the two in the sister
to create the really long QT interval.
We don't know the answer to that question yet, but it presents interesting problems
in terms of trying to figure out what the right thing to do for
individuals like this.
And of course we would have never known about an individual like this before there
was genetic testing, we'd have looked at her cardiogram and
said you're off the hook no problem for you.
And it may be that she's not completely off the hook or
her children may be not completely off the hook.
At the very least she should avoid certain drugs
that cause the congenital long QT syndrome.
And after this module is over, we will show you a website that actually
lists the drugs that are particularly prone to cause this reaction
among normal individuals, and among individuals with a congenital
un-QT syndrome this is a really amazingly unusual electrocardiogram.
This is a cardiogram that we encountered in a 26 year old woman,
who was deaf since birth.
She had a life long history of seizure disorder and
she came in with recurrent syncope after the birth of a child.
There's some question about whether the peripartum period is a period
of higher risk, it turns out for this particular form of the long QT syndrome.
I'm not sure that the data support the idea that this is a period of high risk,
but she has not only amazingly QT deformed intervals,
you'll notice the T waves in lead V4.
You'll never see T waves that are taller than that, but
she has a QT interval that is almost a second long.
900 milliseconds that's amazingly long, and
I've labeled this a 1 in 5 million electrocardiogram because what this
woman has is something called the Jervell and Lange-Neil syndrome.
So Jervell and Lange-Neil were two Norwegian investigators who first
described the association between congenital deafness and long QT intervals.
And one of the striking features of their initial family was that
they not only had very, very long QT intervals look in particular,
for example, in the lower right hand panel that's marked V4R.
The QT interval is almost as long as the RR interval, which is really clearly
abnormal, but in the family that they first described, they had six children,
and four of them were deaf, and three of them were dead by the age of ten.
They die suddenly from abnormal heart rhythms.
So our patient was a little bit unusual
in the sense that she lasted until she was 26 before the diagnosis was made and
she has in fact the Jervell-Lange-Nielsen Syndrome.
And the interesting question that you could ask yourself about
this particular individual is who carries a mutant gene in her family tree?
She has a mother and a father, she's the only child.
She's married and she has three children of her own.
And I will tell you that this is an autosomal recessive from of the disease.
The reason her QT interval is so
long Is that she has two copies of an abnormal allele,
two abnormal alleles, one from mother and one from father.
And both of them are abnormal alleles for KCNQ1 gene and
it turns out that individuals who have two loss of functional alleles,
not only have very long QT intervals, but also are congenitally deaf.
And there's an interesting developmental explanation for that,
which I'm not going to go into now.
But the question when you look at a family like this is who actually has
the autosomal dominant form of the disease, where they have one KCNQ1 allele?
And the answer is almost everybody in this family.
The mother and the father are carriers, correct?
And then each one of her three children gets one of the abnormal allele,
it might be different for the different children.
Gets an abnormal allele from mom and a normal allele from dad, assuming mom and
dad are not related.
In this particular family,
the mutations in this young woman were two different mutations.
And what was really even more unfortunate for her, so you could say,
well how do you get two mutations?
You're just incredibly unlucky to have two parents,
each of whom has an abnormal allele.
And they marry each other and
you're the one in four who inherits both of the abnormal alleles.
But she was even more unlucky because it turned out that the mother was
not a mutation carrier, and that the allele that she
got from the mother underwent a process called de novo mutation.
So she gets one abnormal allele from father and
then the allele that she gets from mother carries an abnormality in it
that was not even manifested in the mother, a so called mutation.
This is really really an amazingly unusual situation, but
the point is that each one of her children now carries the autosomal dominant form of
the disease the more benign form.
And may or may not have long QT intervals but they certainly need to be
aware of the fact they shouldn't be taking certain drugs.
So let me think about the problem of variable penetrance and
the way in which we think about the problem of variable penetrance
starts with a genome wide association study of
variability in the normal QT interval in tens of thousands of individuals.
This is one such study that was published in 2009,
there are others that have come later that have much larger numbers of subjects.
But you can see here that there are many low si at which variance,
common variance confer variability in the QT interval.
The amount of variability they confer is really tiny.
It could be a millisecond one way or the other.
And notice that one set of genes are genes which,
again, rare variance caused the congenital long QT syndrome.
Here, common variants cause tiny little changes
in the QT interval among normal individuals,
why my QT interval might be 3 milliseconds less that somebody else's because I have
a set of alleles that make mine a little bit less long than somebody else.
The most important signal, or the signal with the highest speed or the lowest speed
value in this particular genome-wide association is neuro gene called NOS1AP.
In NOS1AP, we think encodes some modulator of cardiac calcium and potassium
occurrence although, it's function and the way in which these particular variants
confer variability in the QT interval is still not really known.
But concentrate on what we call the NOS1AP gene and this is what happens.
First, the bottom part is the important, is one part of the story.
A group looked at on a very large number of families in South Africa,
all of whom have long QT intervals because they all have a mutation or
the members of the family who are affected,
they all have the same mutation in the KCNQ1 gene causing LQT1.
The specific mutation in all these families is the same A341V and
if it turns out.
If you go to the churches and do genealogy,
you can trace all of these families back to a single immigrant
from Holland who came over from Holland to South Africa in the 1600s.
So that's what's called a founder effect, the immigrant brings the mutation,
and then over centuries there are large numbers of families who actually don't
even know about each other.
Who have this mutation, some of whom have sudden death and
some of whom just have the mutation all their lives and
then transmit it to others, and it turns out that the one's who have events.
The one's who have sudden death or syncopy carry
NOS1AP risk alleles for longitude intervals as well as the mutation.
And the graph at the top shows a different study from the Italian registry,
again saying the same thing.
The graph is the important one on the upper left, and
it basically shows that if you have the NOS1AP variant, the common variant that
in the population has a one millisecond effect, in combination with a mutation in
one of the long qt disease genes you have a much higher chance of having an event.
And the table on the upper right merely shows that no matter what combinations
you look at, you could look at LQT1 with or without a NOS1AP variant or
LQT3 With or without a NOS1AP variant.
LQT2 with long QT intervals at baseline or short QT interval at baseline.
No matter how you cut the data, the presence of the NOS1AP variant always
confers about a 25 to 50% increased chance of having an event.
So what we have here is a story where the common variant
modulates the pentetrants of the disease,
which is an interesting new advance that comes out of genome wide association.
So again, I have this picture that I've shown before of large,
rare variants that have very large effect sizes in families compared to
common variants that have very small effect sizes across large populations.
And the sweet spot for modern genomics and personalized medicine is in the middle
now, where we have combinations of rare and
common variance together that conspire to produce clinical phenotypes.
I'm beginning to believe that there is no such thing as a monogenic disease.
That all these diseases have their clinical manifestations modulated by other
rare variants or common variants or their combinations, and
that's how we get variability in the way in which patients present.
So, the bottom lines for personalized medicine from the long QT syndrome and
these modules has been that there's highly variable penitrants.
We think we'd begin to understand, the mechanisms for highly variable penetrance.
Clearly, there's a form of the disease that is autosomal recessive,
which is very severe and there's a form of the disease which is autosomal dominant,
which has much more variability in penetrance.
And the problem that certain drugs may bring out the clinical phenotype and
cause abnormal rhythms is particularly important for patients because as
we now develop genetic testing even if the genetic testing shows variant and
the patient has a totally normal QT interval the advice has to be avoid
drugs that might make this worst.
[SOUND] >> [APPLAUSE]
