[Instructor] Hello and welcome to the second lecture
in Module Five entitled Mendelian Inheritance.
Just a quick review of some of the material
we've already covered.
One copy of each autosome, so remember what autosomes are.
Those are the numbered chromosomes,
so those are chromosomes one through 22.
One copy is inherited from each parent,
plus one X chromosome from the mother
and one X or Y chromosome from the father, so,
this will become important
when we start discussing diseases
related to genes on autosomes versus the X or Y chromosome.
We each have two copies of each autosomal genes,
so genes on the autosomes,
that's what an autosomal gene means.
Males have only one copy of each gene on the X chromosome
while females have two copies.
Remember, one X chromosome
is randomly inactivated in females in each cell,
and we'll talk about why that matters
when it comes to those X-linked genes and their disorders
in a few slides.
Different alleles of a gene may encode differences
in the function of the protein encoded,
that's what we just spent quite a bit of time discussing
in the previous lecture.
So, remember what alleles are,
those are slightly different versions
of slight different changes in the sequence of a gene,
which results in differences in the phenotype,
or the trait that is observed.
So a few important terms and definitions.
And we'll talk through each of these throughout the lecture,
but just to give you a heads up from the beginning,
homozygous, this means the same allele present
for both copies of a gene, so, you inherited,
if you remember the analogy I was talking about
with the playing cards and each different card
represents a different allele.
And let's say you're playing with two or three
or four different decks,
so each deck has 52 different cards in it.
So if you're playing with four,
you're combining four different decks together
and you're playing with that.
And you're basically, say,
randomly choosing two cards from the deck.
If the two cards that you choose are are the same,
so let's say both cards that you choose
are the eight of hearts, then that would be homozygous,
so you'd have two identical alleles,
so both alleles that you inherited, one from each parent,
happened to be the same.
Heterozygous means you have different alleles present
for each copy of a gene,
so that means from each one of your parents,
you inherited two different alleles for a particular gene.
Autosomal is a disorder involving a gene on an autosome,
and X-linked would be a disorder
involving a gene on the X chromosome.
Dominant, with dominant and recessive,
here's where we're starting to talk about
allelic interactions.
And basically how we go from the genotype
to a specific phenotype.
'Cause as you know, in the genotype,
if you have two copies of a gene,
so you have two alleles, they could be the same,
and if they're the same, you're homozygous.
Or they could be different,
and if they're different you're heterozygous.
Basically, how does that get translated
into the phenotype,
'cause we only have one phenotype, right,
there's only one of us.
But each one of us has two copies of each gene,
so how do they interact with each other
to give us that one single phenotype?
Well one way that's been worked out,
and these are genes for genes
which have what are called Mendelian inheritance.
These would be alleles that take on characteristics
of either being dominant or recessive to one another
when they're combined together.
So, a dominant allele is an allele
that determines phenotype
regardless of the other allele present.
So it determines phenotype
when the individual is either homozygous or heterozygous,
so if you have at least one copy of a dominant allele,
that will determine the phenotype
regardless of what the other allele is.
Recessive alleles are alleles that only affect phenotype
when both copies are the same,
so this determines phenotype
only when the individual is homozygous for this allele.
Otherwise, if the individual is heterozygous,
then the other allele is dominant,
and that's the phenotype that you will see.
Some Mendelian inheritance, this is a weird word, Mendelian,
who is Gregor Mendel?
He was an Austrian monk who lived in the 1800s
and is considered the father of genetics,
he worked with pea plants,
and did a lot of different crosses between pea plants,
and took detailed notes, and made some great strides
in deducing from the patterns of inheritance that he saw,
certain laws that he basically was able to define
and have really held up pretty well, rather remarkably well,
for, you know, 200 years later,
in that we're still really referring back to those.
So it's quite remarkable, this was in a time, obviously,
before any modern technology that we use today
for genetic analysis, so, very impressive.
And so we use his name, Mendel,
and the name Mendelian is derived from that.
And this is basically inheritance of monogenic diseases,
so these would be diseases caused by a single gene,
these are considered more simple diseases to understand.
because they don't involve a lot of extraneous factors
and multiple genes and, you know, just,
things become very complicated very quickly
in multifactorial diseases,
but in Mendelian inheritance, it's rather straightforward.
Okay, and he translated the different patterns you saw
of inheritance in pea plants into human disease
as recessive and dominant inheritance
of single-gene disorders.
So classifications of single-gene diseases,
genetic diseases categorized broadly
by how genotype affects phenotype
and where the gene is located.
Okay, so two parts.
So if we're looking first, on which type of chromosome
is the gene causing this disease located?
Well, is it on an autosome, if so it's called autosomal.
If it's on the X chromosome, it's called X-linked.
And the gene causing this disease is on the X chromosome,
so males are more likely to be affected
as they have only one X chromosome.
So inheritance of a single recessive disease-causing allele
is enough to cause the disease.
Okay.
So that takes care of where it's located,
so if we're categorizing a particular disease,
first we would say, is it autosomal or is it X-linked?
And then we would classify it based upon the alleles.
Okay.
So the alleles are, again, what are alleles?
Slight variations in a single gene,
that result in different phenotypes.
So how do two alleles a person has for the gene
interact to produce the disease phenotype?
How do they interact and produce the disease phenotype?
So there are two categories, really, from that,
and those would be either dominant disease.
So you only need one disease allele to get the disease,
other allele may be perfectly functional,
which would be called what?
Wild type, that's right.
So an example of a dominant disease
would be Huntington's disease,
so if you inherit a single allele,
if only one of your two alleles
that you inherit from one of your parents
is a mutated version of the Huntington gene,
that causes Huntington's disease,
you will have Huntington's disease.
On the other hand, recessive diseases
need both disease copies to get the disease.
So no wild type allele is present.
So those with only one copy do not have the disease
but are carriers, as they can pass it on to their children.
So this would be, an example would be cystic fibrosis.
So if you only have one copy of the disease allele
and the other copy is wild type
or the normal functioning,
you actually probably don't have any symptoms of a disorder,
but you can pass that on.
So recessive diseases often are thought of
as skipping generations.
Because you may go into the carrier phase,
where an individual for a generation
is carrying the allele for the disease,
but they themselves don't have it.
However, their children, depending upon their partner,
their children might have disease
or at least may be carriers for the disease.
Let's start with autosomal dominant inheritance,
and we will take it from there,
so again, autosomal dominance, let's go back for one second.
We're combining, we first have to say
is where's the gene causing the disease located?
Okay, if it's on an autosome, it's autosomal,
it's on an X chromosome, it's X-linked.
And then you say,
how do the alleles interact with one another
to cause the disease if it's dominant or if it's recessive?
So, in this case, it would be autosomal dominant,
and that tells you that the gene causing this disease
is on an autosome, and that the alleles interact
in a way so that the disease allele,
the mutant disease allele,
is dominant to the recessive wild type allele.
Which means you only need one copy of the disease allele
to cause the disease.
Alright, so what I'm starting to show you here,
this will be the first time I'm showing you this,
and we're going to it a lot throughout this lecture,
so I'm going to orient you first
to what it is we're actually looking at
on this table to the right.
So this is actually called a punnet square.
So let me just click through here.
Sorry I didn't actually realize
I had them appearing that way.
Okay (chuckles).
Alright.
So a punnet square is a tool to estimate risk
of offspring having genetic disease or being a carrier,
so it's just a way to kind of write it out,
so you can figure out what the probabilities are
for two individuals, given their genotype,
given basically their two alleles,
what are the probabilities
that their children will be either unaffected,
so not have the disease, will have the disease,
or will be a carrier for it?
And the way we draw it, remember,
each person has two alleles.
And the father and the mother each contribute one allele
for each child.
So the mother has two alleles, father has two alleles,
that means there are four possible combinations
of each of those two alleles.
Okay?
So if you draw out in this manner,
let's say going down vertically,
in the columns here, rather in the rows,
we're going to do the mother's alleles,
and we're gonna designate those alleles,
those alleles are gonna be designated.
So of the standard nomenclature
when you're doing a punnet square
is the dominant allele is capitalized,
and the recessive allele is lowercase.
So that way you can kind of keep track
of what it is you're looking at.
Let's say we're looking at a case of a father
who has Huntington's disease and a mother who does not.
So the father is Huntington's, so it's a dominant disorder.
So that means he has at least one copy,
one of his alleles is the Huntington disease-causing allele.
And the other may be wild type
or it may also be the Huntington disease allele,
but let's assume as is the case in most dominant disorders,
that the individual who has the disorder
is actually heterozygous,
so they have one copy that is wild type and normal.
And the other copy is disease.
And the reason why that is normally the case,
that an individual with a dominant disorder is heterozygous
is because many times, if you are homozygous
for a dominant disorder, it's actually lethal.
It's lethal, because you don't even have
a single normal copy of the protein,
or rather of the gene around to make a normal,
at least half normal version of the protein.
But there certainly are cases
where you have a dominant disorder
and individuals can be homozygous for the dominant,
but let's just assume in this case,
'cause this is sort of the most likely case,
that an individual here is heterozygous,
so, the big H represents his disease-causing allele,
and the little H is the wild type allele that he has.
The mother, since she does not have Huntington's disease,
let's say, in this particular example.
Both of her alleles would be lowercase H.
And let's look at every possible combination
of those four alleles.
Well, one combination
would be the big H allele from the father
with the little H allele from the mother.
And so this would be basically like
looking at one of the possible outcomes for a child.
Another possible outcome would be that the big H
with the mother's other little H or other wild type allele,
so that would be this combination for the child.
And then another possibility, right,
would be combining the little H allele from the mother
with the little H allele from the father.
So both, so this individual,
this child is inheriting both wild type alleles
from their parents.
Same with this individual,
so they're inheriting this wild type
and this wild type allele from their parents.
Now what does that mean?
So now we have our four possible genotypes
for a child that may be born to this couple.
And now we can determine what the phenotype would be,
because we know that the impact of this genotype,
since we know it is a dominant disorder,
we would know that having a single copy
of the disease allele
is going to result in an individual
having the disease phenotype.
So both of these possible outcomes,
which are actually the same, but we draw it out like this
because it just kind of makes it easier.
So you would say big H, little H,
that's Huntington's disease,
this possible combination of alleles
would result in a child with Huntington disease,
as would this one as well.
Whereas these two outcomes would both be unaffected.
So if we add these up,
this would be two out of the four possible outcomes, or 50%,
there's a 50% chance that a child will be unaffected.
And there's a 50% chance
that the child will have Huntington's disease
because two out of four of the possible combinations
of their different alleles from the Huntington gene
would result in both alleles being wild type.
So these two out of four, this two outta four is 50%.
There's a 50% chance that the child will be unaffected
and a 50% chance the child will have Huntington's disease.
As you recall, there are no carriers of genetic disease,
and it's typically a gain of function mutation,
if you remember the mutations I was talking about,
gain of function isn't necessarily a good thing.
And in this case it is definitely not.
So there's a mutation in the gene,
and that results in the protein
doing some different things than it should be doing,
so that's called a gain of function,
it's doing an additional function,
but that's a bad thing, actually, in this case,
that causes a lot of problems, for the individual.
And so that's why having just one copy
and not requiring both copies,
is having just one copy that is the disease allele
is enough to give the person the disease,
because it's basically, that mutated version
isn't just like the protein isn't functional anymore.
In which case you could say, well yeah,
they have one normal copy,
so why isn't that enough to make up for it?
Well yeah, they have one normal copy,
but now they have one rogue crazy copy
that's going around doing some weird additional functions,
and that's causing the disease.
So having one copy is sufficient
to cause the disease in a dominant disorder.
So a few other examples
of autosomal dominant disorders
would be Marfan syndrome and myotonic dystrophy.
Oops.
Let's take another quick peek
at another way of looking at this,
which is a little more visual.
Would be saying, for example,
in this case, an autosomal dominant disorder.
And this, what they're showing here, pink would indicate
that an individual is affected with the disorder,
blue would be unaffected, so if you look at them,
if you're looking at, say, the two chromosomes
that the father has for, you know,
there are two homologous chromosomes.
On one of those chromosomes exists the allele
that is the disease allele,
and on the other chromosome, that's the wild type.
And the mother, since she's unaffected,
both would be wild type,
and what are their possible children they could have?
Well, each child could inherit this chromosome from dad,
this chromosome from mom, this chromosome from dad,
this chromosome from mom, or any combination of those,
so that would be four different possible combinations.
And if we look at this, then, again,
you can kind of see that basically 50%
or two outta the four possible combinations
would result in Huntington's disease,
and two out of the four or the other 50%
would be unaffected.
Remember that there really are no carriers
for dominant disorder, because having a single copy,
which is what would make you a carrier
for a recessive disorder,
having a single copy of a disease allele
for a dominant disorder gives you the disease,
so you're not a carrier, I mean you, you have the disease.
Here are some of the different outcomes that you might see,
HD I'm indicating is Huntington's disease.
And the uppercase and lowercase case H are the alleles,
the uppercase being the disease allele
and the lower case being the wild type,
and we know that in this case
because it's a dominant disorder.
Okay, so basically, depending upon the parents,
whether the parents are wild type or heterozygous
for the Huntington disease allele
or homozygous for the hunting disease allele,
there can be some different outcomes,
so, I'll let you look through this on your own,
and let me know if you have any questions on it,
but, the net result is that with the most common type,
which would be one Huntington disease parent
who is heterozygous and one wild type, again,
50% of their children will have Huntington disease.
Autosomal recessive disorders.
So here we're talking about the need
to have both copies of the gene to be disease alleles
before you actually have the disease.
And there typically is a loss of function mutation,
which can be made up for
by the presence of one functional copy,
so as long as you have one wild type,
as long as one of your two alleles is wild type,
you actually won't have the disorder
because while the disease allele
actually knocked out the function of the proteins,
the proteins just imagine like, you know,
it's not even produced anymore,
so you don't have that copy of it.
But let's say if instead,
you have both of your alleles are the mutated version,
then you wouldn't have a functional copy of the protein,
and that could result in the disease.
Carriers, so here in autosomal recessive disorders,
this is where you can have carriers.
So they have a single disease allele
but do not have the disease
because they have one wild type allele as well.
It is often thought to skip generations, and normal,
so here let's look at cystic fibrosis
and we'll designate the normal allele for the CFTR gene
as uppercase F.
Right, so that's the wild type allele,
and the disease allele is lowercase F.
So remember that in our designations in punnet squares,
uppercase is always the dominant allele
and lowercase is the recessive.
So for a dominant disease,
the uppercase indicates the disease allele
because it's dominant.
In a recessive disease, when you're doing a punnet square,
lowercase is the disease allele because it is recessive.
Okay.
Again, we're showing the mother's alleles
on the vertical axis
and the father's alleles on the horizontal.
And when we look at all possible combinations,
what we start to see,
let's assume that we have a pairing of both carriers,
so a mother's a carrier for cystic fibrosis
and a father is as well.
And they want to know,
they want to know what's the likelihood
that their child will have cystic fibrosis.
Well you can certainly estimate this.
Again, using every possible combination
of each of the two alleles,
one from the mother, one from the father.
And from that, you know the four possible combinations.
You can determine what the ratios or probability is
for each of those outcomes.
So first of all, we take the combination,
let's say where, you know, an individual could inherit,
so one of their offspring could inherit the wild type allele
from both their mother and the father,
this individual would be completely unaffected,
they're not even a carrier.
Because they didn't inherit a single disease allele
from either parent.
Okay, and let's say some other possibilities
would include inheriting the wild type copy from mom
and the disease copy from dad.
This would be a carrier.
Same thing here, in the end, same outcome.
You inherit a wild type copy from dad
and a mutant or a disease-causing copy from mom.
This is also a carrier,
because remember, you need both copies to be the recessive
in order for recessive disease to present.
And then the final type of combination
would be inheriting disease alleles from both parents.
And this would be the individual
who would have cystic fibrosis,
so if we add all of these up,
you could have an unaffected individual
be one out of the four combinations, so 25%.
You could have one, two of the four combinations
would result in a child who is a carrier,
so that'd be 50%, two outta the four.
Or one out of the four or 25% having cystic fibrosis
because they inherited one disease allele from each parent.
Okay, so just a quick peek here,
you can look through this yourself,
but, this is just another way of looking at
what we just described.
And here are some other possible outcomes
depending upon the genotype of the parents.
So you could look at, so if instead,
let's say you had a couple approach you,
and one of them knows that he or she
is a carrier for cystic fibrosis,
and the other is not a carrier, has been tested,
and is determined to have the wild type genotype,
so that means both their alleles are wild type.
Well we would know that actually 0% of their children
will have cystic fibrosis,
because you need both parents to be at least carriers
in order for a recessive disorder
to present in that generation, in the next generation
that those two individuals would produce.
So again, look at all the different combinations,
let me know if you have questions as you go through.
But this is just giving every possible combination
of really what the parents could be,
so are the parents unaffected carriers,
or are they homozygous,
so they actually have cystic fibrosis?
And what would be the likelihood
of their children having that, so let's take an example of,
it probably wouldn't be the case with cystic fibrosis
given the issues with fertility,
and also life expectancy,
but let's just say there are two individuals
who both have cystic fibrosis
who are planning to have children with one another.
What is the likelihood that their children
will have cystic fibrosis?
Well it's actually 100%.
Because both parents, if they have cystic fibrosis,
that means they are homozygous, right,
both copies are the same
and both copies are the disease copy.
So both the mother and the father
have two copies of the disease allele,
that means the only combinations that can occur
would be disease allele,
disease allele, disease, disease,
so that would result in, there's no chance
that they will have a child
who doesn't have cystic fibrosis,
so 100% chance their offspring will have cystic fibrosis.
So it really varies
and depends upon the genotypes of the parents,
whether they're both carriers,
one is whether one or both has the disease
will affect the probabilities
of their children having disease with it.
Alright, let's look at X-linked diseases.
So these would be diseases involving a gene
that's on the X chromosome.
So they're generally inherited from the mother
and expressed in sons,
for X-linked recessive, which is the most common,
X-linked dominant disorders are actually pretty rare.
Most X-linked diseases are recessive,
so females may be asymptomatic carriers, remember recessive,
remember females have two X chromosomes,
and males only have one.
So in a recessive disorder,
the males inheriting a single copy of the disease allele
will be sufficient to result in them having a disease,
and females, on the other hand, if they inherit,
if one of their X chromosomes has, say, the disease allele,
but then the other X chromosome that they have
has the wild type allele.
Well then they will be carriers,
but they won't actually have disease.
Males have only one allele for each X-linked gene,
so there's no backup copy.
Females have two copies,
though one is inactivated randomly in each cell,
remember X inactivation?
But having one functional copy in half of the cells
is usually enough to compensate for the loss.
So you can think of female carriers as really mosaics,
and you know what I mean when I say that
because we had that whole section on it
in the previous module, isn't it cool
when things start to come together a little bit?
I don't know, I think it is.
X-Linked dominant disorders are generally lethal in males
because they lack any functional copy of the gene,
remember as I was saying before
when we were talking about autosomal dominant disorders,
that usually it's a heterozygous condition,
so usually individuals who have the disorder
will have one normal copy,
like one wild type copy,
and the other copy will be the disease copy,
and that's because in most dominant disorders,
having both copies be the disease copy results in lethality
because there's no rescue copy, there's no normal copy
to kind of come back and balance it out to any extent.
And in males that's the case
because they only have one copy
of every gene on the X chromosome.
A few examples of X-linked diseases: Rett syndrome,
which is one of those more rare X-linked dominant disorders.
Duchenne muscular dystrophy, which is recessive,
and hemophilia, which is recessive.
And these are all X-linked.
So let's take a peek at X-linked recessive disorders.
And here we'll look at hemophilia.
Hemophilia A caused by mutation on the F8 gene.
F8 gene is located on the X chromosome.
And here we're gonna designate capital H
as the wild type because it's recessive, remember that.
And lowercase H as the disease allele.
Again, 'cause it's recessive.
Now when we do a punnet square for this,
it's a little different,
because, in the father's case, he only has one X chromosome,
so he only has one allele that he can contribute.
The mother has two alleles,
so we would draw it like this,
and here we're actually showing possible combinations
in a female offspring or a daughter that they would have
and possible combinations in male
or their son that they would have.
Because remember, the sons are only going to inherit
one X chromosome,
and then they're going to have the Y chromosome.
But the Y chromosome does not contain the same genes
as the X chromosome, so it's totally different.
There were very few genes on the Y chromosome,
and very few disorders actually associated
with Y-linked genes,
so we're not actually gonna bother talking about that.
So here we're kinda showing something a little different,
these are all the daughters, this column here,
because they inherit two.
They inherit both one of the two X chromosomes
from their mother
and the X chromosome from their father.
Whereas the sons do not inherit an X chromosome
from their father,
they inherit the Y chromosome from the father,
so they inherit either one of the two X chromosomes
from their mother.
And that will determine
whether or not they have the disorder,
so in this case, basically it's, in an X-linked D disorder,
inheritance is is typically coming
from the mother as as a carrier,
because the father would know if he had the disease allele,
because he would have the disease,
'cause he only has one one allele.
So if we add these up, then we would see
that one of the two combinations for daughters
would be inheriting both the wild type copy from the father,
which is the only copy she'd get from the father.
And the wild type copy from the mother,
which would leave her unaffected.
Or she could inherit the disease copy from the mother.
And of course, she continues to inherit
the wild type copy from the father,
in which case she is a carrier.
The sons on the other hand,
here you can actually start to get
the expression of the disorder, so, they will inherit
one of the two X chromosomes from the mother,
and of course the Y chromosome from the father.
But again, that doesn't play a role in X-linked disorders,
the Y chromosome does not.
So, they would either get the wild type,
50% of sons would inherit the wild type allele,
this particular X chromosome from the mother.
And 50% would inherit the disease allele,
or the other X chromosome from the mother,
and this individual would present with a disorder,
so this individual would have hemophilia.
So in total we would say 50% of daughters
would be unaffected,
50% of daughters will be carriers,
but they won't actually have the disease,
they'll be carriers,
and so the next generation might have it.
50% of sons will be unaffected
and 50% of sons will have the disorder.
So as you can see, there's differences
depending upon the gender of the child.
Alright, so a reminder, father only has one allele.
Mother has two alleles, 50% of daughters will be carriers,
and 50% of males or sons will have hemophilia.
And here you can take a peek at some different combinations,
again, just another way of looking at it.
Alright.
X-linked dominant inheritance,
so this would be Rett syndrome,
and here it's gonna look a little different.
Because in most X-linked dominant disorders,
inheritance of the disease allele in sons.
So sons who inherit only the,
they only get one copy, remember,
and if the one copy they inherit is the disease copy,
then it is most likely going to be lethal,
'cause again, they don't have a normal copy
to kinda rescue it, or balance it out at all.
So it's usually lethal in males and homozygous females,
so females who would inherit.
But, I mean you really wouldn't have a homozygous female.
Why do you think that is?
You wouldn't have a homozygous female
if it's lethal in males,
because her father couldn't possibly have
the disease allele to begin with,
'cause if he did, he wouldn't survive.
So, homozygous females are really just not going to occur.
So one example of this would be Rett syndrome,
where you have the normal allele
of the MECP2 gene is designated as lowercase R,
so the wild type is lowercase R
because this is dominant, remember.
Dominant disease allele is uppercase R.
And again, we do our combinations here.
What we would see is that in the daughters,
we have a daughter with Rett syndrome.
And this would be a daughter
who inherited the mutant allele from her mother.
And an unaffected daughter,
so 50% of daughters would have Rett,
50% would be unaffected.
And in the sons, really none of the sons who survive
would be affected.
But there would be likely a loss of the embryos
that are conceived,
that inherited the disease allele from the mother.
So again, reminder, father only has one allele,
mother has two, 50% of daughters will have Rett,
just like an autosomal dominant disorder.
And males inheriting disease allele from the mother
will not survive, because presence of no wild type alleles
increases disease severity.
Here you can take another peek
at some different combinations,
and they're actually showing, oh,
there are the rare, rare exceptions
of X-linked dominant disorders
which are not lethal in males,
and they're showing an example
of what the inheritance patterns for that
might look like on the right here.
Alright, so what are some implications for nursing?
Some red flags of Mendelian genetic disease,
clear multiple generation family history.
If it's dominant, it's seen in every generation,
if it's recessive, it skips generations.
Now let's go back for one second
to seen in every generation with a dominant disorder.
You can also have, if you recall from the previous lecture,
a de novo mutation, which,
we've been really talking about inherited mutations,
so this was a mutation that occurred
sometime way in the past in your ancestors
that's been passed on generation to generation
to generation.
A de nova mutation is a new mutation that has occurred
for the first time, and it occurred in the germline cell
likely of one of your parents.
And so in that case, there may not be a past history
of a family history of the traditional family history
you would expect to see in an individual
if they have a de novo mutation,
and this can be determined
by genotyping both of the parents,
and genotyping the child.
And, you know, of course making sure that the parents,
how do I put this, that the individuals
who are claiming to be the parents of that person
are truly their biological parents.
Once that has been confirmed,
then if the individual has a mutation
that neither parent has,
then you know that this was a de novo mutation,
or one that spontaneously occurred in that generation.
X-linked only presents in males in recessive,
X-linked recessive, or females primarily,
which would be a dominant X-linked disorder in the family.
Remember, because in males, dominant X-linked disorders
primarily are lethal.
There's importance in gathering family history information,
which I'm sure you all appreciate,
genetic testing is available for most Mendelian diseases,
because these are rather simple diseases,
they're monogenic, and we know quite a lot about them.
Granted there are,
I think there are something like 6000 different diseases
that have been classified.
But, we do actually know quite a bit about most of them.
There are some very rare diseases
where there may not be a genetic test available,
but I'd say the vast majority of them
there are genetic tests available.
So knowing both parents' genotypes,
it is possible to predict the likelihood
a couple will have a child with a Mendelian disease
or will be a carrier.
But again, advise referral for genetic counseling
where possible,
as opposed to trying to do back of the envelope
estimations of probability,
not that you would, but, you know,
just to be clear about that.
There are subtleties in these different diseases
and patterns of inheritance.
But just so you know in general
how you could estimate the probability
for these monogenic disorders, and their inheritance.
So some other red flags of genetic disorders.
Consanguinity, so parental relatedness,
and why is that, why is that a red flag?
Well, recessive alleles are actually relatively rare
in the population and in the general population,
and so if you have two individuals coming together
who are completely unrelated with one another,
the likelihood that they'll share much genetic similarity
between one another in terms of their alleles
is relatively low.
But if you have two individuals
who are related to one another,
they have very similar genetic backgrounds,
and the likelihood that they'll both have the same alleles
is very, very high.
So the recessive disorders become much more common
in individuals who are related,
which is why we actually have laws that prohibit marriage
between closely related individuals,
to prevent the expression of recessive disorders.
Abnormal fetal ultrasound is also sometimes a red flag,
as well as cutaneous disorders,
hypotonia is very often associated with genetic disorder,
as is seizure growth abnormalities, developmental delays,
abnormal newborn screens as well.
And along with the developmental delays,
intellectual disability is often a red flag
for some genetic conditions,
especially some of the types of genetic syndromes
that you remember reading about in Module Four.
Many of those are actually associated
with intellectual disability as well,
so that's often a red flag.
Alright, well let's give it a quick summary here.
Recessive disorders require both alleles
to be disease alleles
before the disease phenotype is seen.
Those with one disease allele are carriers
and are generally asymptomatic, and remember,
when we draw out those punnet squares
that you learned about and you're gonna come to love,
I have no doubt,
that when we designate an allele by a single letter,
whether it's uppercase or lowercase,
that indicates whether or not it is recessive or dominant,
not necessarily whether or not
it is disease or wild type.
So, remember that using the lowercase for the letter,
that indicates it's recessive allele.
And it may or may not be the disease allele,
for a recessive disease, it would be,
for something that's a dominant disease, it would not be,
but, recessive alleles, remember, at lowercase.
Dominant disorders require only one of the two alleles
to be a disease allele
for the disease phenotype to be present,
and there are no carriers for dominant disorders,
because if you have one copy, you have the disease.
And remember, again, dominant would be denoted
as an uppercase letter.
Recessive X-linked disorders present primarily in males
and are inherited from the mother,
and remember, they're primarily seen in males,
because males only have one X chromosome.
And so while females are only really expressing
one of the two X chromosomes, because of X inactivation,
they have sort of a mixture of cells
that are going to actually have the normal function,
have a normal functioning copy if they're heterozygous.
So that leaves the males,
so any of the males who inherit a disease allele,
from their, it would be from their mother,
'cause it would be on the X chromosome,
then they're going to have the disease.
So that's often a hallmark of a condition
that's likely to be an X-linked disorder, is if you see,
and say, going through generations of a family tree
and you're taking the history and you're looking at it,
and it's only males that actually have the same disease
generation after generation.
And it seems to be going down the maternal line,
so you can always be tracked back through
the mother's side of the family.
While the mother didn't have the condition, her sons did,
then that would be an indication
that this is an X-linked condition,
and probably a recessive one.
Dominant X-linked disorders present primarily in females,
and are usually lethal in males
who do not have a functional copy,
so remember that, in females,
so if this is a dominant X-linked condition they have,
they inherit one disease allele
they're going to have the disease in,
but they still have that second copy
that is presumably normal and normally functioning,
and again, given that they can be heterozygous with that
and have some cells that are expressing the normal copy,
they can generally make up for some of the loss function.
But that will result in the disease,
but not lethality in the females.
In the males, on the other hand,
having a dominant X-linked condition is oftentimes lethal
because they don't have a single good functioning copy
because they only have one copy to begin with.
So these are some red flags, if you're seeing something
that is really only presenting in females,
it may be an indication
that this is a dominant X-linked disorder.
Alright, well what's up next, well now that we've learned,
and reviewed, for some of you, the basics.
Now we're going to take it a step farther
and start to look at all of the exceptions,
and there are quite a few of them,
and some of them are actually pretty important,
and you may very well see some of these in your practice,
and, the point of talking about them
and going into a little bit of detail with each one of them,
is that you can be aware that if you see a situation
in which something isn't quite fitting
what you would expect from Mendelian inheritance,
even if it's a single-gene disorder,
there may be really good reasons for that,
and that could be falling into one of these categories
of exceptions and extensions to Mendel
and to Mendelian inheritance,
so, that is what's up next, thanks very much.