The alpha 3.7 deletion is the most common genetic alteration underlying alpha-thalassemia, a group of inherited blood disorders. This condition involves a reduced production of alpha-globin, a protein component necessary for forming hemoglobin, the molecule in red blood cells that transports oxygen. Humans possess a cluster of alpha-globin genes, and a defect in these genes leads to a reduction in the alpha-globin chains available for synthesis. The clinical severity of alpha-thalassemia is directly related to the number of functional alpha-globin genes that are lost or inactivated.
The Molecular Mechanism of the 3.7 Deletion
The molecular basis of the alpha 3.7 deletion lies within the alpha-globin gene cluster located on chromosome 16. A typical human cell carries four alpha-globin genes (two copies of HBA1 and two copies of HBA2), with two genes on each chromosome 16. These genes are highly similar in structure and are arranged in tandem, making the region susceptible to errors during cell division.
The 3.7 deletion is caused by unequal crossing-over, a process where chromosomes misalign during the formation of sperm or egg cells. This misalignment occurs between highly homologous DNA segments, known as Z boxes, situated approximately 3.7 kilobases (kb) apart. The resulting deletion removes a segment of DNA, including the end of one gene and the beginning of the other.
This unequal exchange leads to the loss of one functional alpha-globin gene from the chromosome, replacing the two original genes with a single, fused HBA2/HBA1 hybrid gene. The chromosome carrying this deletion is designated as \(\text{-}\alpha\), meaning it has one functional alpha-globin gene instead of the normal two. A person who inherits one normal chromosome and one chromosome with the deletion will have the genotype \(\text{-}\alpha/\alpha\alpha\), signifying the loss of one of the four total alpha-globin genes.
Clinical Manifestations of Alpha-Thalassemia
The clinical presentation of alpha-thalassemia varies widely and is directly proportional to the total number of alpha-globin genes that are deleted or inactivated. The mildest form results from the loss of a single gene, known as the Silent Carrier state (\(\text{-}\alpha/\alpha\alpha\)). Individuals are generally asymptomatic and show normal red blood cell indices, though they may have subtle microcytosis or hypochromia.
When two alpha-globin genes are lost, the condition is referred to as Alpha-Thalassemia Trait or Minor. This occurs either as the trans configuration (one gene lost on each chromosome: \(\text{-}\alpha/\text{-}\alpha\)), common in African and Mediterranean populations, or the cis configuration (both genes lost on a single chromosome: \(\text{–}/\alpha\alpha\)), frequent in Asian populations. Patients with the Trait typically present with mild microcytic, hypochromic anemia and are often mistaken for having iron deficiency.
The loss of three alpha-globin genes leads to Hemoglobin H (HbH) Disease, characterized by a moderate to severe chronic hemolytic anemia. With only one functional alpha-globin gene remaining (\(\text{–}/\text{-}\alpha\)), there is a significant deficiency of alpha-globin chains. The surplus of beta-globin chains aggregates to form abnormal tetramers called Hemoglobin H (\(\text{HbH} / \beta_4\)), which are unstable and damage red blood cells. Symptoms include jaundice, splenomegaly, and gallstones, sometimes requiring blood transfusions during periods of stress or illness.
The most severe form, Hydrops Fetalis, results from the deletion of all four alpha-globin genes (\(\text{–}/\text{–}\)), meaning no alpha-globin is produced. Without alpha-globin, the fetus cannot produce functional adult or fetal hemoglobin. Instead, the gamma-globin chains aggregate to form Hemoglobin Barts (\(\text{Hb Bart} / \gamma_4\)). This molecule has an extremely high oxygen affinity and cannot effectively release oxygen to the tissues. This severe oxygen deprivation causes massive edema and heart failure, usually resulting in death in utero or shortly after birth.
Inheritance Patterns and Genetic Risk
The alpha-thalassemia syndromes are typically inherited in an autosomal recessive pattern, meaning a person must inherit the gene alteration from both parents to express the more severe forms of the disease. The presence of the alpha 3.7 deletion in a parent means they are a carrier and have the potential to pass the trait to their children.
Genetic risk is relevant when both parents are carriers of the alpha-thalassemia trait. If both parents carry the two-gene deletion in the cis configuration (\(\text{–}/\alpha\alpha\), known as \(\alpha^0\)-thalassemia trait), their offspring face specific probabilities. There is a 25% chance that a child will inherit the severe, four-gene deletion leading to Hydrops Fetalis (\(\text{–}/\text{–}\)).
The children also have a 50% chance of inheriting the carrier state and a 25% chance of inheriting two normal chromosomes, meaning they are unaffected. For couples planning a family who are both known carriers, genetic counseling is often recommended. This process helps families understand the potential risks and provides information about prenatal diagnostic options.
Global Prevalence and Screening Methods
The alpha 3.7 deletion is the most common alpha-globin gene deletion worldwide. The persistence and prevalence of this deletion in specific regions are attributed to a selective advantage it confers against severe malaria infection. Carriers of the deletion often experience a milder course of malaria, which improved survival rates in endemic areas.
The highest concentrations of the alpha 3.7 deletion are found in populations originating from Africa, the Mediterranean basin, the Middle East, and parts of Southeast Asia. For instance, the prevalence is high among individuals of African descent, where the two-gene deletion typically occurs in the trans configuration. The high frequency in these areas makes population screening a public health priority to manage and prevent severe disease forms.
Initial screening for alpha-thalassemia often begins with a Complete Blood Count (CBC) to check for hematological indices like low Mean Corpuscular Volume (MCV) and Mean Corpuscular Hemoglobin (MCH). These indices are characteristic of the mild anemia seen in carriers. If preliminary tests suggest a carrier state, further molecular testing is required to confirm the diagnosis and identify the specific deletion. The definitive method for detecting the alpha 3.7 deletion is Gap-Polymerase Chain Reaction (Gap-PCR), which is crucial for carrier identification in high-risk populations.