SCDAA 40 th Anniversary Convention 2012

1. SCDAA 40th Anniversary Convention 2012 Genetic Counseling for the Future Kwaku Ohene-Frempong, MD Children’s Hospital of Philadelphia Sickle Cell Foundation of Ghana Ohene-Frempong 2012

2. Genetic Counseling for the Future Blood from a Person with SCD-SS Ohene-Frempong 2012

3. Genetic Counseling for the Future Outline • Definition of Genetic Counseling • Modern Genetics of Sickle Cell Disease • Common Variants of Sickle Cell Disease • Diagnostic Tests for Hemoglobin Disorders • Inheritance of Sickle Cell Disease • Genetic Counseling and the Modern Family Ohene-Frempong 2012

4. Genetic Counseling for the Future Diagnostic Tests for Hemoglobin Disorders 1. Blood smear 2. Slide sickling preparation 3. Solubility test 4. Complete Blood Count, reticulocyte count 5. Hemoglobin separation tests 6. Quantitation of hemoglobin fractions 7. DNA-based tests 9. Family studies Ohene-Frempong 2012

5. Genetic Counseling for the Future Definition of Genetic Counseling • Genetic counseling is the process of helping people understand and adapt to the medical, psychological and familial implications of genetic contributions to disease. • This process integrates the following: • Interpretation of family and medical histories to assess the chance of disease occurrence or recurrence. • Education about inheritance, testing, management, prevention, resources and research. • Counseling to promote informed choices and adaptation to the risk or condition National Society of Genetic Counselors, 2006 Ohene-Frempong 2012

6. Genetic Counseling for the Future Definition of Genetic Counseling • Genetic counseling is the process through which knowledge about the genetic aspects of illnesses is shared by trained professionals with those who are at an increased risk for either having a heritable disorder or of passing it on to their unborn offspring. • A genetic counselor • provides information on the inheritance of illnesses and their recurrence risks; • addresses the concerns of patients, their families, and their health care providers; and • supports patients and their families dealing with these illnesses WHO: http://www.who.int/genomics/professionals/counselling/en/ (accessed 9-17-12) Ohene-Frempong 2012

7. Genetic Counseling for the Future Hemoglobin Molecule Heme + Globin= Hemoglobin (Hb) Heme is an iron compound; globinis a protein Proteins are made according to instructions in specific genes we inherit from parents Ohene-Frempong 2012

8. Genetic Counseling for the Future Modern Genetics of Sickle Cell Disease Human Hemoglobin Genes and Products Chromosome 16 Globin proteins Chromosome 11 Chromosome 16 Globin proteins Chromosome 11 Chromosome 16 Globin proteins Chromosome 11 Hemoglobins: Birth > 1 yr F: a2 g2 60-90% < 2% A2: a2 d2 < 1% 2-3% A: a2 b210-40% 96% “Embryonic” “Fetal” “Minor adult” -globin gene family b-globin gene family “Major adult” Ohene-Frempong 2012

9. Genetic Counseling for the Future Modern Genetics of Sickle Cell Disease To make Hb A (a2 b2), and in normal amounts … From Mother: 2 alpha and 1 beta genes From Father: 2 alpha and 1 beta genes . we need a total of 6 “normal” genes, 4 for alpha globins and 2 for beta globins Ohene-Frempong 2012

10. Genetic Counseling for the Future 1-family globin + 1-family globin Globins in hemoglobin Assembled in two stages: = Hbdimer 2 dimers form stable Hb tetramer (2 -family globins + 2 -family globins) Ohene-Frempong 2012

11. Genetic Counseling for the Future a a a b d g b d g a a a a2b2 a2 d2 a2 g2 A A2 F At Birth: 10-40% < 1% 60-90% > 1 yr.: 96% 3% 1% Regular Human Hemoglobins Ohene-Frempong 2012

12. Genetic Counseling for the Future Gower 1: z2 e2 Gower 2: a2 e2 Portland: x2 g2 ------------------ F: a2 g2 A2: a2 d2 S:a2 bs2 2-20% 3% 80-95% Hemoglobins in SS by age > 1 yr Hemoglobin Genes and Products in SCD-SS Modern Genetics of Sickle Cell Disease

13. Genetic Counseling for the Future a a b a aG bS b bC b a bS a bC a b aG Modern Genetics of Sickle Cell Disease Globins in Common Hemoglobin Variants a2b2 a2 bS2 a2 bC2 aG2b2 C A S GPhila. Ohene-Frempong 2012

14. Genetic Counseling for the Future Thalassemia(insufficient or no production of globin) Modern Genetics of Sickle Cell Disease Normally, balanced globin synthesis = -family globins  + 12 -family globins  +G + A +  +  = Ohene-Frempong 2012

15. Genetic Counseling for the Future Modern Genetics of Sickle Cell Disease Imbalanced globinsynthesis: -thalassemia = insufficient globin Excess -like globin: Newborn: Hb Bart’s ( tetramers) Adult: Hb H ( tetramers) - high O2affinity, unstable, precipitates, causes hemolysis (RBC destruction) Alpha thalassemia affects clinical course of SCD Ohene-Frempong 2012

16. Genetic Counseling for the Future Pathophysiology of Thalassemias Modern Genetics of Sickle Cell Disease Imbalanced globinsynthesis: -thalassemia =insufficient globin Excess -like globin: -globin precipitation in RBC precursors - ineffective RBC development - hemolysis (RBC destruction) Beta thalassemia and beta-S gene create SCD variants Ohene-Frempong 2012

17. Genetic Counseling for the Future Common Variants of Sickle Cell Disease Variant Hbs in RBC Clinical Course Newborn> 6 mo. FS SFA2 SCD-SS Severe SCFA2 FSC SCD-SC Moderate - severe FS SFA2 SCD-Sbo thal Severe FSA SAFA2 SCD-Sb+ thal Mild FS SFA2 SCD-S(db)o thal Very mild Ohene-Frempong 2012

18. Genetic Counseling for the Future Pathophysiology of Thalassemias Variants of SCD with Hb Phenotype Similar to SCD-SS Variant Hbs in RBC Clinical Course Newborn> 6 mo. FS SFA2 SCD-SS Severe FS SFA2 SCD-Sbothal Severe FS SFA2 SCD-S(db)o thal Very mild FS SFA2 SCD-S/HPFH Asymptomatic Ohene-Frempong 2012

19. Genetic Counseling for the Future Inheritance of Sickle Cell Disease In Modern Terminology Ohene-Frempong 2012

20. Inheritance of Sickle Cell Disease When both parents have no abnormal hemoglobins or thalassemia, … bA bA bA bA bA Every sperm will be a beta-A sperm Every egg will be a beta-A egg bA bA bA bA .. every baby they make will have normal hemoglobins. bA bA (AA) Ohene-Frempong 2012

21. Inheritance of Sickle Cell Disease When both parents have Sickle Cell Trait (AS)….. Usually only egg is ready each cycle bA bS If it is the beta-A egg ready this cycle bA bS bA Millions of sperm race to the egg bA ..and a beta-A sperm is winner bA bA bS … they will have a baby with no abnormal hemoglobin. bA bA (AA) Ohene-Frempong 2012

22. Inheritance of Sickle Cell Disease When both parents have Sickle Cell Trait (AS)….. bA bS If it is the beta-S egg ready this cycle bA bS bS bS ..and a beta-A sperm is winner bA bA bS … they will have a baby with sickle cell trait (AS). bA bS (AS) Ohene-Frempong 2012

23. Inheritance of Sickle Cell Disease When both parents have Sickle Cell Trait (AS)….. bA bS If it is the beta-A egg ready this cycle bA bS bS bA ..and a beta-S sperm is winner bA bS bS … they will have a baby with sickle cell trait (AS). bS bA (AS) Ohene-Frempong 2012

24. Inheritance of Sickle Cell Disease When both parents have Sickle Cell Trait (AS)….. bA bS If it is the beta-S egg ready this cycle bA bS bS bS ..and a beta-S sperm is winner bS bA bS … they will have a baby with sickle cell disease SS. bS bS (SS) Ohene-Frempong 2012

25. Inheritance of Sickle Cell Disease So, when both parents have Sickle Cell Trait (AS)….. bA bS bA bS … each and every time they make a baby, the baby may have …. bS bS bA bA bA bS bS bA (AA) (AS) (AS) (SS) Ohene-Frempong 2012

26. Inheritance of Sickle Cell Disease Similarly, when one parent has Sickle Cell Trait (AS), and the other has hemoglobin C trait (AC)... bA bS (No S) bC bA … each and every time they make a baby, the baby may have …. bS bS bA bA bA bC bC bA (AA) (AC) (AS) (SC) Ohene-Frempong 2012

27. Inheritance of Sickle Cell Disease When one parent has beta-zero thalassemia trait, and the other has Sickle Cell Trait (AS) bA b0 (No S) If it is the beta-A egg ready this cycle bA bS bS bA ..and a beta-A sperm is winner bA bA b0 … they will have a baby with no abnormal hemoglobins and no beta-thal. bA bA (AA) Ohene-Frempong 2012

28. Inheritance of Sickle Cell Disease When one parent has beta-zero thalassemia trait, and the other has Sickle Cell Trait (AS) b0 bA (No S) If it is the beta-S egg ready this cycle bS bA bS bS ..and a beta-A sperm is winner bA bA b0 … they will have a baby with sickle cell trait (AS). bA bS (AS) Ohene-Frempong 2012

29. Inheritance of Sickle Cell Disease When one parent has beta-zero thalassemia trait, and the other has Sickle Cell Trait (AS) b0 bA (No S) If it is the beta-A egg ready this cycle bS bS bA bA ..and a beta-zero sperm is winner bA b0 b0 … they will have a baby with beta-zero thalassemia trait b0 bA (Ab0) Ohene-Frempong 2012

30. Inheritance of Sickle Cell Disease When one parent has beta-zero thalassemia trait, and the other has Sickle Cell Trait (AS) bA b0 (No S) If it is the beta-Segg ready this cycle bS bS bA bS ..and a beta-zero sperm is winner bA b0 b0 ..they will have a baby with S beta-zero thalassemia b0 bS (Sb0) Ohene-Frempong 2012

31. Inheritance of Sickle Cell Disease When one parent has beta-zero thalassemia trait, and the other has Sickle Cell Trait (AS), ….. b0 bA (No S) bA bS Each and every time they make a baby, the baby may have …. bA bA b0 b0 bS bS bA bA (Ab0thal) (Sb0thal) (AA) (AS) Ohene-Frempong 2012

32. Inheritance of Sickle Cell Disease Similarly, when one parent has beta-plus thalassemiatrait, and the other has Sickle Cell Trait (AS), ….. b+ bA (No S) bA bS Each and every time they make a baby, the baby may have …. bA bA b+ b+ bS bS bA bA (Ab+thal) (Sb+thal) (AA) (AS) Ohene-Frempong 2012

33. Genetic Counseling for the Future Genetic Counseling and the Modern Family • Traditional models: • Married couple – pre-pregnancy, with or without affected child; • Single adult seeking counseling for possible risk • Modern models: • Married couple – pre-pregnancy, with or without affected child; • Unmarried mother or couple – pregnant, with or without affected child; or, • Single adult seeking counseling for possible risk WHO: http://www.who.int/genomics/professionals/counselling/en/ (accessed 9-17-12) Ohene-Frempong 2012

34. Genetic Counseling for the Future Genetic Counseling and the Modern Family • Pre-Pregnancy Reproductive Choices • Regular pregnancy • Adoption • “Surrogate” parentage • Pre-implantation genetic diagnosis (PGD) with In Vitro Fertilization (IVF) • Polar body DNA (before fertilization) • Blastomere DNA (after fertilization) • Post-Pregnancy Reproductive Choices • Newborn screening • Prenatal diagnosis - with or without selective termination Ohene-Frempong 2012

35. Genetic Counseling for the Future Genetic Counseling and the Modern Family • Pre-implantation genetic diagnosis (PGD) • with In Vitro Fertilization (IVF) • Blastomere DNA analysis (after fertilization) Sperm injection Ohene-Frempong 2012

36. Genetic Counseling for the Future Genetic Counseling and the Modern Family • Pre-implantation genetic diagnosis (PGD) • with In Vitro Fertilization (IVF) • Polar body DNA analysis (before fertilization) Polar body Polar body extraction Ohene-Frempong 2012

37. Genetic Counseling for the Future It’s Sickle Cell Year 102 Thank You! Ohene-Frempong 2012