Meriel McEntagart: Are genetic conditions always inherited from parents?

In this explainer episode, we’ve asked Meriel McEntagart,
Clinical Geneticist in the NHS and Clinical Lead for Rare Disease
Technologies at Genomics England, to explain how genetic
conditions can be inherited, and other ways they may arise.


You can also find a series of short videos explaining some of the
common terms you might encounter about genomics on our YouTube
channel.


If you’ve got any questions, or have any other topics you’d like
us to explain, feel free to contact us on
info@genomicsengland.co.uk.


To learn more about X-linked inheritance, as mentioned in the
episode, tune in to our explainer episode, how does X-linked
inheritance work?


You can download the transcript or read it below.


Florence: Are genetic conditions always inherited from parents?
I'm joined by Meriel McEntagart, clinical geneticist for the NHS
to find out more. So, Meriel, first things first. How can a
genetic change cause a condition?  


Meriel: We have about 20,000 genes. That's the estimate and they
are the code or blueprint for how to grow and develop a human
being. And, if you think about a code, you can have a
mistake in a code or a variant in a code. And if that happens,
such as one genetic letter being changed for another, the result
can be that the code doesn't give the correct instructions about
how to grow and develop that human being. There are lots of
different ways in which those changes can happen. 


Florence: And how can we inherit conditions from our parents?
 


Meriel: Well, for the most part, like I mentioned, we've got
20,000 pairs of genes and we get one of each pair from our mother
and our father. And so, for lots of genetic conditions, they
follow a pattern of inheritance where one copy of that pair of
genes has got the variant or spelling mistake in it, which causes
the condition. 


So just having a single mistake in that pair of genes is enough
to cause you to develop the symptoms of the condition. Other
conditions show where you only develop the condition if both
copies of the pair, the one you get from your mother and the one
you get from your father have got a variant or a spelling mistake
in the gene. 


So, you actually don't have a working copy of that gene. There
are other patterns of inheritance as well. And so, we talk about
X-linked inheritance. That can arise because women have what we
call two X chromosomes; men only have one X chromosome. 


Florence: If you want to learn more about X-linked Inheritance,
you can check out our previous podcast. How does X-linked
inheritance work? So then do parents who have a condition always
pass it on to their children? 


Meriel: So, this is again, where we think about some of those
patterns of inheritance that I've just mentioned. If somebody has
a condition, for example, a dominant condition, they will have
that variant or genetic change that's causing their condition in
one of their pair of genes. So then it's 50:50 when they have a
child, whether they pass on the gene that's carrying that variant
or not, because the child will be getting the other copy of that
pair from their partner. 


If they do inherit that copy with the variant in it, then they
will develop the symptoms of the condition in most cases. In some
situations, however, a parent can have a genetic condition. So,
they develop symptoms of the condition, and as I've mentioned,
it's 50:50, whether it gets passed onto the child, so the child
could actually inherit that genetic variant, but potentially not
show signs of the condition. And this is what we call ‘reduced
penetrance’. This means you can carry a genetic variant and
probably some other event has to take place to cause you to
develop symptoms. 


So that might be that there's other genetic factors that you
inherit that trigger you to develop symptoms or there might be an
illness or something that you experience that brings out the
expression of that gene. So that's quite an important,
consideration when we're looking at genetic variants and whether
somebody will develop symptoms. 


Florence: And finally, how do we develop conditions that don't
come from our parents? 


Meriel: Well, I suppose the main explanation for that is what we
call a de novo genetic event. So that can arise when we are
conceived. So for example, genes get copied to be put into the
sperm or our genes get copied to be put into the egg. And in that
process of making the sperm and the egg, a spelling mistake or
mutation can arise in the DNA and then that sperm or that egg,
whichever one has it, takes that forward into making the baby.
And then the baby from that point will have that genetic variant
in every single cell in their body. So it hasn’t come from the
parents, so it’s not inherited but it still is a
genetic condition.


This is something that now that we're able to do
whole genome sequencing, we are finding is a more common
explanation for developmental disorders or conditions in children
than we previously appreciated. And quite a lot of conditions
where the child has congenital abnormalities when they're born,
like a congenital heart problem with some global development
delay or difficulties or some other sort of problem, when we do
their whole genome sequencing, we find that they have a de novo
mutation in an important developmental gene. 


There are also some more unusual ways in which a genetic
condition can arise for the first time in the family. The first
example I might give is, the condition, Huntington's disease.
Huntington's disease is a neurodegenerative condition that causes
a movement disorder, often starting in adult life. And sometimes
people will know that it's in their family. However, sometimes it
can arise in somebody and there's no history of it in the family
at all.  Huntington's disease is what we call a triplet
repeat condition. This is where, in our DNA sometimes we have
little strings of letters that are repeating after each other.
So, usually we'd have 25 repeats or less. This can slip up on
transmission from a parent to the child, so it can increase in
size and if it slips up into the range of 40 repeats or more,
then that person will develop symptoms of the condition. 


Another example I thought that might be worth mentioning is what
we call imprinting. When we inherit our genes from our parents,
for some genes, it actually matters whether the gene copy has
come from your mum or from your dad, and it will have an imprint
or a mark on it that says, this is the maternal copy, this is the
paternal copy. 


The reason that imprint is there is that it may potentially
switch off that gene and say, this shouldn't be expressed in the
baby. And if this doesn't work properly, you can get some
conditions like for example, Prader-Willi Syndrome. This is where
a child has developmental delay and maybe a very increased
appetite. And it's because the differential gene expression
hasn't worked.


Florence: That was Meriel McEntagart, explaining whether genetic
conditions are always inherited. If you would like to hear more
explainer episodes like this, you can find them on our website at
www.genomicsengland.co.uk. Thank you for listening.