Beta-thalassemia is a genetic condition in which the body cannot make enough of a protein called beta-globin, one of the building blocks of haemoglobin, the molecule inside red blood cells that carries oxygen throughout the body. Without enough beta-globin, red blood cells cannot be built or maintained properly, and this leads to anaemia — a shortage of healthy red blood cells — that can range from barely noticeable to severe and life-threatening depending on how much beta-globin the body can still make.

Haemoglobin is normally made of two different protein chains working together in a balanced pair: two alpha-globin chains and two beta-globin chains. The instructions for building the beta-globin chain come from a single gene called HBB. When a person has a pathogenic variant, meaning a harmful change, in one or both copies of the HBB gene, the body produces too little beta-globin, or none at all. This creates an imbalance: the alpha-globin chains, which are still being made normally, have no matching partner and begin to clump together inside developing red blood cells. These clumps damage the red blood cells from the inside, causing many of them to die before they even leave the bone marrow, a process called ineffective erythropoiesis, and causing the ones that do reach the bloodstream to break down early, a process called haemolysis. The bone marrow responds by working harder and expanding, which is why more severely affected individuals can develop broadening of the facial and skull bones over time if the condition goes untreated.

How much beta-globin a person can still make depends on which HBB variant they carry. A variant that stops beta-globin production completely is called a beta-zero variant, while one that allows some reduced production is called a beta-plus variant. The combination of variants a person inherits — for example, two beta-zero variants versus one beta-zero and one beta-plus — is a major reason why beta-thalassemia ranges from a mild, often unnoticed trait to a severe, transfusion-dependent condition, which is described further below.

Beta-thalassemia is not caused by anything a parent did during pregnancy, and it cannot be caught from another person or spread through contact. It comes entirely from the specific combination of HBB gene copies a child inherits from each parent.