Molecular epidemiology and hematologic characterization of δβ-thalassemia and hereditary persistence of fetal hemoglobin in 125,661 families of greater Guangzhou area, the metropolis of southern China

Abstract

Background: Individuals with δβ-thalassemia/HPFH and β-thalassemia usually present with intermedia or thalassemia major. No large-scale survey on HPFH/δβ-thalassemia in southern China has been reported to date. The purpose of this study was to examine the molecular epidemiology and hematologic characteristics of these disorders in Guangzhou, the largest city in Southern China, to offer advice for thalassemia screening programs and genetic counseling. Methods: A total of 125,661 couples participated in pregestational thalassemia screening. 654 subjects with fetal hemoglobin (HbF) level ≥ 5% were selected for further investigation. Gap-PCR combined with Multiplex ligation dependent probe amplification (MLPA) was used to screen for β-globin gene cluster deletions. Gene sequencing for the promoter region of HBG1 /HBG2 gene was performed for all those subjects. Results: A total of 654 individuals had hemoglobin (HbF) levels≥5, and 0.12% of the couples were found to be heterozygous for HPFH/δβ-thalassemia, including Chinese G γ ( A γδβ) 0 -thal, Southeast Asia HPFH (SEA-HPFH), Taiwanese deletion and Hb Lepore-Boston-Washington. The highest prevalence was observed in the Huadu district and the lowest in the Nansha district. Three cases were identified as carrying β-globin gene cluster deletions, which had not been previously reported. Two at-risk couples (0.0015%) were required to receive prenatal diagnosis. We also found 55cases of nondeletional-HPFH (nd-HPFH), including 54 with Italian nd-HPFH and one with the A γ-197C-T heterozygous state. It is difficult to discriminate between Chinese G γ ( A γδβ) 0 -thal and Italian nd-HPFH carriers using hemoglobin (Hb) analysis. (Continued on next page)Conclusions: This study is the first to describe the familial prevalence of HPFH/δβ-thalassemia and the high-risk rate in Greater Guangzhou Area, and the findings will support the implementation of thalassemia screening for three common deletions by gap-PCR. We also presented a systematic description of genotype-phenotype relationships which will be useful for genetic counseling and prenatal diagnostic services for β-thalassemia intermedia.

Analysis of rare thalassemia genetic variants based on third-generation sequencing

“…It is worth mentioning that participant #6 showed an increased HbF content of 16.3%, yet only one clinically significant variant of HBA2 c.300 + 34G > A was identified. We suspected that some other HPFH-causing variants in the gamma globin genes HBG1 or HBG2 may be responsible for the increased HbF level 27 . Thus, we conducted full-length Sanger sequencing for HBG1 and HBG2 genes.…”

Detection of four rare thalassemia variants using Single-molecule realtime sequencing

“…The HBG2 - HBG1 fusions cause ? -thalassemia and have been described in the literature ( Shimizu et al, 1986 ; Jiang et al, 2020 ). However, in the cases that we reported, the blood cell parameters were normal and the HbF content was normal or increased, which is inconsistent with the above literature.…”

Analysis of Rare Thalassemia Genetic Variants Based on Third Generation Sequencing

“…It is worth to mention, the participant #6 showed an increased HbF content of 16.3%, yet only one clinically signi cant variant of HBA2 c.300 + 34G > A was identi ed. We suspected that some other HPFHcausing variants in the gamma globin genes HBG1 or HBG2 may be responsible for the increased HbF level [27]. Thus, we conducted a full-length sanger sequencing for HBG1 and HBG2 gene.…”