Practical-Haemostasis.com

A Practical Guide to Laboratory Haemostasis

 

Data Interpretation: Genetics



Introduction

This section of Practical-Haemostasis.com is designed to allow you to work thorough a number of clinical genetic scenarios that range from the relatively straightforward to the more taxing.

Question 1
This is the pedigree of a family with severe Haemophilia A. From the pedigree data shown below, what is the risk that III-3 is or is not a carrier?



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When you have derived this risk - if III:3 decided to have another child what is the risk that if this a boy he will have severe haemophilia A?


Question 2
This is the pedigree of a family with severe Haemophilia B [FIX:C <1 IU/dL.] From the pedigree data shown below, what is the risk that II-3 is or is not a carrier?




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If I:2 decided to have another child - what is the risk that this will be a boy with severe haemophilia B?


Question 3
This is the pedigree of a family with severe Haemophilia A.
1. From the pedigree data shown below, what is the risk that III-3 is or is not a carrier?
2. Why is II-2 an obligate carrier of severe haemophilia A?




Question 4
This is the pedigree of a family with severe Haemophilia B.

1. From the pedigree data shown below, what is the risk that III-5 is or is not a carrier? Using this data calculate the risk that she will have a child with severe haemophilia B.

2. Do you think that that the father of II:2 had severe Haemophilia B?



Question 5
This is the pedigree of a family with severe Haemophilia A [FVIII:C <1 IU/dL].

1. From the pedigree data shown below, what is the risk that III-4 is or is not a carrier?

2. The additional genetic information is generated using two linked intragenic markers within the F8 gene. The risk of recombination is negligible and can be ignored.
The two alleles are 0.8/1.1 [kb] and 4.8/5.2 [kb].

Using this additional data what is the risk the III-4 is a carrier?




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Is there still a role for linkage analysis in the investigation of families with haemophilia and if so why?

Would you use intragenic or extragenic [linked] markers for these types of studies


Question 6
This is the pedigree of a family with severe Haemophilia A.

1. From the pedigree data shown below, what is the risk that II-3 is or is not a carrier?

2. The additional information is generated using two intragenic markers within the F8 gene [0.8/1.1 and 4.8/5.2] and 1 extragenic marker [5.8/2.8]. The risk of recombination for the two intragenic markers is negligible and can be ignored but is 5% for the extragenic marker.

Using this additional data what is the risk the III-4 is a carrier?


Question 7
These are electropherograms from a region of the human F9 gene. What mutation is shown.




What severity of haemophilia would you predict that this mutation is likely to lead to and why?


Question 8
In the following pedigree, II:3 died from neonatal purpura fulminans secondary to homozygous Protein C deficiency. His sister [II:1] seeks genetic counselling to establish the risk that her baby [III:1] will have homozygous Protein C deficiency.

For the purposes of this exercise, assume the frequency of Protein C deficiency in the population is 1:500.

What is the risk that III:1 will have homozygous Protein C deficiency?




Question 9
In the following pedigree, II-1 has 2N Von Willebrand Disease. He and his partner consult you as they are keen to know the risk that their child will also have 2N VWD.



What is the risk that III:1 will have 2N VWD?
What is the risk that II:3 will have 2N VWD.
[Assume that the frequency of the 2N heterozygosity in the general population is 1:750.]

Would mutational analysis help in this family?


Question 10
In the following pedigree, I-1 has Severe Haemophilia A [FVIII:C <1 IU/dL] and his partner [I-2] has 2N Von Willebrand Disease.

[Assume that the frequency of VWD 2N heterozygosity in the general population is 1:750.]



What are the risks for II-1 that:
1. They will have a son with severe haemophilia A?
2. They will have a son with 2N VWD?
3. They will have a daughter who is a carrier of severe haemophilia A?
4. They will have a daughter with 2N VWD?

Would mutational analysis help in this family?


Question 11

You are asked to see a family with a bleeding disorder and obtain the following information:

My father had severe haemophilia A.
My mother had no problems but her father had severe haemophilia B [I think]. My mother has two elder sisters and an elder brother. Her brother [the eldest in the family] is fine with no problems and her eldest sister is well although has no children. She did bleed heavily after having her wisdom teeth removed and needed to go back to hospital. My mother's other sister is well but she has a boy with severe haemophilia B.
I have a brother and a sister. My elder brother is well and has no children. My younger sister has a boy with severe haemophilia A.
I have two sons. My youngest boy has severe haemophilia A and the other has severe haemophilia B which is odd and I have never understood how this could happen.

From this information - construct the family pedigree. Carefully identify the carriers including both obligate and potential carriers.


Question 12

A 45-year-old man is diagnosed with Type 1 antithrombin deficiency [AT:Act 45 U/dL] and is concerned that he may have passed it onto his three children. His partner has normal functional antithrombin levels. He consults you and asks what is the risk that all 3 of his children will have Type 1 Antithrombin deficiency.
[Remember - Antithrombin deficiency is inherited as an autosomal dominant disorder.] In the pedigree we have assumed all 3 children are affected but this may not be the case.

The Family Pedigree is shown below:


What are the risks that:
1. All 3 of his children will have Type 1 Antithrombin deficiency.
2. All 3 of his children will be normal?
3. 1 of his children will be affected?
4. 2 of his children will be affected?


Question 13

This is the pedigree of a family with severe Haemophilia A. No mutation data was available and linkage analysis was used to establish the carrier status of II:3.

The Family Pedigree is shown below:

1. Why is I:2 an obligate carrier of Haemophilia A?
2. Is II:3 a carrier or not?


Question 14

Look at the following pedigree which is from a family with severe Haemophilia A. III:1 and III:2 are identical twins.
1. What would you predict the FVIII levels to be in twin III:2?
2. Why are II:2 and II:3 identified as obligate carriers of haemophilia?

The Family Pedigree is shown below:




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Try to avoid looking at the answers until you have worked through the questions.