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GENETIC BACKGROUND IN THALASSEMIA

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  1. GENETICBACKGROUND IN THALASSEMIA

  2. a & B GENE CLUSTERS


  3. Hb

  4. Double Helix DNA

  5. CCAAT TATAA Initiation Codon Termination Codon ATG Exon1 GT AG Exon 2 TAA TAG TGA Intron 3’ 5’ HUMAN GENE

  6. Transcription Termination Transcription Initiation ‘CAT ‘TATA’ Box Box Exon 3 Exon1 Exon2 5’ 3’ Promoter region Intron 1 Intron 2 Polyadenylation Signal Translation Initiation Codon (ATG) Translation Termination Codon (TAA)

  7. Mild and Silent Beta-Thalassemia Mutations

  8. SEVERE MUTATIONS • 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)

  9. SEVERE / MILD • 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)

  10. MILD MUTATIONS • 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)

  11. Molecular Basis of Thalassemia Intermedia 1. Homozygous or compound heterozygous state for b thalassemia • Inheritance of mild b thalassemia alleles • Co-inheritance of a thalassemia • Increased Hb F response • Xmn1 –polymorphism • b promoter mutations • Trans-acting HPFH genetic determinants

  12. Molecular Basis of Thal. Int. cont. 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 chainvariants) 3. Compound heterozygous for b thalassemia and b chain variants e.g. Hb E 4. Compound heterozygotes for b thalassemia and HPFH .

  13. Aids to Predict Thal. Intermedia Cases • -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

  14. -Thalassemia

  15. FAILURE OF a-GLOBIN LEADS TO: Hb F a22 (4) Hb Barts Hb A2 a22 Hb A a22 (4)Hb H

  16. -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

  17. 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

  18. DeletionalHb 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

  19. THANK YOU