1. The Haemoglobinopathies: An Introduction Tony Roscioli Clinical Geneticist, Royal Prince Alfred Hospital & NHMRC Research Post-graduate Fellow, Centre for Vascular Research, UNSW

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

7. Developmental Pattern of Human Haemoglobins Based on Voet & Voet (1995)

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

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

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         

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

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