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[Dr. Wildin] Hello,
this is Dr. Bob Wildin.

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This lecture is about family history,

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family health history, and pedigree.

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And this is really talking
about how inheritance

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and of genetic material fits together

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with tools that we use in the clinic,

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namely family history and the pedigree.

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We're gonna start with inheritance basics.

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So as we've discussed before,
we have an egg and a sperm.

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And if those two happen to get
together on a Saturday night,

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you can get a zygote,

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and through mitosis
you generate an embryo,

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which is ball of cells
that grows and grows.

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And as it starts to take shape,

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we begin to it called the fetus.

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Now, in that ball of cells,
there are a few cells

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that are destined to
become germline cells.

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That is the gonads of the
individual the fetus will become.

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Those cells which will contribute

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to the germ cells in the next generation.

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The rest of the cells are
considered somatic cells,

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but all of those are undergoing mitosis

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through embryonic and fetal development.

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Now, if we go back up to the top here,

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what if the information inherited

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from the egg and the sperm is different?

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So we have DNA coming from the egg

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and DNA coming from the sperm.

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And what if there's something different

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about some of that DNA?

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Now what can different mean?

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It can mean that it's
different but normal.

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It can mean that it's different

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and maybe medically important.

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But what happens as a result
of that depends on the biology

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of that gene and its protein.

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It depends on what the status
of the other inherited copy,

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the inherited copy, say
in this case from the egg.

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It may depend upon the contribution

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of other genes and their variations

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and it could depend on other
mechanisms like imprinting,

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which can silence genes in a
normal fashion for some genes

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and an abnormal fashion for others.

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So this is really the
background of what we start

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to think about of and
that we wanna have in mind

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when we think about inheritance.

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And in the context of
taking a family history

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and inferring from the family history,

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what modes of inheritance may be active.

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So the risk of expressing
a genetic disease depends

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on a number of things.

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It depends on the risks of
inheriting disease alleles.

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So again, if you have
two copies from in mom

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and two copies in dad,
your chances are 50/50

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for inheriting any particular copy

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from mom or dad either way.

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And if those are disease alleles,

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it matters who in the family has those

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or is known to have those,

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or you can infer who has those,

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even if it's not your parents.

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Then you can calculate what
the risks your parents had

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of inheriting that and then the risks

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of them passing that on.

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And then there are also risks

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of having a new genetic
change occur when the egg

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and the sperm or the
sperm are being produced.

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Those new genetic changes
are rare but they do happen,

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and those do underlie
a significant portion

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of at least pediatric genetic disease.

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Now the risk of expressing
a genetic disease

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also depends on the mode of inheritance.

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So whether you need to inherit
a copy that is defective

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from mom and a copy that
is different from dad

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or whether you only
need to inherit one copy

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as an autosomal dominant
disorder from either parent

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in order to inherit the
risk of the disease,

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of expressing the disease.

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And the mode of inheritance
depends in turn upon how

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that particular genetic change affects

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the biology of the cell.

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And we'll go into more about that

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in the other parts of this module.

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So the risk of expressing
a genetic disease

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also may depend on other factors,

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whether or not there's
an environmental exposure

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to a substance, to medication,
to radiation, to sun,

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to all kinds of different
things in the environment

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that if you're not exposed
to, you may not ever express

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that disease of the
features of that disease.

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But if you are exposed to them,

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you have a much higher
risk than other people

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of having important
medical effects from that.

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It may depend on factors that
are just stochastic chances

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which we don't control and
don't have a known basis.

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And then there are unknown
influences as well.

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So this sort of smorgasbord
of different influences

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and on expressing a genetic
disease are what we need

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to keep in mind when we're
looking through a family history

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and interpreting a pedigree.

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Alright, when we talk about
an inheritance pattern,

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I'm talking about the mode of inheritance

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that best fits the pattern

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of infected individuals
observed in a family.

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And that, as I'm saying,
depends on the impact

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of genetic sequence and
copy variations on the gene

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and protein function.

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And it depends orthogonally on whether

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that particular gene resides

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on an autosome chromosomes
1 through 22, X or Y.

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And we can simplify the
function part of this equation

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to gain a function which
typically is inherited as a mode

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of inheritance of
dominant, loss of function,

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which typically has a mode
of inheritance of recessive,

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and dose sensitive, which
typically has a mode

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of inheritance of dominant, okay.

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Now here's my sort of inheritance grid.

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And this again, can have exceptions,

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but overall if you have
a gene on an autosome

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and it's a gain of function
or a dose sensitive,

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in other words you end up with
loss of one copy of your gene

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and that's sufficient to cause disease,

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then that's autosomal
dominant inheritance.

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If you live on an autosome

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and you have a loss of function mutation,

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and one good allele preserves
normality or prevents disease,

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then that's an autosomal
recessive mode of inheritance.

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If you live on the X chromosome,

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you have a gain of function,

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it's X-linked or X-linked dominant,

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loss of function X-linked recessive.

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If you live on the Y
chromosome, spoiler alert,

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very few genes on the Y chromosome,

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very few diseases are Y-linked.

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Again, a function or dose
sensitive is Y-linked

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or Y-linked dominant.

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You wouldn't necessarily say dominant

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because those Y genes
are uniquely on the Y,

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they're not on the X,

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the ones that we're talking
about being Y-linked.

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And so the dominance
doesn't come into play.

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The same thing for loss
of functional Y-linked

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is it's actually irrelevant

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'cause in males there's no
second copy of a Y-link gene

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except in that top PR
pseudoautosomal region

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which is also present on the X chromosome.

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Alright, so these are
also the abbreviations

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that we use very often.

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So autosomal dominant is AD.

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Autosomal recessive, AR.

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X-linked recessive XLR and
X-linked dominant XL(D).

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And those you'll see throughout genetics

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and they're good
abbreviations to understand.

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Alright, so what is a
family health history?

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So you look on, you know,
the TV and then on the web

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and you can hear about family history

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and you're talking about,
"Oh that's ancestry,

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that's about, you know, my grandfather,

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where my grandfather came from,

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and where my great-great-great
grandmother came from,"

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and those kinds of things.

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We're talking about family health history,

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which is a list of relatives

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with a set of metadata
associated with them.

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First one is are they alive or passed?

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Second is what are their health issues

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and what were the age of onset

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of those health health issues?

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Third is their relationship
to the consultand.

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In other words, are
these mothers, fathers,

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great maternal grandparents,

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maternal great uncles, et cetera?

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What are the relations to
the person, your patient,

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for whom you are collecting
this family health history?

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Family health history
can be considered a tool

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that is used to estimate
the risk of diseases

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in your patient and that
have a genetic component.

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And that's often by divining

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the most likely inheritance pattern.

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So the idea is you look
at the family history,

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you draw it out on a pedigree, you say,

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"Well what inheritance pattern
is this most consistent with,

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and what would be the risk
that my patient inherited

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that disease risk given
that inheritance pattern?"

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Okay, so it's a good
exercise to go through

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and repeat what I just said.

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Alright, the family health
history is typically obtained

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by a verbal interaction or
a written questionnaire.

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There are very few means currently

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to collect family health history directly

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from other family members' health records

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because of HIPAA concerns.

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So primarily you need to consider

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this a verbal recounted
history that has some potential

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to be both biased,
inaccurate, and incomplete.

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If it's really important
that you understand it,

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then you need to fill in those blanks,

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order the family member's
health history records

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and confirm what you need to know is true

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before making any critical
decisions on the basis of that.

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The family health history
is ideally supported

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by medical documentation,
what I was just saying.

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And it's really a required
part of medical history taking

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because it gives you information
about the patient's health

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and health risks that you really
can't get in any other way.

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So what is a pedigree?

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Pedigree is a visual representation

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of a family health history.

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It is a tool to visualize
all of the family history

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that you've collected at once in a kind

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of concise shorthand that
tends to be much easier

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to understand what's
going on in the family

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than a couple paragraphs of text.

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The pedigree also allows you
to encode family relationships,

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which is really important

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for understanding the
dynamics in a family.

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Pedigree is also useful as I
mentioned in the last slide,

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for inferring inheritance
and inheritance patterns

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and in estimating disease risks
to different family members.

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What does that last part mean?

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The last part means that some,

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if you have an individual
who has a disease

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with a genetic component,

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one of the things that you need
to be able to do is to say,

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"Well you have this
relative and this relative

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who aren't affected but they're at risk.

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So they need to understand
their risk better

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and let's try to help them do that."

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So having a complete family history

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in a pedigree allows you
to see who else might be

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in that line of inheritance,

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who else might be at risk
of a genetic condition.

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So what is the language of the pedigree?

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It's quite simple.

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And I've kind of broken
it out into these parts.

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This is also in your book

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and available on the web and other places.

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So this is the sort of
basics of pedigree language.

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In the next module we will talk

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about the more complex types of families,

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more modern types of families
and how to represent those

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because there are ways to do that.

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So the first thing is
that you have a person

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who's a male, a female, an unknown gender,

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represented by squares, circles,
and diamonds respectively.

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If you are doing shorthand
and you're saying,

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"Well my grandmother had
three brothers and two sisters

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and none of them had any
health issues of importance,"

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you can collapse those
into just say two symbols

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with a number in the middle of that shows

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there were three males in
that sibship, all right?

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In the next panel we're
talking about the status

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of that individual.

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Are they alive or are they deceased?

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In which case you draw a horizontal line

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from about 7:30 to about
2:30, 1:30 or 2:30,

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00:14:56,610 --> 00:15:00,720
and that represents a patient
who is no longer with us,

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00:15:00,720 --> 00:15:02,463
a person who's no longer with us.

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The second part of their
status is are they affected

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with any genetic condition?

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00:15:09,480 --> 00:15:13,860
Unaffected means there is an empty symbol,

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00:15:13,860 --> 00:15:16,470
affected as a filled symbol,

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00:15:16,470 --> 00:15:18,690
and if you have multiple
disorders you're tracking

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00:15:18,690 --> 00:15:22,770
in a pedigree, you can use
different kinds of symbols

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00:15:22,770 --> 00:15:25,590
or partial filling kinds of quadrants

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00:15:25,590 --> 00:15:30,090
or something like that to
represent different parts,

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00:15:30,090 --> 00:15:34,080
different disorders that are
all running in the family.

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Whenever you do that, you have
to remember to add a legend.

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In other words, put a
little box in the corner

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00:15:40,980 --> 00:15:42,570
of your pedigree drawing,

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00:15:42,570 --> 00:15:47,460
and draw and assemble
with a filling pattern

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00:15:47,460 --> 00:15:49,380
and then write down what disease

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00:15:49,380 --> 00:15:51,030
that filling pattern really means,

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00:15:51,030 --> 00:15:55,320
or what color it is, what
disease that really means.

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So that's the important
part of the affected.

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00:16:03,240 --> 00:16:06,218
Now a carrier, I left off this slide,

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and you can probably shout it out,

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but the carrier status
is represented by a dot

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00:16:15,300 --> 00:16:20,237
in the middle of a otherwise empty symbol.

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00:16:21,750 --> 00:16:26,100
The last status has to
do with the difference

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00:16:26,100 --> 00:16:31,100
between individuals in a family
who are genetic relatives

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00:16:31,800 --> 00:16:34,530
and individuals in a family who are part

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00:16:34,530 --> 00:16:37,143
of the family by virtue of adoption.

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00:16:39,030 --> 00:16:40,320
And you'll see in the book

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00:16:40,320 --> 00:16:44,760
and you'll see in older
references that adoption in,

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00:16:44,760 --> 00:16:48,150
you know, adopted into a family
or adopted out of a family,

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00:16:48,150 --> 00:16:50,550
have two different representations.

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00:16:50,550 --> 00:16:52,350
But the modern way of doing this is

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00:16:52,350 --> 00:16:56,952
to just use one representation,
which is brackets,

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00:16:56,952 --> 00:16:59,520
square brackets that are facing each other

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00:16:59,520 --> 00:17:01,173
on either side of the symbol.

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00:17:02,160 --> 00:17:04,290
All right, how do you tell

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00:17:04,290 --> 00:17:05,490
whether they're adopted in or out?

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00:17:05,490 --> 00:17:06,990
We'll get to that in a moment.

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00:17:08,700 --> 00:17:10,899
So the next panel is,

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00:17:10,899 --> 00:17:15,899
it focuses on sort of the
vertical lines in a pedigree.

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00:17:17,160 --> 00:17:21,450
Vertical lines tie together individuals

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00:17:21,450 --> 00:17:23,490
in generational relations.

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00:17:23,490 --> 00:17:27,171
Parent, child, grandparent, parent,

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00:17:27,171 --> 00:17:30,180
those generational relationships.

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00:17:30,180 --> 00:17:34,500
And they imply a passing on an inheritance

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00:17:34,500 --> 00:17:38,103
of genetic material as
discussed in the first slide.

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00:17:39,570 --> 00:17:42,120
A solid line really refers

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00:17:42,120 --> 00:17:45,690
to a genetic generational relationship

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00:17:45,690 --> 00:17:47,190
and a dash line refers

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00:17:47,190 --> 00:17:49,863
to a non-genetic
generational relationship.

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00:17:50,700 --> 00:17:54,120
So if you're thinking
ahead or looking ahead,

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00:17:54,120 --> 00:17:59,120
you can see that an adopted
person is represented the same

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00:18:00,420 --> 00:18:05,420
as any other sibling but with
square brackets around them

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00:18:06,030 --> 00:18:09,090
and the family that they're adopted into,

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00:18:09,090 --> 00:18:12,090
they do not have a genetic
relationship in with.

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00:18:12,090 --> 00:18:14,223
So the vertical line is dashed.

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00:18:15,270 --> 00:18:17,820
Now that adopted person does have

314
00:18:17,820 --> 00:18:20,850
a genetic generational relationship

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00:18:20,850 --> 00:18:24,380
and that might be represented this way...

316
00:18:29,430 --> 00:18:34,383
With representing the family
that they were adopted out of.

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00:18:35,790 --> 00:18:40,353
So there are ways to
diagram these features.

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00:18:42,570 --> 00:18:46,290
So let's talk about the horizontal lines,

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00:18:46,290 --> 00:18:51,290
which I characterize as social
relationships, marriage,

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00:18:51,780 --> 00:18:56,760
partnering, living together,
raising a family together,

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00:18:56,760 --> 00:19:00,600
even if there's not a mating genetic,

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00:19:00,600 --> 00:19:02,493
combining of genetic information.

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00:19:03,450 --> 00:19:06,420
So a horizontal line is
a formal relationship,

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00:19:06,420 --> 00:19:09,150
a solid line is a formal relationship

325
00:19:09,150 --> 00:19:13,080
such as marriage committed
partnership, so forth.

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00:19:13,080 --> 00:19:15,810
A dash line is an informal relationship,

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00:19:15,810 --> 00:19:18,450
which might be an informal relationship,

328
00:19:18,450 --> 00:19:21,032
a one night stand, who knows what.

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00:19:21,032 --> 00:19:24,600
So you can have a dash line there

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00:19:24,600 --> 00:19:26,970
to represent a second partner

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00:19:26,970 --> 00:19:31,593
that is not necessarily a
formalized relationship.

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00:19:33,630 --> 00:19:36,930
You can also represent here whether

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00:19:36,930 --> 00:19:40,110
that relationship persists.

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00:19:40,110 --> 00:19:42,690
So for example, in this
case you have a male partner

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00:19:42,690 --> 00:19:45,150
on the left, a female
partner in the middle,

336
00:19:45,150 --> 00:19:48,060
and suppose that marriage dissolved

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00:19:48,060 --> 00:19:51,990
and the children are now with their mother

338
00:19:51,990 --> 00:19:54,510
and the father is not in the picture.

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00:19:54,510 --> 00:19:57,630
You draw a double hash line across

340
00:19:57,630 --> 00:20:01,593
that relationship which
shows that it's no longer

341
00:20:01,593 --> 00:20:03,723
an active social relationship.

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00:20:04,590 --> 00:20:07,353
All right, so that's
pretty straightforward.

343
00:20:11,400 --> 00:20:14,760
Okay, so how do we infer
infer modes of inheritance

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00:20:14,760 --> 00:20:19,760
from the pattern of disease
in a family history?

345
00:20:20,730 --> 00:20:22,650
We talked about these
different Mendelian modes

346
00:20:22,650 --> 00:20:25,500
of inheritance, autosomal
recessive, autosomal dominant,

347
00:20:25,500 --> 00:20:28,233
X-linked recessive, X-linked
dominant, and Y-linked.

348
00:20:29,700 --> 00:20:34,540
I'm gonna refer you to this YouTube video

349
00:20:35,430 --> 00:20:40,140
and this is a lecture that I
gave at NHGRI back in 2015.

350
00:20:40,140 --> 00:20:43,500
And this link will take you

351
00:20:43,500 --> 00:20:48,293
to the 21st minute and 28th
second of that lecture.

352
00:20:48,293 --> 00:20:52,350
And you can watch about
eight minutes of that

353
00:20:52,350 --> 00:20:56,700
to understand how you infer
the mode of inheritance

354
00:20:56,700 --> 00:21:00,123
from the pattern observed
in a family history.

355
00:21:05,460 --> 00:21:09,750
All right, so in the
next module we are going

356
00:21:09,750 --> 00:21:14,750
to talk about weird and
complex stuff in inheritance.

357
00:21:16,980 --> 00:21:19,710
We're going to extend our discussion

358
00:21:19,710 --> 00:21:21,210
of Mendelian inheritance with talking

359
00:21:21,210 --> 00:21:24,240
about new mutations, decreased penetrance,

360
00:21:24,240 --> 00:21:26,310
variable expressivity.

361
00:21:26,310 --> 00:21:28,800
We're gonna talk about mutation mechanism

362
00:21:28,800 --> 00:21:31,383
including trinucleotide repeat expansion,

363
00:21:32,250 --> 00:21:33,570
and we're gonna talk

364
00:21:33,570 --> 00:21:37,380
about polygenic
multifactorial inheritance.

365
00:21:37,380 --> 00:21:40,290
We're also going to tie that together

366
00:21:40,290 --> 00:21:43,410
with learning more about
taking a family history

367
00:21:43,410 --> 00:21:46,500
and about the more complex representations

368
00:21:46,500 --> 00:21:49,020
that we can make in pedigrees.

369
00:21:49,020 --> 00:21:50,583
How to do those.