Our third podcast, in this series on basic genetics, is going to deal with
autosomal inheritance and here we'll assume we're talking about Mendelian
inheritance. And you're gonna need to learn how to read symbols on pedigrees.
For this podcast, you at least have to understand what the symbols are for
normal females and males. You need to understand that this double bar between
symbols means a mating between close relatives, in other words a consanguineous
marriage or a consanguineous mating. And here, we'll you see a symbol with a
dot in the middle, that's indicating a carrier. Now, we don't always put that dot
in the pedigree, but you need to know that at least for this discussion in
this podcast. So, let's consider first autosomal dominant inheritance and here
we generally considering a structural defect, particularly like a skeletal
defect or maybe a cardiac defect. Autosomal dominant inheritance usually
arises from a union of an unaffected parent with an affected heterozygote. Now,
do understand that every genetic disease does have a spontaneous mutation
occurrence rate, we're not considering that just yet. So, an affected parent will
pass either a disease gene or a normal gene to a child.
Each of these has a probability of 0.5. The pedigree shows the characteristics
of autosomal dominant inheritance. So, it appears equally in either sex.
It does not skip generations, so we talk about a vertical pattern of inheritance.
There is father-to-son transmission, so it's not x-linked and affected
heterozygotes will pass the trait to roughly half of their children. Now, again,
here was saying roughly half the children, this is a small family pedigree
so you can't divide 3 children, you know, into half. But, you do say the recurrence
risk is always one-half for passing an autosomal dominant mutation to each
child. Each child born as an independent event, the recurrence risk would be 1/2
and that's going to assume complete penetrance. We'll talk about penetrance
in a later podcast. What do we mean by recurrence risk? That's simply a term
that would say what is the likelihood of passing a genetic disease from parent to
child. That is particularly important if a couple presents for counseling if
they've already had a child affected with a genetic condition. They want to
know what's the likelihood that the next child will have the same condition. Here
we're going to look at risk assessment for autosomal dominant inheritance. So,
you would have an affected heterozygous parent, I'm representing that by the big
A colored red, mating with a normal homozygous parent. The affected parent is
usually heterozygous because homozygous autosomal dominant conditions are very
often, not always, but very often genetically lethal. A good example of
genetically lethal autosomal dominant condition in the homozygous form would
be osteogenesis imperfecta. So, the punnett square clearly shows 50%
of the children would be normal, and they'd be little A-little a in this
punnett square, and 50% would be affected with the autosomal dominant condition,
that'd be big A-little a. And again, this is going to assume complete penetrance
and I'll talk about penetrance later. What if both parents are affected
heterozygotes? So, a big A-little a marries another big A-little a, then 50%
of the individuals heterozygous and affected, 25% a likely to be genetically
lethal if this is a condition like osteogenesis imperfecta, 25% would be
normal. Now, let me tell you what I mean by genetically lethal. That doesn't
necessarily mean that an individual won't come to term and be born alive, but
a genetic lethal would assume that the individual cannot reproduce. So,
what's normal? Here's a condition that some of you may
have heard of its called achondroplasia. It's an autosomal dominant condition and
if you're heterozygous for this mutation you're going to be dwarfs. So, it's a genetic
form of dwarfism. These individuals lead a fairly normal life, as they have normal
intellectual capacity and they can do things that most people do. They are just
quite a bit shorter. You have a couple, two dwarfs that marry and they want to
say what's the probability of them having children that looked just like
them. Normal for them would be short children. So, you have to be careful what
you're asking and how you counseling patients. Suppose you have an affected
homozygous parent if the condition is not lethal marrying a normal homozygous
parent, then a 100% of the offspring would be affected
heterozygotes. There are some forms of Marfan, for example, an autosomal dominant
condition or Noonan syndrome, another autosomal dominant condition, which is
not lethal in the homozygous dominant condition and indeed sometimes those
individuals can reproduce. Let's look at autosomal recessive inheritance. This is
generally a metabolic defect and it usually results from the union of
heterozygous carriers. So, in our punnett square example there's a carry apparent big A-
little a with another carry apparent big A-little a.1/4 of the offspring are gonna
be unaffected homozygotes, so big A-big a, half are going to be unaffected carriers
big A-little a, and 1/4 are going to be affected homozygous recessives with the
diseased phenotype. As the pedigree shows characteristics of autosomal recessive
inheritance, it's usually seen in siblings but not in parents. So, on the
pedigree here are two sibs that show the disease but
you don't see it in the parents. It's a horizontal pattern of inheritance. So, you
see it in one generation but you don't see it in preceding generations. Here, the
little dots within the symbols are indicating that these were carriers. If
it's a large family, they'll be equal numbers of males and
females that are affected. And consanguinity, as shown here, is often
present if this is a very rare autosomal recessive disorder. The recurrence risk
is usually 1/4 if the parents are heterozygous carriers, but it can be 1/2
if one of the parents is homozygous for a disease gene. So, what's the risk
assessment for autosomal recessive inheritance? You have normal heterozygous
parents, these are carriers. That would suggest the 25% of the offspring are
going to show the disorder little a-little a .I've indicated the recessive
gene as a little a but colored blue. 50% of the offspring are going to be normal
heterozygotes but carriers, they'll be big A-little a and 25% are going to be
normal and then not going to be carriers. What's the risk for normal children to
be carriers? Well, here you'd have to think of this for a minute in relation
to the punnett square. We know that 25% of the children are going to have the
disease condition, so they're not normal in that case. The normal children are
either going to be homozygous and not show the condition or they're going to
be heterozygous carriers. So, you can see in this situation then that the risk for
phenotypically normal children to be carriers would be 2/3. Suppose an
affected homozygous parent little a-little a marries a normal homozygous
parent big A-big a, then a 100% of the offspring are going to be
phenotypically normal but a hundred percent of the offspring are going to be
carriers big A-little a. Suppose an affected
did homozygous parent little a-little a marries a heterozygous carrier big A-
little a. Again, doing the punnett square, you'll see that 50% of the children are
going to have the recessive disorder and 50% gonna be phenotypically normal but
they will be carriers. So, this cartoon shows autosomal dominant inheritance and
autosomal recessive inheritance. In the autosomal dominant, there's going to be a
50% chance the children will be normal and a 50% chance that children will be
affected. And this, again, assumes complete penetrance. If it's an autosomal
recessive condition 3/4 of the children going to be phenotypically
normal, 1/2 the children are gonna be carriers, 1/4 of the children are going
to be affected with the disorder, and 1/4 of the children are going to be normal
and not carriers. Now, how come this cartoon shows the parents as unisex? Let's
say that was a trick question in a sense and it's because we're talking about
inheritance here on the autosomes. We're not talking about inheritance by the sex
chromosomes.