Beta thalassaemia intermedia due to co‐inheritance of three unique alpha globin cluster duplications characterised by next generation sequencing analysis

Abstract

Beta thalassaemia intermedia due to co-inheritance of three unique alpha globin cluster duplications characterised by next generation sequencing analysis Co-inheritance of a thalassaemia reduces chain imbalance and disease severity in b thalassaemia homozygotes, while increasing a globin output in heterozygotes increases chain imbalance, converting a typically asymptomatic carrier state to that of thalassaemia intermedia. The outcome depends on the number of a globin genes inherited as one or two copies of triplicated (/aaa), or quadruplicated (/aaaa) a globin complexes, and the type of b thalassaemia mutation (b 0 or b + ) (Thein, 2008). Another mechanism of increasing a globin output is through segmental duplication of the whole a globin complex (Harteveld et al, 2008) but breakpoints of the reported duplications have not been fully characterised due to technological limitations. Here, we applied a previously described next generation sequencing (NGS) methodology (Shooter et al, 2015a,b) to characterise three a globin cluster duplications, permitting to-the-base resolution in two of the three cases. Patient samples were referred for work-up of unusually severe phenotype in b thalassaemia carriers. In Family 1 (Fig 1A), the proband was a 54-year-old Chinese male with hypochromic microcytic anaemia since infancy. His partner (Anglo-Saxon English) and two older sons had normal haematological profiles; the youngest son (aged 14 years) had a haematological profile similar to that of the father. Both father and son had (Fig 1C) is due to iron deficiency.Correspondence 160 ª

Next‐generation sequencing as a tool for breakpoint analysis in rearrangements of the globin gene clusters

“…This is not a limitation of the technology but a consequence of the chronological order of what was investigated and what was deemed publishable at the time. We characterized a collection of three alpha globin cluster duplications in 2016 . In each case, the duplicated alpha globin gene cluster was inherited in combination with a beta thalassemia gene variant and led to a beta thalassemia intermedia phenotype in the affected individual.…”

“…We characterized a collection of three alpha globin cluster duplications in 2016. 28 In each case, the duplicated alpha globin gene cluster was inherited in combination with a beta thalassemia gene variant and led to a beta thalassemia intermedia phenotype in the affected individual. In all three cases, a nuclear family was investigated with clear association of the phenotype with the digenic inheritance.…”

Thalassaemia intermedia caused by coinheritance of a β‐thalassaemia mutation and a de novo duplication of α‐globin genes in the paternal allele

“…However, in normal individuals, the phenotypic effect of this duplication on the mean corpuscular haemoglobin and mean corpuscular volume is unclear due to the absence of a heterozygous duplication. Previous reports in heterozygotes with comparable duplications suggest a normal haematological phenotype (Liu et al, 2015;Hu et al, 2016;Clark et al, 2018).…”

Three Mexican Families with β thalassemia intermedia with different molecular basis

“…The minor form corresponds to the simple heterozygote condition whereas the beta-thalassemia major type refers to the more severe disorder with transfusion dependency as a result of the inheritance of two b 0 alleles. b-thal intermedia comprises a wide range of clinical features and is mainly characterized by occasional blood transfusions; b-thal intermedia is observed in different molecular forms such as, two b-thal alleles (b 0 /b +/+ , b 0 /b 0 ), one b-thal allele and additional copies of a-globin genes (b 0 /b A ; aaa/aa, aaaa/aa, aaaa/aaa) or the presence of a single dominant b-thal allele (b D /b A ) (Origa et al, 2014;Ben-Salah et al, 2017, Clark et al, 2018.…”

“…First, the type of b allele (b 0 , b + or b ++ ), correlated to the amount of residual b-globin chains (Mettananda et al, 2015;Ben-Salah et al, 2017;Shang and Xu 2017;Zhong et al, 2018). Second is the co-inheritance of alpha globin locus defect, either an alpha-thalassemia deletion (a-thal) which is often observed in b-thal patients, resulting as a positive modifier or, conversely, the presence of additional copies of HBA2 or HBA1 genes which causes a more severe form of b-thal (Ben-Salah et al, 2017;Theodoridou et al, 2018;Clark et al, 2018;Harteveld et al, 2008). And third is the presence of genetic variants associated with increased fetal hemoglobin (HbF) production.…”