SCDAA 40 th Anniversary Convention 2012

Genetic Counseling for the Future

Ohene-Frempong 2012

Kwaku Ohene-Frempong, MD

Children’s Hospital of Philadelphia Sickle Cell Foundation of Ghana

Genetic Counseling for the Future

Blood from a Person with SCD-SS

Ohene-Frempong 2012

Genetic Counseling for the Future

Outline

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

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

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

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

Ohene-Frempong 2012

WHO: http://www.who.int/genomics/professionals/counselling/en/ (accessed 9-17-12)

Ohene-Frempong 2012

Genetic Counseling for the Future

Hemoglobin Molecule

Heme +

Globin

= Hemoglobin (Hb) Heme is an iron compound;

globin

is a protein Proteins are made according to instructions in

specific genes

we inherit from parents

Genetic Counseling for the Future

Modern Genetics of Sickle Cell Disease

Human Hemoglobin Genes and Products “Embryonic” “Fetal” “Minor adult”  -globin gene family

Ohene-Frempong 2012

“Major adult” Hemoglobins: Birth > 1 yr F:  2 g 2 60-90% < 2% A 2 :  2 d 2 < 1% 2-3% A:  2 b 2 10-40% 96% b -globin gene family

Genetic Counseling for the Future

Modern Genetics of Sickle Cell Disease To make Hb A (

 2 b 2

), 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

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

Ohene-Frempong 2012

Genetic Counseling for the Future

Regular Human Hemoglobins

 b  2 b 2

A

b  At Birth: > 1 yr.: 10-40% 96%  d  2 d 2

A 2

d  < 1% 3%  g  2 g 2

F

g  60-90% 1%

Ohene-Frempong 2012

Genetic Counseling for the Future

Modern Genetics of Sickle Cell Disease

Hemoglobin Genes and Products in SCD-SS Gower 1: z 2 e 2 Gower 2:  2 e 2 Portland: F:  2 g 2 x 2 g 2 ----------------- 2-20% A 2 :  2 d 2 S:  2 b s 2 3% 80-95% Hemoglobins in SS by age > 1 yr

Genetic Counseling for the Future

Modern Genetics of Sickle Cell Disease Globins in Common Hemoglobin Variants

 b  2 b 2

A

b   b

S

 2 b

S

2

S

b

S

  b

C

 2 b

C

2

C

b

C

 

G

b b 

G



G

2 b 2

G Phila.

Ohene-Frempong 2012

Genetic Counseling for the Future

Modern Genetics of Sickle Cell Disease

Normally, balanced globin synthesis  -family globins z +  1   2 = = e b -family globins + G g + A g + d + b

Ohene-Frempong 2012

Thalassemia

(insufficient or no production of globin)

Genetic Counseling for the Future

Modern Genetics of Sickle Cell Disease

Imbalanced globin synthesis:  -thalassemia = insufficient  globin Excess b -like globin: Newborn: Hb Adult: Hb H ( b Bart’s ( g tetramers) tetramers) - high O 2 affinity, unstable, precipitates, causes hemolysis (RBC destruction)

Ohene-Frempong 2012

Alpha thalassemia affects clinical course of SCD

Genetic Counseling for the Future Imbalanced globin synthesis: b -thalassemia = insufficient b 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

Genetic Counseling for the Future

Common Variants of Sickle Cell Disease

Variant Hbs in RBC Clinical Course Newborn > 6 mo.

SCD-SS F S S F A2 Severe SCD-SC SCD-S b o thal F S SCD-S b + thal F S A SCD-S( db ) o thal

Ohene-Frempong 2012

F SC F S SC F A2 S F A2 S A F A2 S F A2 Moderate - severe Severe Mild Very mild

Genetic Counseling for the Future

Pathophysiology of Thalassemias

Variant with Hb Phenotype Similar to SCD-SS Hbs in RBC Clinical Course Newborn > 6 mo.

SCD-SS F S S F A2 Severe SCD-S b o thal F S S F A2 Severe SCD-S( db ) o thal F S S F A2 Very mild SCD-S/HPFH

Ohene-Frempong 2012

F S S F A2 Asymptomatic

Ohene-Frempong 2012

Genetic Counseling for the Future Inheritance of Sickle Cell Disease

In Modern Terminology

Inheritance of Sickle Cell Disease When both parents have no abnormal hemoglobins or thalassemia, … b A b A b A b A Every sperm will be a beta-A sperm b A b A b A b A Every egg will be a beta-A egg .. every baby they make will have normal hemoglobins.

b A (AA) b A

Ohene-Frempong 2012

Inheritance of Sickle Cell Disease When both parents have Sickle Cell Trait (AS )…..

b A b S b A b S Usually only egg is ready each cycle Millions of sperm race to the egg b b A S b A ..and a beta-A sperm is winner b A If it is the beta-A egg ready this cycle … they will have a baby with no abnormal hemoglobin.

b A (AA) b A

Ohene-Frempong 2012

Inheritance of Sickle Cell Disease When both parents have Sickle Cell Trait (AS )…..

b A b S b A b S b b A S b A ..and a beta-A sperm is winner b S If it is the beta S egg ready this cycle … they will have a baby with sickle cell trait (AS).

b A (AS) b S

Ohene-Frempong 2012

Inheritance of Sickle Cell Disease When both parents have Sickle Cell Trait (AS )…..

b A b S b A b S b b A S b S beta S ..and a sperm is winner b S If it is the beta-A egg ready this cycle … they will have a baby with sickle cell trait (AS).

b S (AS) b A

Ohene-Frempong 2012

Inheritance of Sickle Cell Disease When both parents have Sickle Cell Trait (AS )…..

b A b S b A b S b b A S b S beta S ..and a sperm is winner b S If it is the beta S egg ready this cycle … they will have a baby with sickle cell disease SS.

b S (SS) b S

Ohene-Frempong 2012

Inheritance of Sickle Cell Disease So, when both parents have Sickle Cell Trait (AS )…..

b A b S b A b S … each and every time they make a baby, the baby may have ….

b A (AA)

Ohene-Frempong 2012

b A b A (AS) b S b S (AS) b A b S (SS) b S

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

b A (AA)

Ohene-Frempong 2012

b A b A (AC) b C b S (AS) b A b S (SC) b C

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

b A (AA) b A

Ohene-Frempong 2012

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

b A (AS) b S

Ohene-Frempong 2012

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

Ohene-Frempong 2012

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

Ohene-Frempong 2012

Inheritance of Sickle Cell Disease When one parent has beta-zero thalassemia trait, and the other has Sickle Cell Trait (AS ), …..

b A b 0 b A b S (No S) Each and every time they make a baby, the baby may have ….

b A (AA)

Ohene-Frempong 2012

b A b A (AS) b S b 0 (A b 0 b A thal) b 0 (S b 0 b S thal)

Inheritance of Sickle Cell Disease Similarly, when one parent has beta-plus thalassemia trait, and the other has Sickle Cell Trait (AS ), …..

b A b + b A b S (No S) Each and every time they make a baby, the baby may have ….

b A (AA)

Ohene-Frempong 2012

b A b A (AS) b S b + (A b + b A thal) b + (S b + b S thal)

Genetic Counseling for the Future Genetic Counseling and the Modern Family 1. Traditional models: • Married couple affected child; – pre-pregnancy, with or without • Single adult seeking counseling for possible risk 2. Modern models: • Married couple affected child; – pre-pregnancy, with or without • Unmarried mother or couple – pregnant, with or without affected child; or, • Single adult seeking counseling for possible risk

Ohene-Frempong 2012

WHO: http://www.who.int/genomics/professionals/counselling/en/ (accessed 9-17-12)

Genetic Counseling for the Future Genetic Counseling and the Modern Family 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

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

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

Genetic Counseling for the Future

It’s Sickle Cell Year 102 Thank You!

Ohene-Frempong 2012