SCDAA 40 th Anniversary Convention 2012 Genetic Counseling for the Future Kwaku Ohene-Frempong, MD...

SCDAA 40th Anniversary Convention 2012

Genetic Counseling for the Future

Kwaku Ohene-Frempong, MDChildren’s Hospital of PhiladelphiaSickle Cell Foundation of Ghana

Ohene-Frempong 2012

Blood from a Person with SCD-SSGenetic Counseling for the Future

Ohene-Frempong 2012

OutlineGenetic 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

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

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, 2006Ohene-Frempong 2012

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

http://www.who.int/genomics/professionals/counselling/en/

Hemoglobin Molecule

Heme + Globin = Hemoglobin (Hb)

Heme is an iron compound;globin is a protein


Ohene-Frempong 2012

Proteins are made according to instructions in specific genes

we inherit from parents

Modern Genetics of Sickle Cell DiseaseHuman Hemoglobin Genes and Products

Chromosome 16 Globin proteins Chromosome 11Chromosome 16 Globin proteins Chromosome 11

-globin gene family

b-globin gene family

“Embryonic”

“Fetal”

“Minor adult”

“Major adult”

Chromosome 16 Globin proteins Chromosome 11

F: a2 g2 60-90%< 2%

A2: a2 d2 < 1% 2-3%

A: a2 b2 10-40% 96%

Hemoglobins: Birth > 1 yr


Ohene-Frempong 2012

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

Modern Genetics of Sickle Cell Disease

Ohene-Frempong 2012

Globins in hemoglobin

1 -family globin + 1 -family globin = Hb dimer

2 dimers form stable Hb tetramer


Assembled in two stages:

(2 -family globins + 2 -family globins)

Ohene-Frempong 2012

a2b2

A

ba

ab

Regular Human Hemoglobins

A2

a2 d2

da

ad

F

a2 g2

ga

ag

< 1% 60-90%10-40%At Birth:

3% 1%96%> 1 yr.:


Ohene-Frempong 2012

Hemoglobin Genes and Products in SCD-SS

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

Modern Genetics of Sickle Cell DiseaseGenetic Counseling for the Future

S C GPhila.

a2b2

A

aG

aG

b

b

ba

ab

a

abS

bS

bC

bCa

a

a2 bS2 a2 bC

2 aG2b2

Globins in Common Hemoglobin Variants



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Thalassemia(insufficient or no production of globin)

Normally, balanced globin synthesis

=



-family globins +G + A + +

-family globins + 12

=

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Excess -like globin:Newborn: Hb Bart’s ( tetramers)Adult: Hb H ( tetramers) - high O2 affinity, unstable, precipitates, causes hemolysis (RBC destruction)

Imbalanced globin synthesis:-thalassemia = insufficient globin


Alpha thalassemia affects clinical course of SCDOhene-Frempong 2012

Excess -like globin:-globin precipitation in RBC precursors

- ineffective RBC development- hemolysis (RBC destruction)

Pathophysiology of Thalassemias

Imbalanced globin synthesis:-thalassemia = insufficient globin



Beta thalassemia and beta-S gene create SCD variants Ohene-Frempong 2012


Common Variants of Sickle Cell Disease

SCD-SS SevereSFA2

SCD-Sbo thal SevereSFA2

SCD-S(db)o thal Very mildSFA2

SCD-Sb+ thal MildSAFA2

SCD-SC Moderate - severeSCFA2

Variant Hbs in RBC Clinical Course

FS

FS

FS

FSA

FSC

Newborn > 6 mo.

Ohene-Frempong 2012

Pathophysiology of ThalassemiasGenetic Counseling for the Future

Variants of SCDwith Hb Phenotype Similar to SCD-SS

SCD-SS SevereSFA2

SCD-Sbo thal SevereSFA2

SCD-S(db)o thal Very mildSFA2

Variant Hbs in RBC Clinical Course

FS

FS

FS

Newborn > 6 mo.

SCD-S/HPFH AsymptomaticSFA2FS

Ohene-Frempong 2012


Inheritance of Sickle Cell Disease

In Modern Terminology

Ohene-Frempong 2012

bA bA

bA bAbA bA

When both parents have no abnormal hemoglobins orthalassemia, …


(AA)bA bA

.. every baby they make will have normal hemoglobins.

bAEvery egg will be a

beta-A eggbA

bAEvery sperm will be a

beta-A sperm

Ohene-Frempong 2012

bA bSbA bS

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

(AA)bA bA

… they will have a baby with no abnormal hemoglobin.

bA

If it is the beta-A egg ready this

cyclebA bA

..and a beta-A sperm is winner

Usually only egg is ready each cycle

bS

bAMillions of sperm race to the egg

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bS

bA

bA bSbA bS


(AS)bA bS

… they will have a baby with sickle cell trait (AS).

bA bS


bS

If it is the beta-S egg ready this

cycle

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bS

bA

bA bSbA bS


(AS)bS bA


bS bS

..and a beta-S sperm is winner

bA


cycle

Ohene-Frempong 2012

bS

bA

bA bSbA bS


bS bS

..and a beta-S sperm is winner

bS


cycle

(SS)bS bS

… they will have a baby with sickle cell disease SS.

Ohene-Frempong 2012

(AA)

bAbA

(AS)

bSbA

(AS)

bAbS

bA bSbA bS

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

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

(SS)

bSbS

Ohene-Frempong 2012

(AA)

bAbA

(AC)

bCbA

(AS)

bAbS

bA bCbA bS

… 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)


(SC)

bCbS

Ohene-Frempong 2012

b0

bA

bA bSbA b0


(AA)bA bA

… they will have a baby with no abnormal hemoglobins and no beta-thal.

bA bS


When one parent has beta-zero thalassemia trait, and the other has Sickle Cell Trait (AS)

bA


cycle

(No S)

Ohene-Frempong 2012

b0

bA


(AS)bA bS


bA bS



bS


cycle

bA bSbA b0

(No S)

Ohene-Frempong 2012

b0

bA


(Ab0)b0 bA

… they will have a baby with beta-zero thalassemia trait

b0 bS

..and a beta-zero sperm is winner

bA


cycle

bA bSbA b0

(No S)


Ohene-Frempong 2012

b0

bA


b0 bS

..and a beta-zero sperm is winner

bS


cycle

bA bSbA b0

(No S)


(Sb0)b0 bS

.. they will have a baby with S beta-zero thalassemia

Ohene-Frempong 2012

(AA)

bAbA

(AS)

bSbA

(Ab0 thal)

bAb0

Each and every time they make a baby,the baby may have ….

bA bSbA b0

(No S)

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


(Sb0 thal)

bSb0

Ohene-Frempong 2012

(AA)

bAbA

(AS)

bSbA

(Ab+ thal)

bAb+

Each and every time they make a baby,the baby may have ….

bA bSbA b+

(No S)

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


(Sb+ thal)

bSb+

Ohene-Frempong 2012

Genetic Counseling and the Modern Family


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/ (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

http://www.who.int/genomics/professionals/counselling/en/



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



Pre-implantation genetic diagnosis (PGD)

with In Vitro Fertilization (IVF)• Blastomere DNA analysis (after fertilization)

Sperm injection

Ohene-Frempong 2012



Pre-implantation genetic diagnosis (PGD)

with In Vitro Fertilization (IVF)• Polar body DNA analysis (before fertilization)

Polar body extractionPolar body

Ohene-Frempong 2012


It’s Sickle Cell Year 102

Thank You!

Ohene-Frempong 2012

SCDAA 40 th Anniversary Convention 2012 Genetic Counseling for the Future Kwaku Ohene-Frempong, MD...

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