Genotype-Phenotype Association Analysis Identifies The Role Of A Globin Genes In Modulating Disease Severity Of Beta Thalassaemia Intermedia In Sri Lanka

beta thalassaemia intermedia (beta TI) are a heterogeneous group of disorders known to be extremely phenotypically diverse. This group is more complex to manage as no definitive treatment guidelines exist unlike for beta halassaemia major (beta TM). There are only a few studies looking at genotype phenotype associations of beta TI outside the Mediterranean region. The reasons for the diverse clinical phenotype in beta TI are unknown. We categorized fifty Sri Lankan patients diagnosed with beta TI as mild, moderate or severe according to published criteria. DNA samples were genotyped for beta thalassaemia mutations, alpha globin genotype and copy number and known genetic modifiers of haemoglobin F production. There were 26/50 (52.0%) in mild group and 12/50 (24.0%) each in moderate and sever categories. 18/26 (69.2%) classified as mild were beta heterozygotes and 17/18 (94.4%) had excess a globin genes. 11/12 (91.6%) classified as moderate were beta heterozygotes and 8/11 (72.2%) had excess alpha globin genes. In contrast, 8/12 (66.7%) classified as severe were beta homozygotes and 7/8(87.5%) had alpha globin gene deletions. In Sri Lanka, co-inheritance of either excess alpha globin genes in beta thalassaemia heterozygotes or alpha globin gene deletions in beta thalassaemia homozygotes is a significant factor in modulating disease severity.