Test Catalog

Test ID: WGSEQ    
Gamma Globin Full Gene Sequencing, Varies

Useful For Suggests clinical disorders or settings where the test may be helpful

An adjunct in the interpretation of hemoglobin electrophoresis results

 

Evaluation for suspected gamma variants or nondeletional hereditary persistence of fetal hemoglobin (HPFH)

 

Assess for unstable gamma chain variants (there are occasionally newborns who are jaundiced at birth, often requiring phototherapy, in which all other tests for causes of hemolysis are unrevealing)

Genetics Test Information Provides information that may help with selection of the correct genetic test or proper submission of the test request

The beta-like hemoglobins include the epsilon, gamma, beta, and delta globins, whose genes are present on chromosome 11 in a linked cluster (ie, the beta globin complex). The gamma genes, HBG1 (Ay) and HBG2 (Gy), contain 3 exonic coding regions and 2 intronic intervening sequences (IVS). The genes produce gamma globin chains that form tetramers with alpha globin chains to create fetal hemoglobin (Hb F). HBG1 and HBG2 differ only in which amino acid is located at position 136 (alanine or glycine). The resultant proteins are named A-gamma and G-gamma, respectively. Although G-gamma is predominant at birth, this gradually reverses during the first year of life to become the normal adult G-gamma/A-gamma ratio, which is 2:3. Some people maintain an increased G-gamma:A-gamma ratio throughout life, which has been linked to certain polymorphisms in either gene. Additionally, some alterations in the promoter regions of the gamma globin genes are known to cause a form of hereditary persistence of fetal hemoglobin (HPFH), which is characterized by a significant but harmless elevation of Hb F into adulthood. If coinherited with sickle cell disease, HPFH has a strong modulating effect on the condition and appears to protect against some, but not all, of its complications. Some gamma mutations result in gamma chain hemoglobin variants, most of which are clinically insignificant; however, an incompletely studied subset causes neonatal disorders, such as hemolytic anemia, cyanosis, and methemoglobinemia.

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

Hemoglobin F (Hb F) is the dominant hemoglobin at birth but is gradually replaced by adult hemoglobin (Hb A) during the year after birth (normal value < or =1% of total hemoglobin after age 2). Increased Hb F levels may continue after the neonatal period and into adulthood for various reasons. Genetic causes include deletional and nondeletional forms of hereditary persistence of fetal hemoglobin (HPFH) and delta-beta thalassemia mutations. Over 100 mutations have been described in the gamma genes and, if detectable, the protein expression will vary over time according to the overall Hb F expression. Gamma globin mutations can manifest either as a quantitative (gamma thalassemia or nondeletional HPFH) or a qualitative (gamma variant) abnormality. Nondeletional HPFH mutations frequently modulate the expected severity of sickling disorders due to the inhibitory properties of Hb F on sickle formation. Many gamma chain variants are benign, although some, such as unstable, high- and low-oxygen affinity, or M hemoglobin variants, cause hemolytic anemia/hyperbililrubinemia, erythrocytosis, cyanosis, and methemoglobinemia, respectively. The percentages of gamma variants will vary according to if they are present on the HBG1 or HBG2 genes, as these genes are differentially expressed depending on the age of the patient. Symptoms due to gamma variants are expected to decrease along with the normal decrease in Hb F and therefore most resolve after the first 6 months of life.

Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.

An interpretive report will be provided.

Interpretation Provides information to assist in interpretation of the test results

An interpretive report will be provided and will include specimen information, assay information, and whether the specimen was positive for any mutations in the gene. If positive, the mutation will be correlated with clinical significance, if known.

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

This test cannot be used in isolation to confirm or exclude hemoglobin conditions. Large deletions, crossover events, as well as other mutations may not be detected. This test is used in conjunction with adequately studied protein analysis results.

 

If multiple mutations are identified, gamma globin gene sequencing is not able to distinguish between mutations that are found in the same allele (in cis) and mutations found on different alleles (in trans). This limitation of sequencing may complicate diagnosis or classification and has implications for inheritance and genetic counseling. To resolve these cases, molecular results must be correlated with electrophoretic and protein data and/or family studies.

Clinical Reference Recommendations for in-depth reading of a clinical nature

1. Crowley MA, Mollan TL, Abdulmalik OY, et al: A hemoglobin variant associated with neonatal cyanosis and anemia. N Engl J Med 2011;364:1837-1843

2. Cui J, Baysdorfer C, Azimi M, et al: Identification of three novel Hb F variants: Hb F-Hayward [Gy(NA1)Gly->Asp, GGT>GAT], Hb F-Chori-I [AyT16(A13)Gly->Asp, GGC>GAC] and Hb F-Chori-II [AyI29(B11)Gly->Glu, GGA>GAA]. Hemoglobin 2012;36:305-309

3. Akinsheye I, Alsultan A, Solovieff N, et al: Fetal hemoglobin in sickle cell anemia. Blood 2011;118:19-27

4. Disorders of Hemoglobin Genetics, Pathophysiology, and Clinical Management. Second edition. Edited by M Steinberg, B Forget, D Higgs, D Weatherall. New York, Cambridge University Press, 2009

5. Molecular Hematology. Third edition. Edited by D Provan, J Gribben. Malden, Massachusets, Blackwell Publishing, 2010

6. Color Atlas of Hemoglobin Disorders: A Compendium Based on Proficiency Testing. Edited by JD Hoyer, SH Kroft. Northfield, IL. College of American Pathologists, 2003

7. Merchant S, Oliveira JL, Hoyer JD, Viswanatha DS: Chapter 24. Molecular diagnosis in hematopathology. In Hematopathology: A Volume in the Series: Foundations in Diagnostic Pathology. Second edition. Edited by J Goldblum. E Hsi. Churchill Livingstone. 2012

Special Instructions Library of PDFs including pertinent information and forms related to the test