[Wildin] Hello, this is Dr. Bob Wildin.
Welcome to Module 6, Lecture 3 in Pedigree Part 2.
This part of the module talks about
some unusual, but not at all uncommon these days,
variations in pedigree nomenclature
that are necessary for us to correctly represent
the types of patients that we see in our clinics today.
I did want to start out with a review
of penetrance and expressivity,
which you will have experienced in Tamara Williams' lecture
earlier in this module.
Penetrance, the concept is if you have full penetrance,
is what you think of when you say a gene causes a disease.
Full penetrance is if you have the gene,
you will get the disease.
No getting around it, no reduced risk,
no increased risk question about it.
Eventually you'll get that disease.
Reduced penetrance means that you have less than 100% chance
of getting the disease, even if you have inherited
the disease gene (allele).
So what that means is when you're counseling families
who are studying the inheritance
of a particular disease in their family,
if that condition has reduced penetrance observed,
then that means that the message
to the person who was inherited that gene change
but hasn't grown old enough, say, to express the disease,
is that you have an increased risk.
And sometimes we can put a number on that.
For example, with BRCA1, the risk of having breast cancer
in your lifetime is approximately 80%.
So it has reduced penetrance,
but it's still pretty high penetrance, all right?
Low penetrance means
many people who inherit the disease allele
or the disease alleles, depending on the type of
inheritance you're talking about,
will not be affected by the disease,
but the risk of getting the disease is still much higher
than if you hadn't inherited the disease genotype.
Now what does that mean?
In the case of rare diseases, the chance that someone who
doesn't have a disease gene running in the family
will get it, is very, very, very, very small.
When we talk about low penetrance,
we're saying something like individuals who have inherited
the genetic makeup that you would ordinarily think
would cause the disease have perhaps
a 20, 30, 40, 50% chance of expressing that disease.
That's still a whole lot higher than if they didn't have
a disease gene set running in the family.
The other important point is even people who
don't express the disease due to decreased penetrance
will still have the same risks of passing on that gene
to their children, right?
So the Mendelian inheritance patterns and frequencies
of passing on are not connected to reduced penetrance.
If you have questions about that,
let's talk about it on the discussion board.
So the next term, which is frequently
confused with penetrance is expressivity.
So penetrance, we're really talking about the fraction
of people who are at risk who will get the disease
With expressivity,
we're not talking about the fraction of individuals,
we're talking about
which specific manifestations of the disease
will a person who does manifest it express.
So a uniform expressivity means that the disease,
everybody who has this disease
will pretty much have the same clinical manifestations.
Whereas variable expressivity means
some people who have this disease will be more severe
or have different subset of features than others,
even if they inherit exactly the same genetic variant.
So one example is neurofibromatosis type 1,
which is a complex disorder that causes learning disability,
cutaneous and subcutaneous tumors that are
benign tumors of the nerve sheath, more advanced tumors,
they may also have short stature,
they may have facial differences,
and a variety of other features.
I'm leaving out the one
that is most prominent and most common
is multiple cafe au lait maculas on the skin.
So-called birthmarks,
although they often appear in the first few years of life
instead of being present at birth.
So variable penetrance in the case of neurofibromatosis
means that some people may have a very severe case,
whereas others may have cafe au lait spots,
what's called Crowe sign, which is freckles
in the armpits in the groins,
and maybe a few cutaneous or subcutaneous neurofibromas,
which don't cause much problem,
and they may not have any significant learning disability.
Whereas others may have a really severe case.
So that's an example of variable expressivity.
Now, what are the origins of decreased penetrance
and variable expressivity?
Some of it has to do with environmental exposures.
Some of it may have to do with somatic mutations
and the frequency of somatic mutations.
A lot of the tumor manifestations in neurofibromatosis
are due to somatic mutations that occur
potentially at different frequencies depending on exposures,
environmental differences, and fundamental differences
in genetic stability.
In conditions with decreased penetrance
and variable expressivity,
there's a lot of new research going on
talking about the genetic landscape.
And what is meant by genetic landscape?
It took me a while to figure this out.
And what people mean is that there are,
in addition to the specific genetic change
associated with the disease in a particular gene,
there's a wide variety of other variations in the genome,
a few of which may influence penetrance and expressivity.
So when you hear about learning about the genetic landscape
of a particular disease, what they're learning about is
other genetic variations that underlie
the concepts of penetrance and expressivity.
All right, so I'm gonna move on from that concept,
but I wanted to cover it again because it's
an extremely important concept and frequently is confusing
both to providers and patients.
So last week we talked about the pedigree language
and I showed this slide where there are specific symbols
for persons depending on their gender and their number.
There are specific symbols for status,
including alive and deceased, affected with the condition,
unaffected, carrier, and being adopted.
And this concept of the horizontal and vertical lines
that represent the relationships,
the different kinds of relationships within a family.
So the vertical line, I call a generational relationship.
Solid line means there is a genetic relationship
and a dash line means there's a non-genetic,
perhaps a social relationship, like I have adopted you.
In the horizontal line category,
there are really two types of horizontal lines
that which links partners in a parental-style relationship,
in a couple, whether or not they mate.
And a sibship horizontal line,
which is shown at the bottom of this slide.
Okay, so that's kind of review
and I did also have a dotted line for casual relationships
or relationships that are no longer active.
For example, divorced couples.
All right, so this is from Robin Bennett,
who's a genetic counselor
who really defined and standardized
the way that we use pedigree symbols.
And this is her definition.
That the horizontal line between partners
is a relationship line.
There's the sibship line,
the horizontal line between siblings,
the individual's line within the sibship,
and then the line of descent
is the vertical line from the partnership.
Adoption, just to go over again,
is represented as a closed brackets,
square brackets that face each other
around the individual who was adopted.
It's important to note that the couple that adopts them,
or the individual that adopts the person who's adopted
does not have a genetic relationship,
a direct genetic relationship with the adopted person,
although it may be another family member.
And so that's represented by a dashed line.
If there is the a solid line,
a vertical or off-vertical, at-an-angle line
can also be present in order to represent
the genetic relationship to the family of origin,
the birth family.
And we'll go through some examples of that.
So the other thing about this slide that you'll notice
if you're watching carefully
is that the parent couples are same-sex couples.
So this is the way that you represent same-sex couples
when there's an adopted child in the family.
I will say that I know a lot of same-sex couples
where one, or the other, or both
have been married in heterosexual partnerships previously
and have genetic children and those would be represented
in the usual solid, vertical line fashion.
But in the relationship line of the male-female partnership,
which was the meeting partners.
Okay, so let's look at pedigree a language advanced.
The first panel shows more person symbols.
A diamond with a P in it represents a pregnancy.
Oftentimes, you'll see the diamond be small
in the case of a pregnancy.
If you have done sexing on the pregnancy,
you know the sex of the pregnancy,
you can turn it sideways or round it out
and make it a male or a female.
But keep the little P inside of it to represent
it's still a fetus in the womb.
If a person is an egg donor, you put a D inside a circle
because women donate eggs.
Female.
To be more precise,
those with the ability, ovaries to create eggs
are the only ones who can donate them.
Similarly, those who have the ability to produce sperm
are the only ones who donate them,
so they're represented by a square with a D in the middle.
A surrogate is an individual who carries a pregnancy
with an implanted embryo.
And occasionally, the surrogate can also be,
essentially, the donor of the egg,
so you have to take that into account too.
But the S in the middle represents surrogate.
Transgender individuals are represented
by their identification,
the gender symbol with which they identify.
And so a person who was assigned a traditional gender
of female at birth and transitioned to male
has a male symbol with the annotation of FTM
standing for female to male above
or just over to the side and above that symbol.
Likewise, a male to female transgender person
is represented as a female with MTF for male to female
annotated above or above and to the side.
So those are new symbols
but actually come in handy fairly often these days.
I wanted to make the point in the next panel
about this vertical generational relationship.
And it doesn't always have to be drawn absolutely vertical.
Sometimes there are places
where we need to make it vertical-ish.
So if the line is mostly vertical,
it still represents that generational relationship.
Has a new twist that we didn't talk about last year,
which is a horizontal line between the partners
that is doubled.
And a double line represents...
I've got some extra animations in here.
Sorry, there's a line. (laughs)
So a double partnership line means there is consanguinity.
What does that mean?
Consequently literally means they contain the same blood.
From a genetic standpoint,
it means that they had a common ancestor.
So if you take their family history and keep going
back and back and back, eventually,
there will be an individual who was in
their great-great-grandmother, grandfather lineage
for both the male and the female partner.
This can happen in the same generation,
it can happen across generations.
It can happen in a lot of different ways.
And the reason that we put that in there
is because some degree of consanguinity,
particularly if the common ancestor
is fairly recent in the family,
increases your risk of recessive disorders in the children
because there are more segments of the genome,
which are identical by dissent or shared
between these two individuals and if any of those contains
a recessive gene allele, it could be passed on
from both parents with reasonably high frequency.
So a double line means consanguinity.
There's a little flag for potentially
an increased risk for recessive disorder,
unless that common ancestor relationship
is far enough away that the partners
are more than second cousins separated.
Okay, one of the things we see quite often
is assisted reproductive technology.
That a couple, either same-sex couple or opposite-sex couple
find that they need assisted reproductive technology
and a donor of a sperm.
In this case, the D represents a sperm donor,
and a pregnancy is conceived between the egg
from a female partner and the donated egg.
So this is how you represent that
in pedigree nomenclature.
So notice that the line between the D
and the fetus of the pregnancy is not horizontal.
It's not representing a direct mating
because there's not usually a formal relationship
between the sperm donor
and the person who's receiving the embryo.
Sometimes there is, in which case you would draw a line
between them, but it would be a dotted line
because, by definition, if it's a donor, it's not a partner.
All right.
This is an example of a pedigree from Afghanistan.
There are a number of places in the Middle East
where the culture dictates that
people marry someone within an extended family.
And so there can be quite a lot of consanguinity
represented in those family trees
and it can be intergenerational as well.
So sometimes these pedigrees get pretty complex
and pretty hard to parse,
but this is just an example of what that looks like.
All right, so that's the end of this.