A novel α(0) -thalassemia deletion in a Greek patient with HbH disease and β-thalassemia trait.
OBJECTIVE
To determine the molecular basis in a Greek child suspected of having HbH disease and β-thalassemia trait.


METHODS
Standard hematology, Hb electrophoresis, and HPLC. Multiplex ligation-dependent probe amplification (MLPA), direct sequencing, and breakpoint characterization by NimbleGen fine-tiling array analysis.


RESULTS
The index patient showed a moderate microcytic hypochromic anemia with normal ZPP and elevated HbA(2) , indicative for β-thalassemia trait. However, the moderate microcytic hypochromic anemia along with the observation of HbH inclusions in occasional red blood cells suggested a coexisting α-thalassemia. Molecular analysis indicated that the propositus inherited the β(+) -thalassemia mutation IVS2-745 (c>g) and a novel α(0) -thalassemia deletion from the mother, and the common non-deletion α-thalassemia allele α(2) (-5nt)α from the father. The α(0) -thalassemia deletion, named - -(BGS) , is approximately 131.6 kb in length. It removes the major regulatory elements along with the functional α-globin genes but leaves the theta-gene intact.


CONCLUSIONS
The compound interaction of a β-thalassemia defect along with a single functional α-globin gene is quite rare. Although patients with HbH/β-thal and simple HbH disease have comparable levels of Hb, the absence of free β-globin chains and thus detectable non-functional HbH means that in HbH/β-thal, the levels of functional Hb are higher, resulting in a better compensated functional anemia. Rare large deletions as the one described here remain undetected by gap-PCR in routine molecular screening. The introduction of MLPA as a diagnostic screening tool may improve laboratory diagnostics for these defects. The use of NimbleGen fine-tiling arrays may give additional information about the precise location of breakpoints.
Department of Human and Clinical Genetics, Hemoglobinopathies Laboratory, Leiden University Medical Center, Leiden, The Netherlands.
Marion
M
Phylipsen
Jan
J
Traeger-Synodinos
Martijn
M
van der Kraan
Peter
P
van Delft
Greet
G
Bakker
Mariska
M
Geerts
Emmanuel
E
Kanavakis
Alexandra
A
Stamoulakatou
Markissia
M
Karagiorga
Piero C
PC
Giordano
Cornelis L
CL
Harteveld
D000483:Alleles; D002675:Child, Preschool; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D055028:Comparative Genomic Hybridization; D005192:Family Health; D005260:Female; D017353:Gene Deletion; D006115:Greece; D006801:Humans; D008297:Male; D017422:Sequence Analysis, DNA; D055542:alpha-Globins / Q000235:genetics*; D017085:alpha-Thalassemia / Q000235:genetics*; D055544:beta-Globins / Q000235:genetics*; D017086:beta-Thalassemia / Q000235:genetics*
D055542:alpha-Globins; D055544:beta-Globins