1. Monogenic Disorders Case Studies
Noelene Kinsley
Genetic Counsellor MSc (Med) Wits
7 June 2017

2. Outline
Use case studies to demonstrate the different features of monogenic disorders and the genetic counselling process.

3. Case Study 1: Sickle Cell Disease
A couple come to the prenatal clinic asking about the risk for their child to be ‘SS’ as their two other children, a son and daughter, both have the sickle disease. The woman is about 12+ weeks pregnant and wants to know the risk to her baby.
What disease are they talking about?
Do you know the difference between AS,AA and SS?

4. Case Study 1: Sickle Cell Disease
A couple come to the prenatal clinic asking about the risk for their child to be ‘SS’ as their two other children, a son and daughter, both have the sickle disease. The woman is about 12+ weeks pregnant and wants to know the risk to her baby.
What disease are they talking about?
Sickle cell disease
Do you know the difference between AS,AA and SS?
Heamoglobin presented in the blood
A-Adult Hb and S- Sickle HB
AA Unaffected AS Carrier SS Affected

5. Case Study 1: Sickle Cell Disease
You ask for the family history. The woman (IV-5) says that it is not in her family as there is no history and she is not Nigerian. Her great grandfather came from the Tanzania. The man (IV-4) mentions it doesn’t come from his family. He has twin brothers one died at 2 years from a stroke, the other is fine. His half sister may have sickle but she is AS.
Using the pedigree, what would you say the inheritance in the father’s family is?
What is the woman’s view regarding the cause of Sickle cell disease in her children?
Can the sister have Sickle Cell Anaemia and be AS?
What emotions do you think the man/woman are experiencing?

6. Case Study 1: Sickle Cell Disease
Discuss risk and confirm testing is available for pregnancy. Sample using amniocentesis at 16 weeks. Miscarriage risk <1%. Discuss options if result is positive. Man worried about miscarriage risk. Woman does not want to terminate after 12 weeks – it is “what they have been given”.
What test would you do on a prenatal sample – biochemical or genetic?
If genetic, what do you need to know to test?
What is the couple’s perceptions regarding loss: miscarriages, termination and sick children?
Access to alternate testing options?

7. Pedigree: Case Study1 I II
III 1 2 3 4 5 IV 1 2 3 4 5 6 V

8. Case Study 1: Sickle Cell Disease
You ask for the family history. The woman (IV-5) says that it is not in her family as there is no history and she is not Nigerian. Her great grandfather came from the Tanzania. The man (IV-4) mentions it doesn't’t come from his family. He has twin brothers one died at 2 years from a stroke, the other is fine. His half sister may have sickle but she is AS.
Using the pedigree, what would you say the inheritance in the father’s family is?
Autosomal recessive – pseudo-dominance
Can you draw in the obligate carriers?
What is the woman’s view regarding the cause of Sickle cell disease in her children?
Husband’s fault as she has no family history. Attitude towards other ethnicity – Nigeria vs Tanzania
Can the sister have Sickle Cell Anaemia and be AS?
Testing often performed at school – error in understanding
What emotions do you think the man/woman are experiencing?
Blame, denial, anger, fear, guilt and shame

9. Pedigree: Case Study 1 I II
III 1 2 3 4 5 IV 1 2 3 4 5 6 V

10. Case Study 1: Sickle Cell Disease
Discuss risk and confirm testing is available for pregnancy. Sample using amniocentesis at 16 weeks. Miscarriage risk <1%. Discuss options if result is positive. Man worried about miscarriage risk. Woman does not want to terminate after 12 weeks – it is “what they have been given”.
What test would you do on a prenatal sample – biochemical or genetic?
Genetic
If genetic, what do you need to know to test?
Gene mutation (both parents)
What is the couple’s perceptions regarding loss: miscarriages, termination and sick children?
Loss of pregnancy and loss of healthy children.
Beliefs in terms of timing

11. Case Study 1: Sickle Cell Disease
Result is positive. Couple are devastated. Their son has recently been admitted for a crisis event. Overwhelmed.
How do you deliver this result?
Knowledge of breaking bad news:
Prepare environment
Prior knowledge of risk
“Warning’ shot
Invitation to proceed
Communicate result and explain
Space for feelings and acknowledgement
Support
Belief and termination of pregnancy?
Consideration of previous discussions
Impact if they select TOP
Is a TOP available?

12. Case Study 2: Polycystic Kidney Disease
Couple attend the clinic wanting help with their child’s diagnosis. At the age of four years she started developing severe kidney problems. She is needing a transplant. Based on her diagnosis both parents had abdominal ultrasounds. Father diagnosed with Polycystic Kidney Disease (PKD). Known family history of kidney problems but not considered as relevant. Recently father’s sister was diagnosed with PKD during pregnancy and now requires a transplant. Does not seem to be the same diagnosis in their child, as she is much younger and more severe.
What is the inheritance pattern?
Do you think the child has the same disease? What is her risk? How would you confirm?
Did you detect any unique features associated with a dominant inheritance?
Risk to future children?

13. Pedigree: Case Study 2 v v v v v v v v v v v v Dx: 50s Subtle symptoms
Dialysis 60s
Dx: 40s
Subtle symptoms v
Dx: 32yrs
Symptoms during pregnancy
Needs transplant v v
Dx: 30 yrs
No symptoms v
Dx: 4 years
Needs transplant

14. Case Study 2: Polycystic Kidney Disease
What is the inheritance pattern?
Dominant
Do you think the child has the same disease? What is her risk? How would you confirm?
Yes. 50%
Genetic test: two genes PKD1 and PKD2. Identify family mutation
Did you detect any unique features associated with a dominant inheritance?
Anticipation
Variable expression
Risk to future children?
50%
Prenatal testing options?

15. Case Study 3: Haemophilia
A couple come to the clinic for preconception counselling from Namibia. The woman has a family history of Haeomophilia (HPA) in many generations. She mentions that the disease skipped her grandmother’s generations, so she think she’s not at risk. Her mother and aunts all had testing in the 1980s to see if they are carriers. Her mother and her one aunt were reported to not be carriers and one as a carrier. Her carrier aunt had no children. Her other aunt has a daughter. She is confused as her brother has HPA. She herself has a history of bleeding after having her wisdom teeth removed.
What is the inheritance pattern?
Can you identify the obligate female carriers?
What could have caused her mother to be reported as a non-carrier?
What is the chance for this woman to be a carrier?
Can her brother have affected children?
Anything suggestive of her status?

16. Pedigree: Case Study 3 v v v v v v v v v v

17. Case Study 3: Haemophilia
What is the inheritance pattern?
X-linked
Can you identify the obligate female carriers?
What could have caused her mother to be reported as a non-carrier?
Genetic vs biochemical testing
What is the chance for this woman to be a carrier?
50%
Can her brother have affected children? No
Anything suggestive of her status?
Possible symptoms

18. Pedigree: Case Study 3 v v v v v v v v v v

19. Summary
Pedigree provides context to discuss monogenic disorders and associated complexities.