7356190_MEDN67561_MidTerm

MSc Genomic Medicine

2016-17 1st Semester

MEDN67561: An Introduction to
Human Genetics and Genomics

Student Number: 7356190

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Assignment questions
An Introduction to Human Genetics 2016-17
MSc Genomic Medicine
(Optional for students on STP programme in Genomic Medicine and Genetic Counselling)

PART 1 (70% of mark)

Zainab Bilal Fatima Usman

Rabia
Zainab and Bilal, who are first cousins, are referred to the Genetics clinic in pregnancy
as they have a relative (Rabia) who died of a very rare severe metabolic condition that
follows autosomal recessive inheritance. They wish to know the chance of having a child
affected by the same condition.

1. On the basis of the pedigree provided above, and outlining any assumptions
you make, estimate the probability that

a. Zainab is a carrier
1 in 2 chance Zainab is a carrier.

Due to the condition being very rare, we can make an assumption that anybody who
is married from outside the family is not affected or unlikely to be a carrier; i.e.
Rabias grandmother, Zainabs mother and Fatimas father are not carriers or affected.
We already know Rabia had the disorder which means both of her parents were
carriers. Which indicates that Zainabs mother, father or both might have also been
carriers (higher chance of them being carriers as we are 100% certain that one of their
children were a carrier).
Studies have also indicated that siblings of known carriers of rare genes have a higher
chance of being carriers.

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b. Bilal is a carrier
1 in 8 chance Bilal is a carrier.

Bilals mums chance is

Chance of bilals mum being a carrier is because she is Zainabs fathers sister who
has a chance.
Any second degree relative of the affected have chance of being a carrier and any
relative a step away from that, i.e. third degree will be chance of that.

c. Their current pregnancy is affected

Chance of Bilal and Zainabs child being affected is x 1/8 x which is 1 in 64.

When two parents are carriers:

R r

R RR (p2) Rr (pq)

r Rr (pq) rr (q2)

So the child can either be RR 1 in 4 chance, Rr 2 in 4 (1 in 2) or rr. 1 in 4

chance.

2. DNA testing is available for this condition, but only picks up 80% of disease-
causing mutations. If Zainab and Bilal want carrier testing, what further
information/samples would you ideally want to help interpret their results?

Only picks up 80% of disease causing mutation, so even if Bilal has the disease
causing mutation, there is a 20% chance that it might not show up on the DNA
testing.
It isnt possible to test Bilal or Zainabs parents to calculate their chance of
inheritance as they have passed; however, you can test Fatima, to work out if she is a
carrier, in turn it could give us an idea if Bilals mother or father was a carrier.

Bilals sister Fatima and her (unrelated) partner Usman are also then referred to the
Genetic clinic in pregnancy.

3. Use Hardy-Weinberg to estimate the probability that Usman is a carrier, if the

incidence of the condition in the population is 1 in 1,000,000.

p2+2pq+q2=1
p+q=1

Frequency of individuals = Individuals / Total population

Incidence of condition = 1 in 1,000,000 = 0.000001

percent of population that has recessive trait: 0.000001%

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Punnet square with frequency:

R r

R RR (p2) Rr (pq)

r Rr (pq) rr (q2)

Incidence of condition = 1 in 1,000,000 = 0.000001%

Rr = 0.001998%

q2= 0.000001Recessive frequency rr

q = 0.001
p = 1 0.001 = 0.999
p2 = 0.998001 frequency of individuals with dominant genotype
2pq = 0.001998 frequency of individualswith heterozygous genotypes Rr

Although Hardy-Weinberg doesnt work with consanguinity, if a recessive disease occur

within consanguineous families; by using HW it will overestimate the frequency of carriers
in the general population.

4. Fatima and Usman each have the carrier test that picks up 80% of the disease-
causing mutations. Fatima is found to be a carrier, but Usman has no detectable
mutations. Use Bayes to refine the probability that:

a. Usman is a carrier

Usman Gene carrier Not gene carrier

Prior risk
(on basis of population 0.001998 0.998002
carrier frequency)

Conditional
(Negative test result with 2/10=0.2 1
80% sensitivity)

0.001998*0.2= 0.998002*1=
Joint Risk
0.0003996 0.998002

0.0003996/ 0.998002/
Final Risk (0.0003996+0.998002)= (0.0003996+0.998002)=
0.00040024 0.99959976

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b. their current pregnancy will be affected

0.00040024x1x0.25=0.00010006

PART 2 (30% of mark)

1. Describe the features of a pedigree that might make you suspect X-linked recessive
inheritance.
X-linked recessive disorders mostly occur in males. Male only have 1 X chromosome
and a single mutant gene on that X chromosome can cause the disorder.
If the mother is a carrier all male offspring are affected.
If a mother who is a carrier has a child with a man who is not affected, then there is
chance of a healthy boy, chance of having a son with the disorder, chance of
having a healthy girl and of having a girl who is a carrier but does not have the
disorder.
Whereas if a man with the disorder has a child with a woman without the disorder, the
expected outcomes would be 100% chance of having a healthy boy and 100% chance
of having a baby girl who is a carrier of the disorder but without the disorder.
All female offspring of infected male are carriers, they themselves will not show traits
however their sons will.
In a lot of families, affected individuals have affected maternal uncles.
X-linked disorders are never transmitted father to son.

Examples of X-linked recessive disorders include:

Ichythyosis
Red-Green colour blindness
Duchene Muscular Dystrophy
Haemophilia

2. For a severe X-linked recessive condition that always causes males who are affected to
die in early childhood, in the absence of any genetic testing explain how you could
estimate the probability that the mother of an isolated affected boy (i.e. no known
prior family history of the condition) is a carrier. Clearly state any assumptions
involved.

2/3 chance of mother being carrier

1 in 3 of all the X chromosomes in population belong to males; therefore 1/3 of all X

chromosomes in population are in males
Males only have 1 x chromosomes therefore just a single recessive gene on that x
chromosome may case the disease.

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If a mother has an affected son, but we dont know if other members of the family is affected
then the probability of her being a carrier is:
(u+v)/(2u+v)
Where u = mutation rate of female germ cells
Where v = is the mutation rate in male germ cells

The probability that she is not a carrier and that the son is therefore the result of a new
mutation is:
1-[(u+v)/2(2u+v)] = u/(2u+v)

End of question

https://www.ncbi.nlm.nih.gov/books/NBK22113/

https://medlineplus.gov/ency/article/002051.htm
Feero WG, Zazove P, Chen F. Clinical genomics. In: Rakel RE, Rakel D, eds. Textbook of
Family Medicine. 9th ed. Philadelphia, PA: Elsevier Saunders; 2016:chap 43.

Groden J, Gocha AS, Croce CM. Human basic genetics and patterns of inheritance. In:
Creasy RK, Resnik R, Iams JD, Lockwood CJ, Moore TR, Greene MF, eds. Creasy and
Resnik's Maternal-Fetal Medicine: Principles and Practice. 7th ed. Philadelphia, PA:
Elsevier Saunders; 2014:chap 1.

https://www.urmc.rochester.edu/Encyclopedia/Content.aspx?
ContentTypeID=90&ContentID=P02164

https://medlineplus.gov/ency/article/002051.htm

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