Gamma Globin (HBG1 and HBG2) Sequencing
Assess for gamma globin gene variants resulting in neonatal hemolytic anemia, cyanosis, or methemoglobinemia in symptomatic infants when other etiologies have been excluded.
Assess for nondeletional HPFH in individuals with elevated fetal hemoglobin.
Characterize abnormal hemoglobins identified by electrophoresis suspected to represent gamma chain variants.
Comprehensive test for diagnosis of thalassemia or hemoglobinopathy in an individual with hematologic or clinical findings.
Not recommended for routine carrier screening in healthy adults for purposes of reproductive decision-making.
Determine etiology of unexplained hemolytic anemia or family history of unexplained hemolytic anemia.
Determine etiology of unexplained hyperbilirubinemia in neonates.
Effective test for screening and follow-up of individuals with known hemoglobinopathies.
The optimal test for the initial diagnosis of a suspected hemoglobinopathy is Hemoglobin Evaluation Reflexive Cascade.
Fetal hemoglobin (Hb F) is the predominant hemoglobin in the fetus and is comprised of two alpha globin chains and two gamma chains. A-gamma is expressed from the HBG1 gene and G-gamma is expressed from the HBG2 gene. Promoter variants in either HBG1 or HBG2 can result in nondeletional hereditary persistence of fetal hemoglobin (HPFH), a clinically benign condition but can ameliorate disease severity in sickle cell disease and thalassemia. The majority of genetic variants in the gamma genes are clinically benign; however, rare variants that result in qualitative defects may produce a clinical phenotype in neonates. Unstable variants may result in hemolytic anemia/hyperbilirubinemia, high- or low-oxygen affinity variants may present as erythrocytosis or cyanosis, and M-hemoglobin variants may cause methemoglobinemia. Such clinical symptoms related to gamma chain variants typically resolve after 6 months of age due to the gamma- to beta-globin switch.
Expression of variant gamma proteins is related to the overall expression of Hb F and will vary over time.
Clinical symptoms related to gamma chain variants commonly resolve after the first 6 months of life, given the normal switch from fetal hemoglobin expression to adult hemoglobin expression that occurs at that time.
Clinical presentations in neonates include:
- Hemolytic anemia/hyperbilirubinemia
HPFH may occur in adults:
- A clinically benign disorder characterized by elevated Hb F into adulthood
- When coinherited with sickle cell disease or beta thalassemia, HPFH may ameliorate disease severity
HBG1 (A-gamma) and HBG2 (G-gamma)
Over 100 gamma globin variants have been described, many of which are clinically benign.
- Qualitative defects:
- Unstable variants may result in hemolytic anemia/hyperbilirubinemia
- High- or low-oxygen affinity variants may result in erythrocytosis or cyanosis, respectively
- M hemoglobin variants may cause methemoglobinemia
- Quantitative defects
- Promoter region variants may be associated with non-deletional HPFH, a clinically benign condition
- Polymorphisms may influence expression of the gamma genes
- Clinical sensitivity: Unknown
- Gamma globin variants are a rare cause of neonatal hemolytic anemia, cyanosis, erythrocytosis, or methemoglobinemia
- Analytical sensitivity/specificity: >99%
- Long-range polymerase chain reaction (PCR) followed by nested PCR and bidirectional sequencing of all coding regions, intron/exon boundaries, proximal promoter, and 5’ and 3’ untranslated regions of the HBG1 and HBG2 genes
- No pathogenic variants detected
- Reduces the likelihood of a gamma globinopathy or nondeletional gamma HPFH
- Pathogenic variant detected
- Consistent with a diagnosis of a gamma globinopathy or nondeletional gamma HPFH
- Clinical manifestations are variable and dependent on the effect of the identified variant on protein function/expression and on the age of the patient
- Correlation with hematologic parameters and hemoglobin electrophoresis results is strongly recommended
- Gamma globin gene sequencing may identify variants of unknown clinical significance
- Diagnostic errors can occur due to rare sequence variations or repeat element insertions
- Large deletions/duplications, distal regulatory region variants, deep intronic variants, and hybrid gene events will not be detected
- Manca L, Masala B. Disorders of the synthesis of human fetal hemoglobin. IUBMB Life. 2008; 60(2): 94-111. PubMed
- Patrinos GP, Giardine B, Riemer C, Miller W, Chui DH, Anagnou NP, Wajcman H, Hardison RC. Improvements in the HbVar database of human hemoglobin variants and thalassemia mutations for population and sequence variation studies. Nucleic Acids Res. 2004; 32(Database issue): D537-41. PubMed
Last Update: November 2019