Modern Genetics of Sickle Cell Disease 

Report
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
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.
2.
3.
4.
5.
6.
7.
9.
Blood smear
Slide sickling preparation
Solubility test
Complete Blood Count, reticulocyte count
Hemoglobin separation tests
Quantitation of hemoglobin fractions
DNA-based tests
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
Ohene-Frempong 2012
National Society of Genetic Counselors, 2006
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)
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
Ohene-Frempong 2012
Genetic Counseling for the Future
Modern Genetics of Sickle Cell Disease
Human Hemoglobin Genes and Products
Chromosome
16
Chromosome
Chromosome16
16
Globin
proteins
Globin
Globinproteins
proteins
Chromosome
11
Chromosome
Chromosome11
11
Hemoglobins: Birth
“Embryonic”
F:
2 g2
A2: 2 d2
> 1 yr
60-90%
< 2%
< 1%
2-3%
10-40%
96%
“Fetal”
A:
“Minor adult”
-globin gene
family
Ohene-Frempong 2012
b-globin gene
family
“Major adult”
2 b2
Genetic Counseling for the Future
Modern Genetics of Sickle Cell Disease
To make Hb A (2 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
Genetic Counseling for the Future
Globins in hemoglobin
Assembled in two stages:
1 -family globin
+ 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
At Birth:
> 1 yr.:
Ohene-Frempong 2012

b

d

g
b

d

g

 2 b2
2 d2
2 g2
A
A2
F
10-40%
< 1%
60-90%
96%
3%
1%
Genetic Counseling for the Future
Modern Genetics of Sickle Cell Disease
Hemoglobin Genes and Products in SCD-SS
Gower 1: z2 e2
Gower 2: 2 e2
Portland: x2 g2
-----------------F: 2 g2
2-20%
A2: 2 d2
3%
S: 2 bs2
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

bS

bC
G
b
b

bS

bC

b
G
Ohene-Frempong 2012
 2 b2
2 bS2
2 bC2
G2b2
A
S
C
GPhila.
Genetic Counseling for the Future
Modern Genetics of Sickle Cell Disease
Normally, balanced globin synthesis
-family globins
z + 1  2
b-family
globins
==
e +Gg + Ag + d + b
Thalassemia
(insufficient or no production of globin)
Ohene-Frempong 2012
Genetic Counseling for the Future
Modern Genetics of Sickle Cell Disease
Imbalanced globin synthesis:
-thalassemia = insufficient  globin
Excess b-like globin:
Newborn: Hb Bart’s (g tetramers)
Adult: Hb H (b tetramers) - high O2 affinity, unstable,
precipitates, causes hemolysis (RBC destruction)
Alpha thalassemia affects clinical course of SCD
Ohene-Frempong 2012
Genetic Counseling for the Future
Pathophysiology
of Sickle
Thalassemias
Modern
Genetics of
Cell Disease
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
Newborn
Clinical Course
> 6 mo.
SCD-SS
FS
SF
SCD-SC
FSC
SCFA2
SCD-Sbo thal
FS
SF
SCD-Sb+ thal
FSA
SAFA2
Mild
SCD-S(db)o thal
FS
SFA2
Very mild
Ohene-Frempong 2012
A2
A2
Severe
Moderate - severe
Severe
Genetic Counseling for the Future
Variants
SCD
Pathophysiology
of of
Thalassemias
with Hb Phenotype Similar to SCD-SS
Variant
Hbs in RBC
Newborn
Clinical Course
> 6 mo.
SCD-SS
FS
SF
A2
Severe
SCD-Sbo thal
FS
SF
A2
Severe
SCD-S(db)o thal
FS
SFA2
Very mild
SCD-S/HPFH
FS
SFA2
Asymptomatic
Ohene-Frempong 2012
Genetic Counseling for the Future
Inheritance of Sickle Cell Disease
In Modern Terminology
Ohene-Frempong 2012
Inheritance of Sickle Cell Disease
When both parents have no abnormal hemoglobins or
thalassemia, …
bA
Every sperm
will be a
beta-A sperm
bA
bA
bA
bA
bA bA
bA
Every egg
will be a
beta-A egg
.. every baby they make will have normal hemoglobins.
bA
bA
(AA)
Ohene-Frempong 2012
Inheritance of Sickle Cell Disease
When both parents have Sickle Cell Trait (AS)…..
bA
Millions of
sperm race
to the egg
bS
bA
bA
bS
bA bA
..and a
beta-A sperm is winner
bS
Usually only
egg is ready
each cycle
If it is the
beta-A egg
ready this
cycle
… they will have a baby with no abnormal hemoglobin.
bA
Ohene-Frempong 2012
bA
(AA)
Inheritance of Sickle Cell Disease
When both parents have Sickle Cell Trait (AS)…..
bA
bS
bA
bA
bS
bA bS
..and a
beta-A sperm is winner
bS
If it is the
beta-S egg
ready this
cycle
… they will have a baby with sickle cell trait (AS).
bA
Ohene-Frempong 2012
bS
(AS)
Inheritance of Sickle Cell Disease
When both parents have Sickle Cell Trait (AS)…..
bA
bS
bA
bA
bS
bS bAS
..and a
beta-S sperm is winner
bS
If it is the
beta-A egg
ready this
cycle
… they will have a baby with sickle cell trait (AS).
bS
Ohene-Frempong 2012
bA
(AS)
Inheritance of Sickle Cell Disease
When both parents have Sickle Cell Trait (AS)…..
bA
bS
bA
bA
bS
bS bS
..and a
beta-S sperm is winner
bS
If it is the
beta-S egg
ready this
cycle
… they will have a baby with sickle cell disease SS.
bS
Ohene-Frempong 2012
bS
(SS)
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 ….
bA
bA
(AA)
Ohene-Frempong 2012
bA
bS
(AS)
bS
bA
(AS)
bS
bS
(SS)
Inheritance of Sickle Cell Disease
Similarly, when one parent has Sickle Cell Trait (AS),
and the other has hemoglobin C trait (AC)...
bA
bS
bA
bC
(No S)
… each and every time they make a baby,
the baby may have ….
bA
bA
(AA)
Ohene-Frempong 2012
bA
bC
(AC)
bS
bA
(AS)
bS
bC
(SC)
Inheritance of Sickle Cell Disease
When one parent has beta-zero thalassemia trait,
and the other has Sickle Cell Trait (AS)
bA
b0
bA
bS
(No S)
bA
b0
bA bAS
..and a
beta-A sperm is winner
If it is the
beta-A egg
ready this
cycle
… they will have a baby with no abnormal hemoglobins
and no beta-thal.
bA
Ohene-Frempong 2012
bA
(AA)
Inheritance of Sickle Cell Disease
When one parent has beta-zero thalassemia trait,
and the other has Sickle Cell Trait (AS)
bA
b0
bA
bS
(No S)
bA
b0
bA bS
..and a
beta-A sperm is winner
If it is the
beta-S egg
ready this
cycle
… they will have a baby with sickle cell trait (AS).
bA
Ohene-Frempong 2012
bS
(AS)
Inheritance of Sickle Cell Disease
When one parent has beta-zero thalassemia trait,
and the other has Sickle Cell Trait (AS)
bA
b0
bA
bS
(No S)
bA
b0
b0 bAS
..and a
beta-zero sperm is winner
If it is the
beta-A egg
ready this
cycle
… they will have a baby with beta-zero thalassemia trait
b0
Ohene-Frempong 2012
bA
(Ab0)
Inheritance of Sickle Cell Disease
When one parent has beta-zero thalassemia trait,
and the other has Sickle Cell Trait (AS)
bA
b0
bA
bS
(No S)
bA
b0
b0 bS
..and a
beta-zero sperm is winner
If it is the
beta-S egg
ready this
cycle
.. they will have a baby with S beta-zero thalassemia
b0
Ohene-Frempong 2012
bS
(Sb0)
Inheritance of Sickle Cell Disease
When one parent has beta-zero thalassemia trait,
and the other has Sickle Cell Trait (AS), …..
bA
b0
bA
bS
(No S)
Each and every time they make a baby,
the baby may have ….
bA
bA
(AA)
Ohene-Frempong 2012
bA
bS
(AS)
b0
bA
(Ab0 thal)
b0
bS
(Sb0 thal)
Inheritance of Sickle Cell Disease
Similarly, when one parent has beta-plus thalassemia
trait, and the other has Sickle Cell Trait (AS), …..
bA
b+
bA
bS
(No S)
Each and every time they make a baby,
the baby may have ….
bA
bA
(AA)
Ohene-Frempong 2012
bA
bS
(AS)
b+
bA
(Ab+ thal)
b+
bS
(Sb+ thal)
Genetic Counseling for the Future
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
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
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
Ohene-Frempong 2012
Polar body extraction
Genetic Counseling for the Future
It’s Sickle Cell Year 102
Thank You!
Ohene-Frempong 2012

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