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The Haemoglobinopathies: An Introduction Tony Roscioli Clinical Geneticist, Royal Prince Alfred Hospital & NHMRC Research Post-graduate Fellow, Centre for Vascular Research, UNSW
Haemoglobin disorders as a model ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Autosomal Recessive Inheritance • When both parents are  heterozygotes – 1/4 offspring affected,  2/4 will be carriers, 1/4 unaffected  in each pregnancy Unaffected Thalassaemia: An Important Diagnosis because of Recurrence Aa Aa Aa Aa aa AA
Haemoglobin Structure ,[object Object],[object Object]
Adult Haemoglobins ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Fetal Haemoglobins ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Developmental Pattern of Human Haemoglobins Based on Voet & Voet (1995)
What are Haemoglobinopathies ? ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Why do Haemoglobinopathies occur? ,[object Object],[object Object],[object Object],[object Object]
Haemoglobin Gene Clusters      2  2  1  G  A     40 20 60 Kbp Chromosome 16 Chromosome 11  1   
MECHANISM OF GENE DUPLICATION/DELETION
Deletions in the     Haemoglobin Gene Cluster HPFH = hereditary persistent fetal haemoglobin  0 thalassaemia Hb Lepore G  A       thalassaemia G  A    HPFH G    HPFH Hb Kenya kbp  G  A     40 20 60
Why do Haemoglobinopathies Persist? ,[object Object],[object Object],[object Object]
 
 
 
Thalassaemia Phenotype ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Treatment  ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Diagnosis of Haemoglobinopathies ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Diagnosis of     Thalassaemia ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Effect of  β - thalassaemia on adult red cells ,[object Object],[object Object],[object Object],[object Object],MCH = 20pg Hb A = 96% Hb A 2  >3.5% β thal Trait MCH = 15-30pg Hb F >80% β thal Major/Intermedia               
Exon 1 Exon 2 Exon 3 IVS1 IVS2 Splicing Mutations Nonsense Mutations Poly A site Deletions (rare) Initiator Codon Transcription Insertions Frameshift Deletions (-1, -2, -4)  -Globin
Diagnosis of    Thalassaemia ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Effect of   - thalassaemia on fetal red cells MCH = 35pg Hb F = 92% Hb A = 8% Normal MCH = 20pg Hb F = 89% Hb   4  = 3% Hb A = 8%     thal Trait MCH = 20pg Hb   4  = 80% Hb   2  2  = 10%     thal Major Hb Barts Hydrops Fetalis               
   Thalassaemia ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],   o :  both genes on one chromosome deleted    + :  one gene on each chromosome deleted or or ( )
Forms of    thalassaemia ,[object Object],   2    1       1 4.2 Kb 3.7 Kb    1       1       1    2    1       1  0 -Thalassaemia caused by large intragenic  deletions    2    1       1    Thalassaemia caused by point mutations: Hb Constant Spring
   Thalassaemia Genotype No. Genes Functional Phenotype α α  /  α α -  α  /  α α -  α  / -  α -- /  α α -  α  / -- -- / -- 4 3 2* 2* 1 0 Normal Normal MCV, MCH MCV, MCH HbH disease Hb Barts hydrops fetalis
Distribution of    thalassaemia ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Molecular Testing ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Substitution Haemoglobinopathy ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Diagnosis of Sickle Cell Disease ,[object Object],[object Object],[object Object]
Sickle Cell Disease ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Sickle Cell Disease ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Thalassaemia in NSW ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
100% 23 TOTAL 13.1% 3 India 26.2% 6 Meidterranean/ Africa 26.2% 6 South East Asia 34.5% 8 Middle East Percentage No of Diagnoses Ancestry
[object Object],[object Object]
Definitions: Genetic Testing and Genetic Screening ,[object Object],[object Object]
Core Ethical Principles of Genetic Counselling* ,[object Object],[object Object],[object Object],[object Object]
 
NSW Health Department Guidelines and take home messages ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

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Haemoglobinopathies

  • 1. The Haemoglobinopathies: An Introduction Tony Roscioli Clinical Geneticist, Royal Prince Alfred Hospital & NHMRC Research Post-graduate Fellow, Centre for Vascular Research, UNSW
  • 2.
  • 3. Autosomal Recessive Inheritance • When both parents are heterozygotes – 1/4 offspring affected, 2/4 will be carriers, 1/4 unaffected in each pregnancy Unaffected Thalassaemia: An Important Diagnosis because of Recurrence Aa Aa Aa Aa aa AA
  • 4.
  • 5.
  • 6.
  • 7. Developmental Pattern of Human Haemoglobins Based on Voet & Voet (1995)
  • 8.
  • 9.
  • 10. Haemoglobin Gene Clusters      2  2  1  G  A     40 20 60 Kbp Chromosome 16 Chromosome 11  1   
  • 11. MECHANISM OF GENE DUPLICATION/DELETION
  • 12. Deletions in the  Haemoglobin Gene Cluster HPFH = hereditary persistent fetal haemoglobin  0 thalassaemia Hb Lepore G  A   thalassaemia G  A  HPFH G  HPFH Hb Kenya kbp  G  A     40 20 60
  • 13.
  • 14.  
  • 15.  
  • 16.  
  • 17.
  • 18.
  • 19.
  • 20.
  • 21.
  • 22. Exon 1 Exon 2 Exon 3 IVS1 IVS2 Splicing Mutations Nonsense Mutations Poly A site Deletions (rare) Initiator Codon Transcription Insertions Frameshift Deletions (-1, -2, -4)  -Globin
  • 23.
  • 24. Effect of  - thalassaemia on fetal red cells MCH = 35pg Hb F = 92% Hb A = 8% Normal MCH = 20pg Hb F = 89% Hb  4 = 3% Hb A = 8%   thal Trait MCH = 20pg Hb  4 = 80% Hb  2  2 = 10%   thal Major Hb Barts Hydrops Fetalis         
  • 25.
  • 26.
  • 27. Thalassaemia Genotype No. Genes Functional Phenotype α α / α α - α / α α - α / - α -- / α α - α / -- -- / -- 4 3 2* 2* 1 0 Normal Normal MCV, MCH MCV, MCH HbH disease Hb Barts hydrops fetalis
  • 28.
  • 29.
  • 30.
  • 31.
  • 32.
  • 33.
  • 34.
  • 35. 100% 23 TOTAL 13.1% 3 India 26.2% 6 Meidterranean/ Africa 26.2% 6 South East Asia 34.5% 8 Middle East Percentage No of Diagnoses Ancestry
  • 36.
  • 37.
  • 38.
  • 39.  
  • 40.

Editor's Notes

  1. Each globin chain is linked to a haem molecule, an iron containing protoporphyrin ring
  2. Hb F is the major foetal haemoglobin and is gradually replaced by Hb A from birth . Most Hb is Hb A by about 6 – 9 months
  3. Heterozygote - Rarely of clinical significance but important in A/N screening Homozygote - Often of major clinical significance
  4. Majority occur in the beta chain. The position of the substitution governs the effect it will have on the molecule
  5. Trait - Rarely has any clinical effects, care should be taken when undergoing anaesthesia and in pregnancy SCD -
  6. Trait - Rarely has any clinical effects, care should be taken when undergoing anaesthesia and in pregnancy SCD -