Several types of anemia are caused by genetic mutations, including sickle cell disease, thalassemia, hereditary spherocytosis, G6PD deficiency, Fanconi anemia, and Diamond-Blackfan anemia. These conditions affect different parts of the red blood cell, from the hemoglobin inside it to the membrane holding it together to the bone marrow machinery that produces it. Some involve a single letter change in one gene, while others result from large deletions or defects across dozens of genes.
Sickle Cell Disease
Sickle cell disease is the most well-known genetic anemia and one of the simplest at the molecular level. It’s caused by a single point mutation in the gene that codes for beta-globin, one of the protein chains in hemoglobin. That one-letter swap (A to T in the sixth codon) replaces the amino acid glutamic acid with valine. The result is an abnormal form of hemoglobin called HbS.
When HbS releases oxygen, it clumps together inside the red blood cell, distorting it into a rigid, crescent-shaped “sickle.” These misshapen cells get stuck in small blood vessels, block blood flow, and break apart faster than normal cells. The blocked blood flow causes episodes of intense pain called vaso-occlusive crises, while the rapid destruction of red blood cells causes chronic anemia. Sickle cell disease follows an autosomal recessive pattern, meaning you need to inherit the mutated gene from both parents to develop the full disease. Inheriting one copy makes you a carrier (sickle cell trait), which usually causes no symptoms.
In December 2023, the FDA approved two gene therapies for sickle cell disease in patients 12 and older. Casgevy is the first approved therapy using CRISPR/Cas9 gene editing. It works by modifying a patient’s own blood stem cells to boost production of fetal hemoglobin, a form of hemoglobin that prevents red blood cells from sickling. Lyfgenia uses a viral delivery vehicle to insert a gene that produces a therapy-derived hemoglobin functioning like normal adult hemoglobin.
Thalassemia
Where sickle cell disease changes the shape of hemoglobin, thalassemia reduces the amount of it. Hemoglobin is built from two types of protein chains: alpha-globin and beta-globin. Mutations or deletions in the genes coding for either chain cause the body to produce too little of that component, and the imbalance leads to fragile, short-lived red blood cells.
Alpha Thalassemia
Four genes control alpha-globin production, two inherited from each parent. The severity depends entirely on how many of those genes are missing. Losing one gene makes you a silent carrier with no symptoms. Losing two causes mild anemia (alpha thalassemia trait). Losing three leads to hemoglobin H disease, which causes moderate to severe anemia. Losing all four is almost always fatal before or shortly after birth, a condition called hydrops fetalis.
Beta Thalassemia
Only two genes control beta-globin production. If one is altered, you have beta thalassemia minor, which typically causes mild anemia. If both are altered, the result is either beta thalassemia intermedia (moderate anemia) or beta thalassemia major, also called Cooley’s anemia, which causes severe anemia requiring regular blood transfusions starting in early childhood.
Hereditary Spherocytosis
Hereditary spherocytosis affects the structural scaffolding of the red blood cell membrane rather than the hemoglobin inside it. Mutations in genes that produce membrane skeleton proteins cause the cell to lose pieces of its outer surface, forcing it from its normal flexible disc shape into a rigid sphere. These spherical cells are less able to squeeze through narrow blood vessels and get trapped and destroyed in the spleen, leading to anemia.
Five genes are responsible for most cases: ANK1 (encoding ankyrin), SPTB (beta-spectrin), SPTA1 (alpha-spectrin), SLC4A1 (band 3 protein), and EPB42 (protein 4.2). In one large study, ANK1 and SPTB mutations together accounted for about 83% of cases. Most forms follow autosomal dominant inheritance, meaning one copy of the mutated gene from one parent is enough to cause the disease. Rarer recessive forms involve mutations in SPTA1 or EPB42, requiring a defective copy from both parents.
G6PD Deficiency
G6PD deficiency is the most common enzyme deficiency in humans, affecting an estimated 400 million people worldwide. It involves a mutation on the X chromosome in the gene for glucose-6-phosphate dehydrogenase, an enzyme that protects red blood cells from oxidative damage. Because it’s X-linked, it predominantly affects males. Fathers cannot pass the trait to their sons, and women with one affected X chromosome are usually carriers with mild or no symptoms.
Most people with G6PD deficiency feel perfectly fine most of the time. The anemia is episodic, triggered when something overwhelms the cell’s weakened defenses against oxidative stress. Common triggers include bacterial or viral infections, certain antimalarial medications, some antibiotics, and fava beans (the reaction to fava beans is so well established it has its own name: favism). During a hemolytic episode, red blood cells break down faster than the body can replace them, causing sudden anemia, dark urine, fatigue, and jaundice. Between episodes, red blood cell counts typically return to normal.
Fanconi Anemia
Fanconi anemia is the most common inherited bone marrow failure disorder, but it works very differently from the conditions above. Rather than destroying mature red blood cells, it impairs the bone marrow’s ability to produce them in the first place. The underlying problem is defective DNA repair. Mutations in any of 22 identified genes (labeled FANCA through FANCW) disrupt the cell’s ability to fix a specific type of DNA damage called interstrand crosslinks, where the two strands of DNA become chemically fused together and replication stalls.
Most FANC gene mutations are recessively inherited. Two exceptions stand out: FANCB is X-linked, and FANCR/RAD51 mutations arise spontaneously (de novo) and act as dominant negatives, meaning a single mutant copy is enough to interfere with the normal protein. Because so many genes are involved and their protein products function at different stages of DNA repair, the clinical picture varies enormously. Beyond anemia, Fanconi anemia carries an increased risk of cancers and is often accompanied by physical abnormalities like short stature and limb differences.
Diamond-Blackfan Anemia
Diamond-Blackfan anemia is a rare condition that specifically shuts down red blood cell production while leaving white blood cells and platelets largely unaffected. It’s caused by mutations in genes that encode ribosomal proteins, the molecular machines responsible for building all proteins in the cell. Nine ribosomal protein genes (including RPS19, RPL5, and RPL11) account for roughly half of diagnosed cases. The other half remain genetically uncharacterized.
The anemia typically appears in the first year of life. Affected infants have very low red blood cell counts with almost no young red blood cells (reticulocytes) visible in blood samples, a sign the bone marrow simply isn’t producing them. Between 30 and 47% of patients also have physical malformations involving the head, thumbs, heart, or urogenital system, and the condition carries an elevated risk of certain cancers, particularly blood cancers and bone tumors.
How Genetic Anemias Are Diagnosed
Traditional diagnosis follows a stepwise process: examining the shape of red blood cells under a microscope, analyzing membrane proteins, running hemoglobin electrophoresis to detect abnormal hemoglobin variants, and measuring specific enzyme levels. Hemoglobin electrophoresis is particularly useful for identifying sickle cell disease and thalassemia because it separates hemoglobin types based on their electrical charge.
Next-generation sequencing has changed the landscape for harder-to-diagnose cases. Targeted gene panels covering the most common disease-causing genes can now serve as a first-line approach for patients with unexplained hereditary anemia. Whole exome sequencing, which reads all protein-coding genes at once, can identify mutations in families where the specific condition is unclear. These molecular tools are especially valuable for conditions like hereditary spherocytosis and Diamond-Blackfan anemia, where the clinical picture alone doesn’t always point to a single gene.