Characterization and identification of Hb Bart’s hydrops fetalis caused by a compound heterozygous mutation ‐‐^SEA/‐‐^CR, a novel α⁰‐thalassemia deletion

Abstract

Alpha (α) thalassemia (α-thal) is one of the most common inherited hemoglobin (Hb) disorders. This type of thalassemia is characterized by reduction or absence of the α-globin chain synthesis due to deletion or mutation of α-globin gene on chromosome 16 (16p13.3).More than 95% documented cases of α-thal report the deletion of one or both α-globin genes. 1 These gene deletions cause mild α + -thal and severe α 0 -thal. The most common mutations of α 0 -thal in the Thai population are the South-East Asian (--SEA ) and Thai (--Thai ) type deletions; the --SEA deletion is approximately 19.3 kb in length, covering both functional α-globin genes but leaving the ζ-globin gene intact, and the --Thai type deletion is approximately 34-38 kb in length, spanning over both α-globin genes as well as the ζ-globin gene. 2,3 -Thal --SEA -Thal --CR e120 |

Development of molecular diagnostic platform for α0‐thalassemia 44.6 kb (Chiang Rai, ‐‐CR) deletion in individuals with microcytic red blood cells across Thailand

“…In Thailand, this variant was called α 0 ‐thalassemia Chiang Rai deletion (‐‐ CR ). To the best of our knowledge, ‐‐ 44.6 or ‐‐ CR was currently noticed only in southern China and frequently identified in northern Thailand with a remarkable allelic spectrum (Ruengdit et al., 2020, 2022, 2021). This may be due to the migration and common ancestors in which northern Thai is genetically close to southern Chinese (Kutanan et al., 2021; Vichinsky, 2005).…”

“…The α‐thalassemia status was interpreted by our investigator and reported back to the laboratory staff. Accuracy was estimated by comparing the results of our developed protocol with two reliable α‐thalassemia diagnostic assays (Ruengdit et al., 2020; Tan et al., 2001). Here, our developed multiplex gap‐PCR showed 100% concordance with those from the reference approaches (Figure 1 and Table S3).…”

“…The α 0 ‐thalassemia 44.6 kb deletion was first discovered in two siblings (‐‐ 44.6 /αα) from southern China (Wang et al., 2017). A couple of years later, this variant was identified in an uncommon Hb Bart's hydrops fetalis‐affected fetus (‐‐ CR /‐‐ SEA ) whose parents were originated from Chiang Rai, the province in northern Thailand (Ruengdit et al., 2020). In Thailand, this variant was called α 0 ‐thalassemia Chiang Rai deletion (‐‐ CR ).…”

“…Therefore, homozygosity or compound heterozygosity of these variants frequently causes Hb Bart's hydrops fetalis in this endemic region (Weatherall & Clegg, 2001). Recently, α 0 -thalassemia 44.6 kb deletion (-- 44.6 ; NC_000016.10:g.144,215_188,841) was first described in southern China (Wang et al, 2017) and has been identified in northern Thailand as Chiang Rai deletion (--CR ) with 1.71% frequency (Ruengdit et al, 2020;Ruengdit et al, 2022). Similar to other α 0 -thalassemia carriers, the --CR carriers displayed asymptomatic with apparent microcytic red blood cells; however, compound heterozygosity of this variant and --SEA or -α 3.7 likewise can cause Hb Bart's hydrops fetalis and HbH disease, respectively (Ruengdit et al, 2020(Ruengdit et al, , 2021.…”

Update in Laboratory Diagnosis of Thalassemia

“…In addition, at least 1,800 mutations causing thalassemia or abnormal hemoglobin variants have been characterized to date, the identification of mutation in samples from subjects suspected of having hemoglobinopathies may require labor-intensive methods ( Singh et al, 2020 ). The application of new technology and high-throughput molecular approaches such as next-generation sequencing (NGS) for screening and accurate diagnosis of hemoglobinopathies is feasible ( Li et al, 2020 ; Ruengdit et al, 2020 ; Wang et al, 2020 ; Zhao et al, 2020 ).…”