Alpha Thalassemia

Hb Bart syndrome is characterized by hydrops fetalis, a condition in which excess fluid builds up in the body before birth. Additional signs and symptoms can include severe anemia, an enlarged liver and spleen (hepatosplenomegaly), heart defects, and abnormalities of the urinary system or genitalia. As a result of these serious health problems, most babies with this condition are stillborn or die soon after birth. Hb Bart syndrome can also cause serious complications for women during pregnancy, including dangerously high blood pressure with swelling (preeclampsia), premature delivery, and abnormal bleeding.

-α3.7 and -α4.2 deletions result in the deletion of a single gene.
-(α)20.5, --SEA, --MED-I, --FIL, and --THAI deletions result in the deletion of both HBA1 and HBA2 genes from the same chromosome Sequence variants and regulatory region variants occur mainly in HBA2 and account for up to 15% of causative variants.

Nondeletional variants include:
Sequence variants that inactivate the gene

Small insertions/deletions
Variants that result in unstable α-globin protein (eg, Hb Constant Spring or HBcS) Nondeletional α-globin variants may be pathogenic or benign.
Both may result in an abnormal protein detectable by Hb evaluation.
Pathogenic nondeletional variants often have a more severe effect than single gene deletions.
Alpha-globin gene duplication results in three or more active α-globin genes on a single chromosome.

Typically benign
May alter expected clinical phenotypes and hematological features when coinherited with beta (β) thalassemia Test Interpretation Featured ARUP Testing Preferred rst-tier genetic test for con rmation of suspected α thalassemia or α thalassemia trait Detects common, rare, and novel deletions or duplications in the α-globin gene cluster and its HS-40 regulatory region Multiplex ligation-dependent probe ampli cation (MLPA) used to detect Hb Constant Spring (HbCS) (HBA2 c.427T>C; p.Ter143Gln); targeted Sanger sequencing is performed to assess HbCS copy number in absence of a concurrent HBA2 deletion.First-tier genetic test for con rmation of suspected α thalassemia or α thalassemia trait Detects common, rare, and novel deletions or duplications in the α-globin gene cluster (HBZ , HBM , HBA1 , HBA2 , HBQ1 ) and its HS-40 regulatory region Comprehensive genetic test for detection of α thalassemia or α thalassemia trait Detect deletional and nondeletional variants in HBA1 and HBA2 Diagnostic testing for α thalassemia in fetus with suggestive clinical ndings or at risk for α thalassemia due to familial HBA1 /HBA2 deletions or HbCS variant Detects common, rare, and novel deletions or duplications in the α-globin gene cluster and Alpha (α) thalassemia is the most common inherited disorder of hemoglobin (Hb) worldwide and is caused by HBA1 and HBA2 gene variants.Decreased or absent synthesis of the hemoglobin (Hb) α chain results in clinical presentations ranging from asymptomatic silent carriers to severe anemia and fetal lethality.The two clinically signi cant forms of α thalassemia are Hb Bart hydrops fetalis syndrome and hemoglobin H (HbH) disease.Alpha thalassemia is found more often in certain ethnicities, including African, African American, Mediterranean, Middle Eastern, and Southeast Asian.Disease Overview Prevalence and/or Incidence Most common inherited disorder of Hb worldwide Carrier frequencies in high-risk populations: African, African American: 1/3 Middle Eastern, Southeast Asian: 1/20 Mediterranean: 1/30-50 Hb Bart hydrops fetalis syndrome and HbH disease are more frequent in SoutheastAsian, Asian Indian, and Mediterranean populations than in African populations.have four functioning α-globin genes (αα/αα).Two genes, HBA1 and HBA2 , are present on each copy of chromosome 16 and α-globin chains function as subunits of fetal Hb (HbF: α2γ2) and adult Hb (HbA: α2β2).The number of α-globin genes deleted or inactivated correlates with different α thalassemia phenotypes.Genotype/phenotype correlations in α thalassemia are complex and may be in uenced by coinheritance of other Hb variants or α-globin gene duplications.large gene deletions account for approximately 90% of pathogenic α-thalassemia variants.