The Sanquin Hemoglobinopathies NGS Panel (test code X017-X020) includes 14 genes and regions of interest.
This panel suits diagnosis in patients suspected to have hereditary anemia due to a hemoglobinopathy other than caused by gross deletions in the globin clusters. The panel covers genes associated with hemoglobin variants, alpha and beta-thalassemia, hereditary persistence of fetal hemoglobin (HPFH) and some genes for sideroblatic anemia. The panel includes control regions for alpha and beta-globin expression, as well as for fetal-globin switching.
Due to one or more regions of segmental duplication or deletions this panel has reduced sensitivity for diagnosing alpha-thalassemia caused by deletions in HBA1 and HBA2. These common forms of alpha-thalassemia can easily be detected by first line methods like gap-PCR (test code N003) or MLPA. Also some HPFH and beta-thalassemia is caused by deletions in the HBD-HBB region and can better be detected by MLPA (test code …..). However, most hemoglobin variants, beta-thalassemia and some alpha-thalassemia’s caused by point mutations or small deletions/ insertions and are picked up with great sensitivity by applying the Hb NGS panel. However the frequency of mutations in transcription factors and regulatory element are unknown we included these regions in the panel so it can also be applied to the group of patients with very rare unknown causes of anemia. Variants in these regions are poorly described and we offer this service for research purposes only (X020).

Panel Hb-pathie, genes, regions and the main phenotypic abnormalities

Genes

Name

OMIM phenotypic abnormalities

HBA1

Hemoglobin Alpha 1

ALPHA-THALASSEMIA (OMIM:604131), HEMOGLOBIN H DISEASE (OMIM:613978), HEINZ BODY ANEMIAS (OMIM:140700)

HBA2

Hemoglobin Alpha 2

ALPHA-THALASSEMIA (OMIM:604131), HEMOGLOBIN H DISEASE (OMIM:613978), HEINZ BODY ANEMIAS (OMIM:140700)

HBB

Hemoglobin Beta

BETA-THALASSEMIA (OMIM:613985), SICKLE CELL ANEMIA (OMIM:603903), HEINZ BODY ANEMIAS (OMIM:140700)

HBD

Hemoglobin Delta

Delta-beta-thalassemia (ORPHA:231237)

HBG1

Hemoglobin Gamma 1

FETAL HEMOGLOBIN QUANTITATIVE TRAIT LOCUS 1 (OMIM:141749)

HBG2

Hemoglobin Gamma 2

CYANOSIS, TRANSIENT NEONATAL (OMIM:613977), FETAL HEMOGLOBIN QUANTITATIVE TRAIT LOCUS 1 (OMIM:141749)

     

Genes/Region

Name

Gene or region function

α-MRE HS-40

α Major Regulatory Element HS-40

α-MRE is involved in the regulation of the expression of the embryonic ζ- and adult α- globin genes

LCRB

Locus Control Region Beta

LCR is involved in the regulation of the expression of globin genes (embryonic ε-, fetal γ- and adult β-, δ-globin) located on Chr11

BCL11A

B cell CLL/lymphoma 11A (zinc finger protein)

BCL11A  represses the expression the fetal  γ-globin genes in adult RBCs by binding to the promotor regions

 

BCL11A erythroid specific enhancers 1,2,3

three regions in intron 2 with GATA1 motif, function as enhancer for KLF1 transcription

KLF1

 Kruppel like factor 1

KLF1 regulates embryonic and fetal-to-adult hemoglobin switching by activating BCL11A, HBA and HBB gene promoters and HS-40 and LCRB regions

GATA1

GATA binding protein 1

GATA1 is involved in fetal γ- to adult β-globin switching

ASF1B

anti-silencing function 1B histone chaperone

ASF1B is involved in fetal γ- to adult β-globin switching

E2F2

E2F transcription factor 2

E2F2 is possibly involved in HbF expression

E2F4

E2F transcription factor 4

E2F4 is possibly involved in HbF expression

MYB

MYB proto-oncogene, transcription factor

oncogene MYB is involved in HbF expression

ZBTB7A

Zinc finger and BTB domain containing 7A

ZBTB7A  represses the expression the fetal  γ-globin genes, independent of the fetal globin repressor BCL11A