**3. Genotype phenotype relationship in β-thalassemia**

Mutations causing thalassemia can affect any step in the pathway of globin gene expression. The most common forms arise from mutations that derange splicing of the mRNA precursors or prematurely terminate translation of the mRNA. The resulting phenotype reflect the effects of the β0 thalassemia in which there is no B-globin gene production and B+ , B++ thalassemia in which there is marked or mild reduction in production of β-chain [5].

#### **3.1. Genetic modifiers**

Several modifier genes have been identified which are able to influence the severity of βthalassemia, so at phenotypic level β-thalassemias are considered multigenic diseases. Improved understanding of the influence of modifier genes involved in modulating the complex pathophysiology of β-thalassemia may allow prediction of disease phenotype [6].

#### *3.1.1. Primary modifiers*

Primary genetic modifiers in homozygous β-thalassemia include genetic variants able to reduce the globin chain imbalance, therefore resulting in a milder form of thalassemia.


#### *3.1.2. Secondary modifiers*

The clinical phenotype of homozygous β-thalassemia may also be modified by the coinheritance of other genetic variants mapping outside the globin clusters.

