1. SCDAA 40 th 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. Blood from a Person with SCD-SS Genetic Counseling for the Future Ohene-Frempong 2012

3. Outline Genetic Counseling for the Future 1.Definition of Genetic Counseling 2.Modern Genetics of Sickle Cell Disease 3.Common Variants of Sickle Cell Disease 4.Diagnostic Tests for Hemoglobin Disorders 5.Inheritance of Sickle Cell Disease 6.Genetic Counseling and the Modern Family Ohene-Frempong 2012

4. Diagnostic Tests for Hemoglobin Disorders Genetic Counseling for the Future 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. Definition of Genetic Counseling Genetic Counseling for the Future 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. Definition of Genetic Counseling Genetic Counseling for the Future 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/http://www.who.int/genomics/professionals/counselling/en/ (accessed 9-17-12) Ohene-Frempong 2012

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

8. Modern Genetics of Sickle Cell Disease Human Hemoglobin Genes and Products Chromosome 16 Globin proteins Chromosome 11  -globin gene family  -globin gene family “Embryonic” “Fetal” “Minor adult” “Major adult” Chromosome 16 Globin proteins Chromosome 11 F:  2  2 60-90%< 2% A 2 :  2  2 < 1% 2-3% A:  2  2 10-40% 96% Hemoglobins: Birth > 1 yr Genetic Counseling for the Future Ohene-Frempong 2012

9. To make Hb A (  2  2 ), and in normal amounts … Genetic Counseling for the Future 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 Modern Genetics of Sickle Cell Disease Ohene-Frempong 2012

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

11.  A     Regular Human Hemoglobins A2A2         F         < 1%60-90%10-40% At Birth: 3%1%96% > 1 yr.: Genetic Counseling for the Future Ohene-Frempong 2012

12. Hemoglobin Genes and Products in SCD-SS Gower 1:  2  2 Gower 2:  2  2 Portland:  2  2 ------------------ F:  2  2 A 2 :  2  2 S:  2  s 2 2-20% 3% 80-95% Hemoglobins in SS by age > 1 yr Modern Genetics of Sickle Cell Disease Genetic Counseling for the Future

13. S C G Phila.  A GG GG        SS SS CC CC      S     C  GG Globins in Common Hemoglobin Variants Genetic Counseling for the Future Modern Genetics of Sickle Cell Disease Ohene-Frempong 2012

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

15. Modern Genetics of Sickle Cell Disease Excess  -like globin: Newborn: Hb Bart’s (  tetramers) Adult: Hb H (  tetramers) - high O 2 affinity, unstable, precipitates, causes hemolysis (RBC destruction) Imbalanced globin synthesis:  -thalassemia = insufficient  globin Genetic Counseling for the Future Alpha thalassemia affects clinical course of SCD Ohene-Frempong 2012

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

17. Genetic Counseling for the Future Common Variants of Sickle Cell Disease SCD-SSSevere S F A2 SCD-S  o thalSevere S F A2 SCD-S(  ) o thalVery mild S F A2 SCD-S  + thal Mild S A F A2 SCD-SCModerate - severe SC F A2 VariantHbs in RBCClinical Course FSFS FSFS FSFS FSAFSA F SC Newborn > 6 mo. Ohene-Frempong 2012

18. Pathophysiology of Thalassemias Genetic Counseling for the Future Variants of SCD with Hb Phenotype Similar to SCD-SS SCD-SSSevere S F A2 SCD-S  o thalSevere S F A2 SCD-S(  ) o thalVery mild S F A2 VariantHbs in RBCClinical Course FSFS FSFS FSFS Newborn > 6 mo. SCD-S/HPFHAsymptomatic S F A2 FSFS Ohene-Frempong 2012

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

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

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

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

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

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

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

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

27. 00 AA AA SS AA 00 Inheritance of Sickle Cell Disease (AA) AA AA … they will have a baby with no abnormal hemoglobins and no beta-thal. AA SS..and a beta-A sperm is winner When one parent has beta-zero thalassemia trait, and the other has Sickle Cell Trait (AS) AA If it is the beta-A egg ready this cycle (No S) Ohene-Frempong 2012

28. 00 AA Inheritance of Sickle Cell Disease (AS) AA SS … they will have a baby with sickle cell trait (AS). AA SS..and a beta-A sperm is winner When one parent has beta-zero thalassemia trait, and the other has Sickle Cell Trait (AS) If it is the beta-S egg ready this cycle AA SS AA 00 (No S) Ohene-Frempong 2012

29. 00 AA Inheritance of Sickle Cell Disease (A  0 ) 00 AA … they will have a baby with beta-zero thalassemia trait 00 SS..and a beta-zero sperm is winner AA If it is the beta-A egg ready this cycle AA SS AA 00 (No S) When one parent has beta-zero thalassemia trait, and the other has Sickle Cell Trait (AS) Ohene-Frempong 2012

30. 00 AA Inheritance of Sickle Cell Disease 00 SS..and a beta-zero sperm is winner SS If it is the beta-S egg ready this cycle AA SS AA 00 (No S) When one parent has beta-zero thalassemia trait, and the other has Sickle Cell Trait (AS) (S  0 ) 00 SS.. they will have a baby with S beta-zero thalassemia Ohene-Frempong 2012

31. (AA) AA AA (AS) SS AA (A  0 thal) AA 00 Each and every time they make a baby, the baby may have …. AA SS AA 00 (No S) When one parent has beta-zero thalassemia trait, and the other has Sickle Cell Trait (AS), ….. Inheritance of Sickle Cell Disease (S  0 thal) SS 00 Ohene-Frempong 2012

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

33. Genetic Counseling and the Modern Family Genetic Counseling for the Future 1.Traditional models: Married couple – pre-pregnancy, with or without affected child; Single adult seeking counseling for possible risk WHO: http://www.who.int/genomics/professionals/counselling/en/http://www.who.int/genomics/professionals/counselling/en/ (accessed 9-17-12) 2.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 Ohene-Frempong 2012

34. Genetic Counseling and the Modern Family Genetic Counseling for the Future 3.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) 4.Post-Pregnancy Reproductive Choices Newborn screening Prenatal diagnosis - with or without selective termination Ohene-Frempong 2012

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

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

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