Sickle cell trait and beta thalassemia carrier status: what your DNA file can and cannot show
HBB is the gene behind both sickle cell disease and beta thalassemia, and it is the most common recessive carrier state we screen. It is also the one where a single answer is least useful, because the changes in this gene combine with each other in ways that matter.
Also known as: sickle cell trait, HbS carrier, beta thalassemia trait, HBB carrier.
- Gene
- HBB
- Inheritance
- Autosomal recessive
- Carrier frequency
- high in people of African, Mediterranean, Middle Eastern, and South/Southeast Asian ancestry
What it is
HBB makes beta-globin, one half of the hemoglobin molecule that moves oxygen around your blood. Different changes in the same gene produce different conditions. The change usually called HbS distorts the shape of red blood cells under low oxygen and causes sickle cell disease. Other changes reduce how much beta-globin gets made at all, which causes beta thalassemia. Both are recessive, so a person carrying one changed copy and one working copy is a carrier, described as having sickle cell trait or beta thalassemia trait depending on which change they carry.
Carriers are generally healthy, and that is the ordinary case. Sickle cell trait has been described as carrying rare risks under conditions that push the body hard, such as severe dehydration or very high altitude, which is a question for a clinician who knows your history rather than something a file can settle.
The reason these changes are common is selection. Carrying one copy offered some protection against malaria, so carrier states reached high frequencies wherever malaria was endemic, which is why they are most often seen in people with African, Mediterranean, Middle Eastern and South or Southeast Asian ancestry. Frequency is a population statistic and not a prediction about you.
How it is inherited
The recessive arithmetic is the usual arithmetic. If both parents carry a change in HBB, each pregnancy has a one in four chance of a child who inherits two changes, a one in two chance of a carrier, and a one in four chance of neither. The odds reset with every pregnancy and are not a sequence that takes turns.
What makes HBB different from most recessive genes is that "two changes" is not one outcome. Because several distinct changes circulate in this gene, two carriers can pass on two changes that are not the same as each other, and the combination has its own name and its own course. HbS inherited alongside a beta thalassemia change gives sickle beta thalassemia; HbS alongside the change called HbC gives HbSC disease. These are related conditions rather than one condition, and they are not interchangeable.
That is why a carrier result for this gene says less on its own than people expect, and why the useful unit of information is both partners' specific changes read together. A carrier result is a fact about a couple, not a diagnosis about a person, and which change each person carries is part of the fact. Interpreting that pairing is genetic counseling work.
What your raw DNA file can and cannot tell you
Start with what a chip file is. A 23andMe, AncestryDNA or MyHeritage export is a genotyping array that reports the bases at a fixed list of positions chosen ahead of time. For most recessive genes that ends the discussion, because the relevant changes are too rare to be on the list. HBB is the exception worth being careful about: the sickle change is common enough that an array may well include that exact position. Aimosti still does not report carrier status from a chip file, for this gene or any other, and a typed position is the reason to be more careful rather than less. Learning that one position is unchanged tells you nothing about the beta thalassemia changes, or about HbC, or about anything else in the gene the array never looked at. A quiet chip result is not a rule-out, and we would rather say that plainly than hand back a reassuring blank.
A whole-genome VCF or gVCF is what our carrier module actually reads, and it can find beta-globin changes anywhere the sequencing covered rather than only at pre-chosen spots. Its limits are specific. Some beta thalassemia is caused by deletions in the beta-globin cluster or by changes in the regulatory sequence that switches the gene on, and a short-variant file represents neither well. Clinical confirmation of these carrier states also normally involves a hemoglobin study, a laboratory measurement of the protein itself, which no amount of reading a variant file replaces. So a file with no HBB finding lowers the odds that you carry one of these changes without taking them to zero.
One distinction matters more here than anywhere else on this site, because the word is ambiguous. Thalassemia comes in an alpha form and a beta form. This page is about the beta form. Alpha thalassemia is caused predominantly by large deletions of the alpha-globin genes, a copy-number change that a standard short-variant file does not capture, so it sits on our published list of conditions we deliberately do not screen. Someone who searched for "thalassemia carrier" and landed here has a real chance of wanting the other letter, and this product has nothing to offer them. Along the same lines, our panel leaves out spinal muscular atrophy for the same callability reason. A re-analysis of a file you already own is a way to look again at data you have paid for; it is not a substitute for carrier screening ordered by a clinician, and for a decision about a pregnancy the clinical test is the one that should carry the weight.
A genotyping chip reads only a few hundred thousand pre-selected positions, about 0.02% of your genome, chosen for common variation. It does not sequence the rest, so it cannot find the rare or novel pathogenic variants the clinical and carrier modules look for: a “no finding” from chip data means “this chip never looked”, far more so than with whole-genome sequencing. Chip data suits common-variant traits, pharmacogenomic tag SNPs, and haplogroup ancestry, not clinical or carrier screening.
Common questions
My 23andMe or AncestryDNA file never mentioned sickle cell. Does that mean I am not a carrier?
No. An array reads a fixed list of positions, and even when that list includes the common sickle position, it says nothing about the beta thalassemia changes or the other variants in HBB. Aimosti does not issue carrier status from chip data at all. Silence from a chip is an absence of looking, not a negative result.
What is the difference between sickle cell trait and sickle cell disease?
Trait means one changed copy of HBB and one working copy, which is the carrier state and is generally compatible with ordinary health. Disease means both copies are affected. They are different states, and one does not become the other over time.
Does this cover thalassemia?
It covers the beta form, and not the alpha form. Alpha thalassemia is mostly caused by large deletions of the alpha-globin genes, which a short-variant file cannot capture, so it is on our published list of conditions we do not screen. If alpha thalassemia is the question, this product cannot answer it and a clinical test is the right route.
My partner and I both carry a change in HBB. What happens now?
This is the situation where the specific changes matter, because two different HBB changes can combine into conditions such as sickle beta thalassemia or HbSC disease rather than into a single expected outcome. It is also the situation a genetic counselor exists for, and results from a re-analysis should be confirmed with a validated clinical test, usually including a hemoglobin study, before anything is decided.