[Dr. Wildin] Hello, this is Dr. Bob Wildin.
This lecture is about family history,
family health history, and pedigree.
And this is really talking about how inheritance
and of genetic material fits together
with tools that we use in the clinic,
namely family history and the pedigree.
We're gonna start with inheritance basics.
So as we've discussed before, we have an egg and a sperm.
And if those two happen to get together on a Saturday night,
you can get a zygote,
and through mitosis you generate an embryo,
which is ball of cells that grows and grows.
And as it starts to take shape,
we begin to it called the fetus.
Now, in that ball of cells, there are a few cells
that are destined to become germline cells.
That is the gonads of the individual the fetus will become.
Those cells which will contribute
to the germ cells in the next generation.
The rest of the cells are considered somatic cells,
but all of those are undergoing mitosis
through embryonic and fetal development.
Now, if we go back up to the top here,
what if the information inherited
from the egg and the sperm is different?
So we have DNA coming from the egg
and DNA coming from the sperm.
And what if there's something different
about some of that DNA?
Now what can different mean?
It can mean that it's different but normal.
It can mean that it's different
and maybe medically important.
But what happens as a result of that depends on the biology
of that gene and its protein.
It depends on what the status of the other inherited copy,
the inherited copy, say in this case from the egg.
It may depend upon the contribution
of other genes and their variations
and it could depend on other mechanisms like imprinting,
which can silence genes in a normal fashion for some genes
and an abnormal fashion for others.
So this is really the background of what we start
to think about of and that we wanna have in mind
when we think about inheritance.
And in the context of taking a family history
and inferring from the family history,
what modes of inheritance may be active.
So the risk of expressing a genetic disease depends
on a number of things.
It depends on the risks of inheriting disease alleles.
So again, if you have two copies from in mom
and two copies in dad, your chances are 50/50
for inheriting any particular copy
from mom or dad either way.
And if those are disease alleles,
it matters who in the family has those
or is known to have those,
or you can infer who has those,
even if it's not your parents.
Then you can calculate what the risks your parents had
of inheriting that and then the risks
of them passing that on.
And then there are also risks
of having a new genetic change occur when the egg
and the sperm or the sperm are being produced.
Those new genetic changes are rare but they do happen,
and those do underlie a significant portion
of at least pediatric genetic disease.
Now the risk of expressing a genetic disease
also depends on the mode of inheritance.
So whether you need to inherit a copy that is defective
from mom and a copy that is different from dad
or whether you only need to inherit one copy
as an autosomal dominant disorder from either parent
in order to inherit the risk of the disease,
of expressing the disease.
And the mode of inheritance depends in turn upon how
that particular genetic change affects
the biology of the cell.
And we'll go into more about that
in the other parts of this module.
So the risk of expressing a genetic disease
also may depend on other factors,
whether or not there's an environmental exposure
to a substance, to medication, to radiation, to sun,
to all kinds of different things in the environment
that if you're not exposed to, you may not ever express
that disease of the features of that disease.
But if you are exposed to them,
you have a much higher risk than other people
of having important medical effects from that.
It may depend on factors that are just stochastic chances
which we don't control and don't have a known basis.
And then there are unknown influences as well.
So this sort of smorgasbord of different influences
and on expressing a genetic disease are what we need
to keep in mind when we're looking through a family history
and interpreting a pedigree.
Alright, when we talk about an inheritance pattern,
I'm talking about the mode of inheritance
that best fits the pattern
of infected individuals observed in a family.
And that, as I'm saying, depends on the impact
of genetic sequence and copy variations on the gene
and protein function.
And it depends orthogonally on whether
that particular gene resides
on an autosome chromosomes 1 through 22, X or Y.
And we can simplify the function part of this equation
to gain a function which typically is inherited as a mode
of inheritance of dominant, loss of function,
which typically has a mode of inheritance of recessive,
and dose sensitive, which typically has a mode
of inheritance of dominant, okay.
Now here's my sort of inheritance grid.
And this again, can have exceptions,
but overall if you have a gene on an autosome
and it's a gain of function or a dose sensitive,
in other words you end up with loss of one copy of your gene
and that's sufficient to cause disease,
then that's autosomal dominant inheritance.
If you live on an autosome
and you have a loss of function mutation,
and one good allele preserves normality or prevents disease,
then that's an autosomal recessive mode of inheritance.
If you live on the X chromosome,
you have a gain of function,
it's X-linked or X-linked dominant,
loss of function X-linked recessive.
If you live on the Y chromosome, spoiler alert,
very few genes on the Y chromosome,
very few diseases are Y-linked.
Again, a function or dose sensitive is Y-linked
or Y-linked dominant.
You wouldn't necessarily say dominant
because those Y genes are uniquely on the Y,
they're not on the X,
the ones that we're talking about being Y-linked.
And so the dominance doesn't come into play.
The same thing for loss of functional Y-linked
is it's actually irrelevant
'cause in males there's no second copy of a Y-link gene
except in that top PR pseudoautosomal region
which is also present on the X chromosome.
Alright, so these are also the abbreviations
that we use very often.
So autosomal dominant is AD.
Autosomal recessive, AR.
X-linked recessive XLR and X-linked dominant XL(D).
And those you'll see throughout genetics
and they're good abbreviations to understand.
Alright, so what is a family health history?
So you look on, you know, the TV and then on the web
and you can hear about family history
and you're talking about, "Oh that's ancestry,
that's about, you know, my grandfather,
where my grandfather came from,
and where my great-great-great grandmother came from,"
and those kinds of things.
We're talking about family health history,
which is a list of relatives
with a set of metadata associated with them.
First one is are they alive or passed?
Second is what are their health issues
and what were the age of onset
of those health health issues?
Third is their relationship to the consultand.
In other words, are these mothers, fathers,
great maternal grandparents,
maternal great uncles, et cetera?
What are the relations to the person, your patient,
for whom you are collecting this family health history?
Family health history can be considered a tool
that is used to estimate the risk of diseases
in your patient and that have a genetic component.
And that's often by divining
the most likely inheritance pattern.
So the idea is you look at the family history,
you draw it out on a pedigree, you say,
"Well what inheritance pattern is this most consistent with,
and what would be the risk that my patient inherited
that disease risk given that inheritance pattern?"
Okay, so it's a good exercise to go through
and repeat what I just said.
Alright, the family health history is typically obtained
by a verbal interaction or a written questionnaire.
There are very few means currently
to collect family health history directly
from other family members' health records
because of HIPAA concerns.
So primarily you need to consider
this a verbal recounted history that has some potential
to be both biased, inaccurate, and incomplete.
If it's really important that you understand it,
then you need to fill in those blanks,
order the family member's health history records
and confirm what you need to know is true
before making any critical decisions on the basis of that.
The family health history is ideally supported
by medical documentation, what I was just saying.
And it's really a required part of medical history taking
because it gives you information about the patient's health
and health risks that you really can't get in any other way.
So what is a pedigree?
Pedigree is a visual representation
of a family health history.
It is a tool to visualize all of the family history
that you've collected at once in a kind
of concise shorthand that tends to be much easier
to understand what's going on in the family
than a couple paragraphs of text.
The pedigree also allows you to encode family relationships,
which is really important
for understanding the dynamics in a family.
Pedigree is also useful as I mentioned in the last slide,
for inferring inheritance and inheritance patterns
and in estimating disease risks to different family members.
What does that last part mean?
The last part means that some,
if you have an individual who has a disease
with a genetic component,
one of the things that you need to be able to do is to say,
"Well you have this relative and this relative
who aren't affected but they're at risk.
So they need to understand their risk better
and let's try to help them do that."
So having a complete family history
in a pedigree allows you to see who else might be
in that line of inheritance,
who else might be at risk of a genetic condition.
So what is the language of the pedigree?
It's quite simple.
And I've kind of broken it out into these parts.
This is also in your book
and available on the web and other places.
So this is the sort of basics of pedigree language.
In the next module we will talk
about the more complex types of families,
more modern types of families and how to represent those
because there are ways to do that.
So the first thing is that you have a person
who's a male, a female, an unknown gender,
represented by squares, circles, and diamonds respectively.
If you are doing shorthand and you're saying,
"Well my grandmother had three brothers and two sisters
and none of them had any health issues of importance,"
you can collapse those into just say two symbols
with a number in the middle of that shows
there were three males in that sibship, all right?
In the next panel we're talking about the status
of that individual.
Are they alive or are they deceased?
In which case you draw a horizontal line
from about 7:30 to about 2:30, 1:30 or 2:30,
and that represents a patient who is no longer with us,
a person who's no longer with us.
The second part of their status is are they affected
with any genetic condition?
Unaffected means there is an empty symbol,
affected as a filled symbol,
and if you have multiple disorders you're tracking
in a pedigree, you can use different kinds of symbols
or partial filling kinds of quadrants
or something like that to represent different parts,
different disorders that are all running in the family.
Whenever you do that, you have to remember to add a legend.
In other words, put a little box in the corner
of your pedigree drawing,
and draw and assemble with a filling pattern
and then write down what disease
that filling pattern really means,
or what color it is, what disease that really means.
So that's the important part of the affected.
Now a carrier, I left off this slide,
and you can probably shout it out,
but the carrier status is represented by a dot
in the middle of a otherwise empty symbol.
The last status has to do with the difference
between individuals in a family who are genetic relatives
and individuals in a family who are part
of the family by virtue of adoption.
And you'll see in the book
and you'll see in older references that adoption in,
you know, adopted into a family or adopted out of a family,
have two different representations.
But the modern way of doing this is
to just use one representation, which is brackets,
square brackets that are facing each other
on either side of the symbol.
All right, how do you tell
whether they're adopted in or out?
We'll get to that in a moment.
So the next panel is,
it focuses on sort of the vertical lines in a pedigree.
Vertical lines tie together individuals
in generational relations.
Parent, child, grandparent, parent,
those generational relationships.
And they imply a passing on an inheritance
of genetic material as discussed in the first slide.
A solid line really refers
to a genetic generational relationship
and a dash line refers
to a non-genetic generational relationship.
So if you're thinking ahead or looking ahead,
you can see that an adopted person is represented the same
as any other sibling but with square brackets around them
and the family that they're adopted into,
they do not have a genetic relationship in with.
So the vertical line is dashed.
Now that adopted person does have
a genetic generational relationship
and that might be represented this way...
With representing the family that they were adopted out of.
So there are ways to diagram these features.
So let's talk about the horizontal lines,
which I characterize as social relationships, marriage,
partnering, living together, raising a family together,
even if there's not a mating genetic,
combining of genetic information.
So a horizontal line is a formal relationship,
a solid line is a formal relationship
such as marriage committed partnership, so forth.
A dash line is an informal relationship,
which might be an informal relationship,
a one night stand, who knows what.
So you can have a dash line there
to represent a second partner
that is not necessarily a formalized relationship.
You can also represent here whether
that relationship persists.
So for example, in this case you have a male partner
on the left, a female partner in the middle,
and suppose that marriage dissolved
and the children are now with their mother
and the father is not in the picture.
You draw a double hash line across
that relationship which shows that it's no longer
an active social relationship.
All right, so that's pretty straightforward.
Okay, so how do we infer infer modes of inheritance
from the pattern of disease in a family history?
We talked about these different Mendelian modes
of inheritance, autosomal recessive, autosomal dominant,
X-linked recessive, X-linked dominant, and Y-linked.
I'm gonna refer you to this YouTube video
and this is a lecture that I gave at NHGRI back in 2015.
And this link will take you
to the 21st minute and 28th second of that lecture.
And you can watch about eight minutes of that
to understand how you infer the mode of inheritance
from the pattern observed in a family history.
All right, so in the next module we are going
to talk about weird and complex stuff in inheritance.
We're going to extend our discussion
of Mendelian inheritance with talking
about new mutations, decreased penetrance,
variable expressivity.
We're gonna talk about mutation mechanism
including trinucleotide repeat expansion,
and we're gonna talk
about polygenic multifactorial inheritance.
We're also going to tie that together
with learning more about taking a family history
and about the more complex representations
that we can make in pedigrees.
How to do those.