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

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

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?

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

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?

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?

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

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

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

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

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?

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?

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

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?

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?

Pedigree: Case Study 3 v v v v v v v v v v

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

Pedigree: Case Study 3 v v v v v v v v v v

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