Download genetics in thalassemia

a & B GENE CLUSTERS
Hb
Double Helix DNA
CCAAT
TATAA
Initiation
Codon
A
T
G
Termination
Codon
Exon1
G
T
Intron
A
G
Exon 2
TAA
TAG
TGA
3’
5’
HUMAN GENE
Transcription
Termination
Transcription
Initiation
‘CAT ‘TATA’
Box
Box
Exon 1
Exon 3
Exon 2
5’
3’
Promoter
region
Intron 1
Translation
Initiation
Codon
(ATG)
Intron 2
Translation
Termination
Codon (TAA)
Polyadenylation
Signal
Mild and Silent Beta-Thalassemia Mutations
Mild beta +-thalassemia
Silent beta-thalassemia
 Transcription
o (CACC box)
-90 (CT), -88 (CT)
-88 (CG), -87 (CG)
-87 (CT), -87 (C
-86 (CA), -86 (CT)
-88 (CG)
o (TATA box)
-31 (AG)
-30 (TA)
-29 (AG)
 Splice site activation
o cd 19 (AG) (Hb Malay)
o cd 26 (GA) (HbE),
o cd 27 (GT) (Hb Knossos)
o cd 19 (AC), cd 24 (TA)
 Consensus sequence
o IVS 1-6 (TC)
 Polyadenylation
o AATAAAAACAAA
o AATGAAAATAGA
A (-AATAA)
 Transcription
o Promoter -101 (C,
o -92 (CT)
 -5 UTR + 1 (AC),
+10-T, +33 (CG)
 -3 UTR + (CG)
o Consensus sequence:
IVS 2-844 (CG)
o Polyadenylation:
Mild beta 0-thalassemia
 Frameshift
o Cd 6 (-A)
o Cd 8 (-AA)
 Splicing junction
o IVS II-I (GA)
Severe beta-thalassemia
 All other mutations
AATAAAAATAAG
IVS 1 - 5 (G->C) / IVS 1 - 5 (G->C)
IVS 1 - 5 (G->C) / - 25 bp del
IVS 1 - 1(G->A) / IVS 1 – 1(G -> A)
IVS 1 - 1 (G-T) / IVS 1 - 1 (G -> T)
-25 bp del / -25 bp del
Cd 8 (-AA) / Cd 8 (-AA)
IVS 1 - 5 (G->C) / - 88 (C->A)
IVS 1 - 5 (G->C) / Poly A
IVS 1– 5 (G->C) / CD 26 (G->A)
IVS 1 – 5 (G->C) / IVS II-837 (T-C)
-25 bp del / CD 27 (G->T)
IVS II–1 (G->A) / IVS II – 1 (G->A)
IVS 1-6 (T->C) / IVS 1-6 (T->C)
CD 27 (G->T) / CD 39 (G->T)
CD 26 (G->A) / 619 bp del
CD 26 (G->A) / IVS 1 – 130 (G->C)
CD 30 (G->A) / CD 30 (G->A)
IVS 1-6 (T->C) / Undefined
IVS 1-6(T->C) / IVS II-848(C->A)
1. Homozygous or compound heterozygous state for
bthalassemia
a) Inheritance of mild b thalassemia alleles
b) Co-inheritance of a thalassemia
c) Increased Hb F response
 Xmn1 –polymorphism
 b promoter mutations
 Trans-acting HPFH genetic determinants
2. Heterozygous state for b thalassemia
a) Co-inheritance of extra a globin genes
(aaaa/aa,aaa/aaa,aaa/aa)
b) Dominantly inherited b thalassemia
(Hyperunstable b chain variants)
3. Compound heterozygous for b thalassemia and b
chain variants e.g. Hb E
4. Compound heterozygotes for b thalassemia and
HPFH .
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b-Thalassemia genotypes of
parents
Hb. F values in parents
Co-inheritance of a thalassemia
Age at presentation
Level of Hb. at presentation
Level of Hb. A
a-Thalassemia
Alpha Genes
Deleted
One
Clinical
Disorder
Hb barts
Cord Blood
Silenta-thal 1-3%
a-thal trait 4-10%
Two
Three Hb H Disease 15-25%
Four Hydrops Fetalis 100%
Hb H
0%
0%
10-25%
-
FAILURE OF a-GLOBIN LEADS TO:
Hb F
a22
Hb A2
a22
Hb A
a2b2
(4) Hb Barts
(b4) Hb H
a-Thalassemia - 1
in Trans
Single gene deletion on both chromosomes
• Very common in our area
• Patients are Microcytic Hypochromic
• Normal Hemoglobin Electrophoresis
• No risk of hemoglobin Bart’s hydrops
fetalis
a -Thalassemia - 1
in CIS
 Deletion of both a genes on one
chromosome.
 Common in Southeast Asian, Filipino.
 Fortunately is not recorded in our area.
 Diagnosis: Microcytic hypochromic, normal
Hb electrophoresis, DNA studies
 Risk of transmission of Hb Bart’s hydrops
fetalis
Deletional Hb H Disease
 3 a genes are detected (-a/--)
 Parents has to be -a/aa&--/aa
 This type is common in South Asia and
not common in our locality.
 Fairly severe anemia with hemolysis