What Is the Alpha 3.7 Deletion in Alpha-Thalassemia?

The alpha 3.7 deletion is the most common genetic change behind alpha-thalassemia, one of the most widespread inherited blood conditions in the world.¹ It means a small piece of DNA is missing, so the body has one fewer working alpha gene for making hemoglobin. For most people that is a mild finding, often noticed only because a blood count shows small red blood cells. Its real importance is often for future children, because what it means for them depends on what genes a partner carries.

What Actually Goes Missing in the 3.7 Deletion

Hemoglobin, the oxygen-carrying protein in red blood cells, is built partly from alpha chains. The instructions for those chains come from the alpha-globin genes, and most people have four of them, two on each copy of chromosome 16. Losing one of the four still leaves three working genes.

The “3.7” refers to the size of the missing piece, about 3,700 DNA letters. The deletion fuses the two alpha genes on that chromosome into a single hybrid gene that still works.² So that chromosome makes alpha chains from one gene instead of two. A related, less common change, the -α4.2 deletion, removes a slightly larger piece from a different spot.³

The two alpha genes on each chromosome 16 sit close together and have very similar DNA sequences, so the cell’s copying machinery can occasionally line them up wrongly. When chromosomes pair up misaligned and swap material while egg or sperm cells are being made, the stretch between the two genes can be cut out, leaving one hybrid gene on one chromosome.

On a lab report, “αα” stands for a normal chromosome with two alpha genes, and “-α” means one gene is missing on that chromosome. So “-α3.7/αα” is one deletion with three genes left, and “-α3.7/-α3.7” is two deletions with two genes left.

This is a trait you were born with, inherited from a parent. It does not develop from diet, lifestyle, or illness.

One Copy Versus Two Copies

The 3.7 deletion accounted for about 57% of alpha-thalassemia changes found at four Italian diagnostic centers.⁴ Of those carrying it, about 55% had one copy and 27% had two.⁵ A US lab testing referred patients found one copy in 27% and two copies in 23%.⁶

People with one copy have traditionally been called silent carriers, meaning they have no symptoms and often normal-looking blood counts. Many newborns with one copy show no warning sign on cord blood screening.⁷ People missing two genes usually have small red cells and sometimes mild anemia. Neither group usually has symptoms that need treatment. “Silent” means no symptoms, not no effect: a silent carrier can still pass the deletion to a child.

The difference between one and two copies comes down to gene count. With one copy, three of four alpha genes still work, which is usually enough to make nearly normal red cells. With two copies, only two genes work, so red cells are made with less hemoglobin and come out smaller.

Losing two genes can happen in two ways. Two 3.7 deletions on opposite chromosomes, one from each parent, is the common arrangement for this deletion. The other arrangement loses both genes from a single chromosome, which leaves the person with the same two working genes but is a different and more serious change to pass on. The two look similar on a blood count, and only DNA testing tells them apart. The difference matters when that person has children, because a chromosome missing both genes can combine with a partner’s change. If your report shows two missing genes, ask which arrangement it is, since the count alone does not say.

What It Can Show on Blood Tests

Children referred for small red cells who carried one 3.7 deletion had lower hemoglobin and smaller red cells than typical children.⁸ They also had higher red blood cell counts, because the body makes more, smaller cells.⁹ Red cell size, shown as MCV (mean corpuscular volume) on a blood count report, was clearly below normal in most of these children over age 2.¹⁰ The drop in hemoglobin was largest in teenage boys.¹¹

The effect is milder than in other types. People with 3.7 deletions keep closer-to-normal red cell size than those with the Southeast Asian deletion, which removes two genes at once.¹² Noticeably small cells with a single 3.7 deletion are possible but usually modest.

The shrinking happens because each red cell is packed with hemoglobin, and with fewer alpha genes there is less alpha chain to build it, so the cell ends up smaller and paler. The bone marrow responds by making more cells to carry the oxygen, which is why the cell count can rise even as each one shrinks.

Iron deficiency can look almost identical. Both give a low red cell size and can lower hemoglobin, so a blood count alone cannot separate them. A ferritin test, which reflects iron stores, is usually low in iron deficiency and normal in thalassemia trait, though ferritin can be falsely raised during inflammation. Small cells with a high red cell count lean toward thalassemia, while small cells with a low count lean toward iron deficiency, but that is one clue among several. Iron pills will not correct thalassemia-related small cells, and taking iron without a low ferritin may add iron the body does not need. Mention your carrier result to future doctors whenever a blood count looks abnormal, and ask for an iron check before any iron treatment.

What It Means for Your Children

If one parent carries one 3.7-type deletion and the other has lost both alpha genes on one chromosome, each pregnancy has a 1 in 4 chance of Hb H disease.¹³ Hb H disease means only one working alpha gene, often causing lifelong moderate anemia. It can also arise from a 3.7 deletion plus a faulty alpha gene called Hb Constant Spring.¹⁴ A partner’s test matters as much as your own.

The 1 in 4 comes from chance in how chromosomes are passed on. When one parent has a single-gene loss and the other has a chromosome missing both genes, the child lands in one of four equally likely combinations. One of them pairs both loss chromosomes and leaves one working alpha gene, the arrangement behind Hb H disease. The other three are a normal chromosome from each parent, the single-gene loss only, or the two-gene loss only.

Hb Constant Spring is not a deletion. The gene is present but makes alpha chains poorly. A 3.7 deletion on one chromosome and a Constant Spring gene on the other can leave a child with too little working alpha chain. A standard blood count may not reveal Constant Spring, so a partner who looks well can still carry it.

Other combinations carry less risk. If both partners carry only single-gene losses like the 3.7 deletion, a child can inherit at most two missing genes, which gives mild trait. The most severe form, losing all four genes, requires both parents to pass on chromosomes missing both genes.

For couples planning a pregnancy, a practical path is to ask for the partner to have a blood count and an alpha-gene DNA test. Ask specifically whether any result shows both genes missing on one chromosome, and whether the test looks beyond the common deletions to things like Constant Spring. If the combination carries Hb H risk, request genetic counseling. Prenatal testing is available at specialist centers.

How the Deletion Is Found

Testing usually starts with something else: unexplained small red cells on a routine count, pregnancy or preconception screening, a relative’s diagnosis, or newborn screening in some regions.

Standard hemoglobin tests often look normal with alpha-thalassemia, unlike beta-thalassemia. Beta-thalassemia shifts the proportions of hemoglobin types in a way a common hemoglobin test can see, but alpha-thalassemia trait often leaves those proportions normal. A person with a 3.7 deletion can therefore have a normal hemoglobin test and still carry it.

That is why DNA tests that look for the common alpha deletions are what confirm the result.¹⁵ Such tests can check for the seven most common alpha deletions at once.¹⁶ Rarer changes may need more specialized testing at a referral center.¹⁷ A result with no deletions found does not fully rule out alpha-thalassemia, and if small cells stay unexplained after a negative panel, a referral center can test the genes more thoroughly.

Why It Is So Common Worldwide

Children with alpha-thalassemia who develop severe malaria carry less total parasite in their bodies.¹⁸ In one Nepalese population living with constant malaria, about 80% of alpha genes carried a deletion.¹⁹ Having two deletions there appeared to cut malaria illness about tenfold.²⁰

Malaria parasites live inside red blood cells, so differences in those cells can change how well an infection takes hold. In regions where malaria killed many children, carriers were more likely to survive to adulthood and have children of their own. Over many generations, that edge made the deletion more common.

One version of the 3.7 deletion is carried by about 22% of people in Vanuatu and 23% in French Polynesia.²¹ The deletion overall is common in African, Mediterranean, Middle Eastern, and South and Southeast Asian ancestry.

So carrying it is ordinary variation in many parts of the world, not a sign of poor health. The benefit was historical, and it offers no proven malaria protection to travelers.

How It Affects Sickle Cell and Beta-Thalassemia

People with sickle cell anemia and two 3.7 deletions had fewer severe pain crises and needed fewer transfusions.²² They also had lower rates of gallstones, leg ulcers, and bone damage.²³ The picture is not uniformly better, though. In one Brazilian group, men with sickle cell anemia and the deletion had more priapism, prolonged painful erections.²⁴

That mixed result makes sense. In sickle cell anemia, fewer alpha chains leave cells less concentrated with hemoglobin, which makes sickling less likely. The same change can make blood thicker because red cells survive longer, which may explain problems like priapism. So the deletion is generally helpful in sickle cell disease but not for every complication.

Alpha deletions found in people with severe beta-thalassemia can soften its course too.²⁵ Hemoglobin needs alpha and beta chains in balance, and in beta-thalassemia there are too few beta chains. The leftover alpha chains cannot form normal hemoglobin and clump inside developing red cells, damaging them. Losing an alpha gene lowers the number of alpha chains, so the imbalance shrinks and cells are damaged less. Researchers are even testing gene editing to reduce alpha chains in beta-thalassemia, borrowing the idea from this natural effect. People with sickle cell or beta-thalassemia can ask whether alpha testing was done, since the results may inform monitoring plans.