Bloodline: A Human Genetics Case

1. Bloodline: A Human Genetics Case By Peggy Brickman University of Georgia This case is based on the CBS show, Ghost Whisperer, Season 4, episode 5, “Bloodline.” Original Airdate: October 31, 2008

2. Opening Scene Olivia, a blond teen, is resoundingly beating her male tennis opponent, Ned. She is new in town and jokes that her partner went easy on her to make her feel welcome. From nowhere, a tennis ball cuts across their court. The dark-eyed brunette who hit it, Diana, stares at them. Olivia seems stunned into silence. Diana sneers at her and says, “Any day now.” Olivia hits the ball back to her, almost directly into her face. “What was that all about? You know Diana Morrison?” Ned asks. “I used to, back when I lived in Granville the first time,” Olivia answers. “Back then we were friends. It was like a million years ago.”

3. Opening Scene Continues… As they walk away, we hear Diana’s tennis coach screaming, “Diana, Diana! Somebody help Diana, please!” “Is she OK? What’s happened?” Olivia gasps after running over. Diana has collapsed to the tennis court, not breathing. “She just dropped unexpectedly,” Diana’s coach responds. “Call 911!” 3

4. Emergency Room Diana is taken by ambulance to the emergency room. Olivia follows by car. At the hospital, Olivia’s brunette mother walks in. “I went to the courts to pick you up and when you weren’t there, they said a girl had collapsed, I thought…” she stammers. “I’m fine, Mom,” Olivia assures her. “I’m sorry for scaring you. I should have called. It’s Diana.” “Diana Morrison?” her mother asks, alarm spreading across her face. “Where’s Diana Morrison?” a blond woman who has just come in demands. “I’m her mother. They told me she was here.” Olivia and her mother turn to stare at the new arrival.

5. Scene Continues “Olivia?” Diana’s mother asks. All three women stare at each other in confusion. “What are you doing here?” “Mrs. Morrison, I was at the courts with Ned, and Diana was there, too, taking a lesson I guess.” Olivia explains. “She just collapsed.” “Was it heat stroke?” Mrs. Morrison asks. “She barely ate any breakfast.”

6. Memorial Scene Night has fallen in downtown Granville. A candle flickers over flowers and stuffed animals at a makeshift memorial. Diana’s mother is there comforting–and being comforted by—several young friends of her daughter. Olivia approaches Mrs. Morrison and tries to speak to her, but Mrs. Morrison rebuffs her.

7. Scene Continues Olivia explains to her friend Ned, “When we were little our moms were such good friends, we did everything together. It was almost like we were sisters. Play dates, sports, camping, we even have the same birthdays so our parties were like this whole big deal every year.” “What happened?” Ned asks. “It just ended,” Olivia explains. “I remember one night I woke up and my Mom was in bed with me—she was rocking me and crying and crying. I asked her what was wrong, but all she would say was that she loved me.”

8. Scene Ends “And then after that, everything changed. Diana’s mom and dad split up. We stopped hanging out with them, and then we got transferred to Texas, or my Dad did, so we left,” Olivia shrugs. “My mom told me to forget about Diana, to make new friends. It was like she was mad at her, too.” Olivia looks up and stares across the street. “What’s Dad doing here?” Olivia’s father heads toward Mrs. Morrison, offering her comfort in an embrace. 8

9. Questions • What do you think is going on with these two families? • The hospital would have simple things like Diana’s blood type on file. How could you use blood type to figure out what is going on?

10. CQ#1: Olivia’s parents, Mrs. Lisa Keller and Mr. Kevin Keller, are (A-) and (O+). You know about the IA/IB/i alleles for ABO blood type and the Rh D factor alleles, +/-. Write down all possible genotypes for Lisa and Kevin Keller and use them to create several Punnett squares to indicate the possible genotypes for their offspring. Olivia has O- blood. Using your Punnett Squares and the phenotypes of the three Kellers, indicate which of the following is the most likely set of genotypes for Lisa and Kevin Keller. LisaKevin • IA /i, -/- i / i, +/+ • IA / IA, -/- i / i, +/- • IA / i, -/- i / i, +/- • IA / IA, -/- i / i, +/+

11. CQ#2: Looking at the Kellers and Morrisons, is it possible that Kevin Keller had an affair with Cynthia Morrison and is Diana Morrison’s biological father?Lisa Keller Kevin Keller Cynthia Morrison Mr. Morrison A- O+ B+ O- Olivia Keller Diana Morrison O- A+ • Yes, Cynthia and Kevin could have a child like Diana with Rh positive blood. • No, Cynthia and Kevin could not have a child who has type A blood. • No, Cynthia and Kevin could not have a child who was Rh positive. Before we go to the next slide, what other problem do you see?

12. Several Days Later: Mercy Hospital A nurse is reminiscing with a colleague: “The day that Diana Morrison was born, there’d been this huge accident on the interstate. We were understaffed, overwhelmed. The bracelets must have come off in the bath. The charge nurse seemed confused. I asked if everything was OK. She ordered me to go to room 214 and get Mrs. Keller up and walking – now. I was fresh out of nursing school. I was trying to learn without asking too many questions. What could I do? I didn’t have any proof that the girls were switched. It was just a feeling. But, I did remember those girls’ names. I saw the mothers bonding, talking in the hallways, cradling their babies. When I saw Diana again 16 years later, I recognized her name when the paramedics brought her in.”

13. Several Days Later: Mercy Hospital The nurse continues, “The circumstances of her death due to that blood clot – the thought of it made me wonder all over again. So, I pulled the girls’ medical records. That’s what confirmed it. You know, I’ve been trying to contact the families ever since. I’m determined to reach them because the blood clot that killed Diana sounds like it could be a genetic condition. It could affect someone else in her biological family. They have to be told.”

14. Inherited Blood Disorders Hemophilia is a group of hereditary genetic disorders that lead to deficiencies of factors used to stop bleeding when a blood vessel is broken. Hemophiliacs don’t bleed more intensely than a normal person, just longer. Even a minor injury can result in blood loss lasting days, weeks, or not ever healing completely. • Hemophilia A (90%, of cases, about 1/10,000 births), clotting factor VIII (gene on chromosome X) is absent. • Hemophilia B, factor IX (on chromosome X) is deficient. • Hemophilia C, factor XI (on chromosome 4) is deficient.

15. Hemophilia C: Autosomal recessive child child Carrier children

16. Autosomal Recessive: Punnett Square Using H and h for the dominant and recessive alleles for hemophilia C, fill in this Punnett Square using the parents on the previous slide and their predicted offspring.

17. Autosomal Recessive Write three rules to keep in mind when counseling someone about the likelihood of inheriting an autosomal recessive condition: • About the parents’ genotypes. • About the parents’ phenotypes. • About the probability of the offspring showing the trait.

18. CQ#3: Lisa Keller and her parents and sister have normal blood clotting, but she has a brother with hemophilia C (autosomal recessive). What is the probability that she is a carrier? • 25% • 50% • 67% • 100% • More information is required.

19. 1 2 3 4 Pedigree Symbols Way to visually represent human family relationships and infer inheritance patterns. • Male • Female • marriage/mating • offspring in order of birth • deceased individuals • individuals showing trait • carriers

20. Pedigree For the following blank pedigree, darken in an offspring to show the inheritance pattern predicted from your rules for an autosomal recessive trait. Indicate carriers.

22. Autosomal Recessive: Punnett Square Using Y, HX for the dominant allele for hemophilia A (normal) and hX for the recessive allele for hemophilia A (hemophilia), fill in this Punnett Square using the parents on the previous slide and their predicted offspring.

23. X-linked Recessive Write three rules to keep in mind when counseling someone about the likelihood of inheriting an X-linked recessive condition: • About the parents’ genotypes. • About the parents’ phenotypes. • About the probability of the offspring showing the trait.

24. CQ#4: If instead of having Hemophilia C (autosomal recessive), Lisa Keller’s brother had Hemophilia A (X-linked recessive), what would be the probability that she was a carrier? • 25% • 50% • 67% • 100% • More information is required to answer this question.

25. Pedigree For the following blank pedigree, darken in an offspring to show the inheritance pattern predicted from your rules for an X-linked recessive trait. Indicate carriers, also.

26. CQ#5: Remember that Lisa’s brother had hemophilia, but her sister and parents did not. It turns out that her mother’s sister died very young, apparently of a massive hemorrhage. Which of the following is an accurate pedigree of Lisa Keller’s ( ) family? A. C. B.

27. CQ#6: Lisa Keller can opt for genetic testing to determine if she is a carrier for hemophilia, but it is expensive, so she wants to use her family pedigree to inform her choice. Given this pedigree, which type of hemophilia can she rule out? X-linked recessive Hemophilia A Autosomal recessive Hemophilia C Neither, not enough information was given. Which family member most influenced your decision?

28. Inherited Blood Disorders • Hemophilia causes a lack of blood clotting, but Diana died from overactive blood clotting. • Factor V Leiden is the most common hereditary hypercoagulability disorder amongst Eurasians: About 5% of Caucasians in North America are affected by this condition, which is inherited as an autosomal dominant mutation of a gene on chromosome 1. It is an over-production of a variant of clotting Factor V that cannot be easily degraded. It can cause deep vein thrombosis, pain, life-threatening strokes, and heart attacks.

29. child child Unaffected children

30. Autosomal Dominant: Punnett Square Using V and v for the dominant and recessive alleles for Factor V Leiden, fill in this Punnett Square using the parents on the previous slide and their predicted offspring.

31. Autosomal Dominant Write three rules to keep in mind when counseling someone about the likelihood of inheriting an autosomal dominant condition: • About the parents’ genotypes. • About the parents’ phenotypes. • About the probability of the offspring showing the trait.

32. Factor V Leiden Tests • The blood types and testimony of the nurses have pretty well confirmed that Diana is really the Keller’s daughter. Once made aware of the potential for carrying Factor V Leiden, Kevin and Lisa Keller both look into their family backgrounds. • Factor V Leiden can exhibit incomplete dominance. It is possible that either parent could carry the dominant allele and have not exhibited symptoms, so they may wish to be tested. They wish to look at their family pedigrees to narrow down who is most likely carrying the allele. • The problem is that heart attacks and strokes are the most common form of death in the US, so these symptoms may not be due to Factor V Leiden. • There are also other effects of clotting disorder phenotypes such as miscarriages (blood clots can form during pregnancy in the veins of the plancenta), pulmonary embolisms, or painful, swollen, sometimes engorged veins.

33. Keller Family Pedigree Kevin Keller’s aunt’s husband and cousin have died of heart attacks, but his mother, sister, and brother are fine. Lisa Keller’s aunt had multiple miscarriages, her mother suffered from deep vein thrombosis, and her grandfather died of a heart attack. Create a pedigree diagramming these relationships to use to answer the clicker question on the next slide.

34. CQ#7: Who do you think is more likely to carry the factor V Leiden mutation and why? Kevin Keller Lisa Keller Both

35. Diana Pedigree of the Keller Family Kevin Keller Lisa Keller

36. Additional Information • Online Mendelian Inheritance in Man has excellent descriptions of the human genetic disorders mentioned in this case: http://www.ncbi.nlm.nih.gov/sites/entrez?db=OMIM • Information about thrombophilia can be found at: http://www.fvleiden.org/ 36

37. Image Credits Images appearing in this presentation were made by the author, Peggy Brickman, except the following which were obtained from WikiMedia and licensed under the Creative Commons Attribution-Share Alike 3.0 Unported license. Slide #15: graphic of autosomal recessive inheritance patterns.Author: Armin Kübelbeckhttp://commons.wikimedia.org/wiki/File:Autorecessive_en_01.png • Slide #21: picture shows the inheritance of a recessive allele on an X-chromosome.Author: Armin Kübelbeck, modified to English by Peggy Brickmanhttp://commons.wikimedia.org/wiki/File:X-chromosomal-rezessive-Vater.png • Slide #29: picture shows the inheritance of a dominant allele on an autosome.Author: Armin Kübelbeck http://commons.wikimedia.org/wiki/File:Autodominant_en_01.png