Risk Calculation in Mendelian Inheritance

Mendelian Inheritance

Part 2
Risk calculations with and without
markers
Slide 2

Objectives
(combined for the two Mendelian inheritance/risk lectures)
• Define allele, gene, genotype, phenotype,
homozygote, heterozygote, hemizygote,
haploinsufficiency
• Recognize the patterns of Mendelian inheritance
from pedigree charts or descriptions.
• Understand Punnett square as a tool in risk
calculations, and understand the expected gametes
in a heterozygous person
• Predict the carrier probablilities in pedigrees with
inherited Mendelian diseases.
• Calculate disease risk (= recurrence risk) in families
with established Mendelian disorders.
• Recognize and make predictions from examples of
unusual inheritance patterns such as sex-limited or
mitochondrial inheritance
• Define the concepts fitness, penetrance,
expressivity, pleiotropy, allelic heterogeneity, locus
heterogeneity, phenocopy, genetic, congenital,
delayed age of onset, genetic marker, and recognize
the presence of any of these in a case description
For all concepts, be prepared for a case description
where your job is to extract which concept is
covered by the description.
• Specifically for Risk Calculations in Mendelian
inheritance:
• Calculate disease risk in families with established
Mendelian disorders.
• Calculate the risk of disease in a family using a
closely linked marker to predict the presence or
absence of a bad allele in different members
• Readings: Turnpenny & Ellard: Emery’s elements of
Medical Genetics: most of chapter 7 and Calculating
risk on pg 266-67, and
• Strategy for determining inheritance patterns (my
own handout)
• Other resources: Kahn’s Academy has plenty of
short videos on fractions if you are foggy on using
those.
•Sample questions will be available in
Ecollege

I have included all objectives for the Mendelian Inheritance Patterns lecture here. This is done
to remind you that all exams are cumulative, you can have questions on all topics from the past.
The new objectives for this lecture are surrounded by a box.
Slide 3

Before We Start
• What is most important in genetics?

• To think of the patient as part of a family!

Facio-scapulo-humeral muscular dystrophy

Slide 4

Albinism
(= Oculocutaneous Albinism = OCA)

1) What is the risk that the incestuous

offspring will suffer from albinism?
2) What is the risk that an offspring of II-4
with an unrelated man will be an albino?

Incestuous is a legal term, not a genetic term. What is incestuous depends on where you are.
However, marriage between siblings have not been encouraged since the Pharaohs of ancient
Egypt.
Slide 5

Strategy
• For whom do you need to know the carrier
risk?
• For each, find the nearest affected
• From that affected, going one step at a time,
calculate the risk through the shortest path to
the unknown person

Apply this strategy for all risk calculations, not only the one presented here.
Slide 6

Question No 1

• Sub-questions:
‘aa’ only produces
What is the genetic ‘a’ gametes
constituency of II-7, Aa Aa
which gametes can he A a
produce?
A AA Aa
What is the risk that II-6
is a carrier of albinism? a Aa aa

I will go through the process described here and in the following slides in class

For the Punnett square shown here: II-6 is the sibling of an affected so both her parents must be
heterozygote carriers (they are not homozygotes because none of them are affected). She is
herself not affected so the lower right-hand corner of the Punnett square does not apply. That
leaves three options, two of which are carriers.
Regarding this conclusion: 2/3 as carrier risk for the sibling of an affected applies if:
• Inheritance pattern is autosomal recessive (none of the others!)
• Both parents are unaffected
Slide 7

Question 1 (Contn’d)

• The risk that II-6 is a carrier is 2/3

• The risk that she passes on an allele for albinism
is?
• If she is a carrier, the risk for passing it on is ½; her
composite risk of passing on an ‘a’ allele is
therefore ½ x 2/3 = 1/3
• II-7 is an albino, can only produce ‘a’ alleles
• The risk of having an albino child is therefore 1/3
x 1 = 1/3 (product of risk that each passes on the
bad allele)

Regarding the first bullet: 2/3 as carrier risk for the sibling of an affected applies if:
• Inheritance pattern is autosomal recessive (none of the others!)
• Both parents are unaffected
Slide 8

Question 2
• II-4 only can produce ‘a’ alleles
• An unrelated man will have a risk that is the
same as the population risk of carrying the
albino allele (except if he is related to an
albino)
• The population risk is 1/50 = 2%
• His risk of passing on an ‘a’ allele is therefore
½ x 1/50 = 1/100 (= 1%)
Slide 9

Cystic Fibrosis

• What is the risk that the marriage

between II-3 and II-4 will produce a child
with CF?
Incidence CF
1/2,500
Incidence new
mutations 1/10,000-
1/100,000

The notes to the right of the pedigree are telling you that the risk is much higher for having CF
as result of regular inheritance than as a result of two new mutations. Answer to the question
will be spelled out in class and is also found on the following slides.
Slide 10

Answer
• II-4 has a 2/3 risk of being CF carrier (Aa);
therefore 2/3 x ½ = 1/3 risk of passing ‘a’ on
• II-3 has a population risk of 1/22 for being a
carrier; 1/22 x ½ = 1/44 for passing the ‘a’
allele on
• Risk for the child is therefore 1/3 x 1/44 =
1/132 = 0.75 %
Slide 11

Answer: Different Look

1/22

2/3
1/22 x ½ x 2/3 x ½ = 1/132 (= 0.75%)
Slide 12

Cystic Fibrosis (2)

• What is now the risk that the marriage between

II-3 and II-4 will produce a child with CF?

Please note the following: A person with genotype Aa has a carrier risk of 1. As a result of that,
the risk of III-4 is different and higher than the risk in the previous pedigree where he was a
sibling of an affected.

That is because the mother has a risk of 1 for being affected and a risk of 1 for passing on the
disease-causing allele.
Slide 13

CF – Marriage of Cousins?

Refer back to the slide with the strategy

Slide 14

CF – Marriage of Cousins?

One of these must have Aa

(each have risk of ½ Aa)

½ Aa Aa Aa

1/4 Aa

2/3 Aa

¼ x ½ x 2/3 x ½ = 1/24 (= 4.17%)

Slide 15

X-linked Recessive
Risk for III-2 being affected?

One very important observation: a healthy male is not a carrier in an X-linked recessive disease:
he has only one X.

When going through this question, there is a multiplication with an extra ½ because among
offspring that receive the disease-causing allele, female offspring are carriers (not affected) but
male offspring are affected. One way of expressing what you do with that extra ½ is to say: you
divide the world into boys and girls. One continuation of that is that you do not need to divide
the world if someone else have done it for you. Consider these two answer choices
• ¼
A) ½ for a son, about 0 for a daughter

These two say precisely the same! If you look at the Punnett square with a carrier mother and a
healthy father you will see that ¼ of all children are affected, but also that the affected person is
one of 2 boys in that Punnett square and that the daughters (as expected) are not affected.
Slide 16

X-linked Recessive
Risk for III-2 being affected?

What is different between this and the previous pedigree?

Slide 17

What is this?
Slide 18

What is this?

Sickle cell =
pseudo-dominant

Pseudo-dominant family in a disease that is a known autosomal recessive

Slide 19

Use of Linked Marker

Slide 20

Inheritance of Two Different Loci?

Locus 1: alleles 1a and 1b

Locus 2: alleles 2a and 2b 1a 1b
2a 2b
• If on different
chromosomes:
random transmission
=> 1a and 2a together
50% of the time
Slide 21

Linked markers Locus 1: alleles 1a and 1b

Locus 2: alleles 2a and 2b
• If close together on the
1a 1b
same chromosome: 2a 2b
linkage, 1a and 2a together
100% of the time
• For this section, we want
loci being so close together
that they are not separated
by recombination

Definition of marker: a polymorphism (e.g., microsatellite) that

is used to identify a chromosomal segment; can for example be
used to predict carrier status of a person

Polymorphisms are pre-existing in the genome, we only detect which alleles are present in a
given person.
Slide 22

What is a marker

• Below are two copies of same chromosome

• Gene is at left, marker (CA-repeat) at right –
these are inherited as a unit!

So if the asterisk illustrate a mutation, what happens to the offspring getting the long allele of
the microsatellite?
Slide 23

Meiosis With Recombination

Recombination happens with a probability correlated with distance along the chromosome. In
this lecture we want gene and marker so close together that we can ignore the risk of
recombination.
Slide 24

What Is the Point?

• If one of the loci has an allele that predisposes
for an inherited disease
• AND you don’t know the sequence of that
gene (or at least not of the disease allele)
• You would be helped by using a linked marker
to predict if a person has inherited the bad
allele
Slide 25

Linked RFLP marker in Huntington Disease pedigree

You will hear much more about Huntington disease during Repro 1
Slide 26

Notes for previous slide

• A and B are two different marker alleles.
• A and B are not alleles of the Huntington gene!
• The alleles present in the Huntington gene are
inferred from the phenotype of those above the
age of onset.
• Strategy: use first two generations to identify the
marker allele in coupling phase with the disease
causing allele
– Then apply that information to generation III.
Slide 27

Coupling Phase
• When looking at a pair of
chromosomes, what is located on
H h the same chromosome?
B A • H and B are in coupling phase
• h and A are in coupling phase
• Haplotype is essentially the same
but not limited to two loci.

One example of haplotype is H and B being together above. Another could be that with four
different markers, one chromosome carry alleles 7, 6, 1, 2 (in that order).
We will return to the concept of haplotype in future lectures.
Slide 28

h h H h
A A B B

H h
B A
h h
A A

H h
B A

Here is an illustration of the two chromosomes in each of the most important people in the
pedigree. Notice that the grandmother has one chromosome carrying disease-causing allele and
marker allele B and another where the normal allele in the gene is together with the same
marker allele B. That might be counter-intuitive for some of you but it is a pattern that is to be
expected.
Slide 29

Markers in HD (2)

Second example of Huntington disease

Slide 30

Markers in HD (3)

And a third example

Slide 31

Notice that for recessive cases, the strategy is different: start with the affected child. For AR,
both chromosomes carry a disease-causing allele so both marker alleles are in coupling with
such an allele. Follow the two chromosomes back to parents (one each) and only apply to other
offspring from the parents. If you try to jump across from the affected to the other offspring
without including the parents, then you will likely get the result wrong.
Slide 32

Second example of AR
Slide 33

Hemophilia

Well

The X-chromosome is much larger than the Y, so for most analyses of X-linked markers, there
will be nothing seen from the Y.

Secondly, if two bands end on top of each other, they may or they may not result in a band that
is wider/heavier than if only one bands is present in that location.

Strategy: For the XR case, the affected boy has only one X chromosome and the marker on that
X is therefore in coupling with the disease causing allele of the gene. Go from him to the
parents and from those to the other offspring.
Slide 34

This is aimed at talking about mutation rate of markers, rate of non-paternity, etc.