Gamma Globin (HBG1 and HBG2) Sequencing

Content Review: August 2019 Last Update:
  • Use to assess for gamma globin gene variants resulting in neonatal hemolytic anemia, cyanosis, or methemoglobinemia in symptomatic infants when other etiologies have been excluded
  • Use to assess for nondeletional HPFH in individuals with elevated fetal hemoglobin
  • Characterizes abnormal hemoglobins identified by electrophoresis suspected to represent gamma chain variants

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.

Disease Overview

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
  • Erythrocytosis
  • Cyanosis
  • Methemoglobinemia

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)


Autosomal dominant


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

Test Interpretation


  • Clinical sensitivity: Unknown
    • Gamma globin variants are a rare cause of neonatal hemolytic anemia, cyanosis, erythrocytosis, or methemoglobinemia
  • Analytic sensitivity/specificity: >99%

Test Methodology

  • Long-range polymerase chain reaction (PCR) followed by nested PCR and bidirectional sequencing of all coding regions, intron/exon boundaries, proximal promoter, and 5’ proximal promoters 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
Additional Resources