Widening the spectrum of deletions and molecular mechanisms underlying alpha-thalassemia

Abstract

Inherited deletions of α-globin genes and/or their upstream regulatory elements (MCSs) give rise to α-thalassemia, an autosomal recessive microcytic hypochromic anemia. In this study, multiplex ligation-dependent probe amplification performed with commercial and synthetic engineered probes, Gap-PCR, and DNA sequencing were used to characterize lesions in the sub-telomeric region of the short arm of chromosome 16, possibly explaining the α-thalassemia/HbH disease phenotype in ten patients. We have found six different deletions, in heterozygosity, ranging from approximately 3.3 to 323 kb, two of them not previously described. The deletions fall into two categories: one includes deletions which totally remove the α-globin gene cluster, whereas the other includes deletions removing only the distal regulatory elements and keeping the α-globin genes structurally intact. An indel was observed in one patient involving the loss of the MCS-R2 and the insertion of 39 bp originated from a complex rearrangement spanning the deletion breakpoints. Finally, in another case, no α-globin gene cluster deletion was found and the patient revealed to be a very unusual case of acquired α-thalassemia-myelodysplastic syndrome. This study further illustrates the diversity of genomic lesions and underlying molecular mechanisms leading to α-thalassemia.

A novel deletion of the major regulatory element flanking the α‐globin gene cluster as a cause of α0‐thalassemia

“…Approximately 30‐70 kb upstream of the α‐globin gene cluster, four highly conserved elements (MCS‐R1 to 4), corresponding to erythroid‐specific DNase I hypersensitive sites (HS‐48, HS‐40, HS‐33, HS‐10, respectively), act as long‐range regulatory elements of the α‐like globin genes 3 . There have been many reports which found that deletions of these regulatory elements lead to α‐thalassemia phenotypes because of severe downregulation of the α‐globin gene expression in the affected chromosome 4‐8 . Interestingly, in almost all reported cases, the MCS‐R2 alone, or along with other MCS‐R elements, is removed.…”

An Overview on Thalassemia Diagnosis and Management Approach, Literature Review

“…Diagnosing and detecting thalassemia and other hemoglobinopathies begin with relevant family history, laboratory screening, and invasive prenatal screening via obtaining amniocentesis and chorionic villus sampling when the parents are at high risk for hemoglobinopathies. Moreover, new molecular genetic technologies to map and detect mutation and deletion by sequencing analysis prenatally [10,12,13]. Most of these technologies include PCR screening for mutations, electrophoresis, high-performance liquid chromatography (HPLC), and DNA test [10,14].…”

Ancestry of the major long-range regulatory site of the α-globin genes in the Portuguese population with the common 3.7 kb α-thalassemia deletion

“…Very rarely, the deletion that gives rise to α-thalassemia only affects one distal regulatory region, such as the HS-40, leaving the α-globin genes intact but partially inactivated [ 17 , 23 – 27 ]. Some of these rare types of deletions that affect the regulatory elements, have also been found in Portuguese individuals, namely the (αα) MM , (αα) ALT , (αα) TI and (αα) CSC [ 22 , 23 , 28 ].…”