Molecular Epidemiology and Hematologic Characterizationof δβ-thalassemia and Hereditary Persistence of Fetal Hemoglobin in 125661 Families of Greater Guangzhou Area, the metropolis of Southern China

doi:10.21203/rs.2.17279/v1

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Molecular Epidemiology and Hematologic Characterizationof δβ-thalassemia and Hereditary Persistence of Fetal Hemoglobin in 125661 Families of Greater Guangzhou Area, the metropolis of Southern China

https://doi.org/10.21203/rs.2.17279/v1

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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 (Hb F) level ≥5% were selected for further investigation. Gap-PCR combined with Multiplex ligation dependent probe amplification (MLPA) were used to screen for β-globin gene cluster deletions. Gene sequencing for the promoter region of HBG1 /HBG2 gene were 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 Gγ(Aγδβ)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 53 cases of nondeletional-HPFH (nd-HPFH), including 52 with Italian nd-HPFH and one with the Aγ-197C-T heterozygous state. It is difficult to discriminate between Chinese Gγ(Aγδβ)0-thal and Italian nd-HPFH carriers using hemoglobin (Hb) analysis. Conclusions: This study is the first to describe the familial prevalence of HPFH/δβ-thalassemia and the high-risk rate in in Greater Guangzhou Area, and the findings will support the implementation of thalassemia screening for three common deletions by gap-PCR. We alsopresented a systematic description of genotype-phenotype relationships which will be useful for genetic counseling and prenatal diagnostic services for β-thalassemia intermedia.Keywords: Prevalence, δβ-thalassemia, HPFH, Guangzhou

Medical Genetics

Prevalence

δβ-thalassemia

HPFH

Guangzhou

Thalassemias (thals) comprise a group of monogenic diseases that are very common in Mediterranean region, North Africa, Southern China, etc. Thalassemia includes α‐, β-, δβ-thal and hereditary persistence of fetal hemoglobin (HPFH), as based on the type of globin chain involved [1]. The characteristic of δβ-thal and HPFH is high fetal hemoglobin (HbF) levels in adults. δβ-Thalassemia results from deletions in δ-globin and β-globin gene region, but the γ-globin genes are seldom involved [2]. HPFH (OMIM #141749) includes deletional HPFH and nondeletional HPFH (nd-HPFH), the former of which is caused by large deletions in the region between the γ- and β-globin genes [3]. Deletional HPFH/δβ-thalassemia typically result in clinical phenotypes with microcytic hypochromic anemia. Moreover, coinheritance with minor β-thalassemia or Hb variants in the β-globin chain has been identified to cause thalassemia intermedia or major [4]. In general, the identification of carriers plays an important role in prenatal diagnosis, especially in regions with high β-thalassemia occurrence. Point mutations or small deletions in the proximal fetal γ-globin gene promoter lead to nd-HPFH. However, as individuals with nd-HPFH are usually healthy, HPFH appears to be a natural and benign mechanism to elevate HbF expression in adults [5]. Although much research has recently been focused on nd-HPFH in efforts to reactivate the fetal γ-globin gene in adulthood for β-thalassemia treatment [6-8], there is little information regarding the prevalence and hematologic characteristics of nd-HPFH in China, which would be helpful for precise genetic counselling.

Guangzhou is the capital of Guangdong province and the largest city in Southern China, with a native population of approximately 14.9 million. Although free thalassemia screening has been performed in this region, carrier screening for deletional HPFH/δβ-thalassemia is not included in routine test performed by the government. Accordingly, no large-scale survey on the molecular epidemiology and hematologic characteristics of deletional HPFH/δβ-thalassemia in Southern China has been reported. To provide data to support thalassemia screening and enhance prevention efficiency, the aim of this study was to determine the molecular epidemiological characteristics and hematologic data of deletional HPFH/δβ-thalassemia in Guangzhou. In addition, we are the first to investigate the prevalence and molecular characterization of common nd-HPFH in this region, which is important for accurate thalassemia genetic counseling and prenatal diagnosis and for offering new ideas for thalassemia therapy.

Human subjects

This study was approved by the Ethics Committee of the Guangzhou Women & Children Medical Center, and informed consent was obtained from all subjects participating in the study. In total, 125,661 couples participated in the pregestational thalassemia screening program from January 2016 to December 2018. Two milliliters of EDTA-anticoagulant-treated peripheral blood was collected for analysis of hemoglobin components and levels using capillary electrophoresis (CE; Sebia, Paris, France). Samples were collected for further screening of α- and β-thalassemia when at least one partner had a low MCV (＜82 fL) or MCH lower than 27 pg [9].

Genetic analysis

We extracted genomic DNA from the peripheral blood samples using a genomic DNA isolation kit (Qiagen; Hilden, Germany). Gap-PCR was used to detect common α-thalassemia deletions, including --SEA, -α3.7, -α4.2 and --Thailand. Three nondeletional α-thalassemia mutations and 17 known β-globin gene mutations were assessed using reverse dot-blot hybridization (RDB). All these assays were used with a thalassemia gene detection kit (Shenzhen Yishengtang Biological Products Co., Ltd.; Shenzhen, China). Gap-PCR was performed for individuals with HbF levels ≥5% to screen two types of β-globin gene cluster deletions, Chinese (^Aγδβ)⁰thalassemia and Southeast Asian (SEA), using specific primers [10]. When the two common deletions were excluded, multiplex ligation-dependent probe amplification (MLPA) was employed to detect copy number variation in the β-globin gene cluster according to the manufacturer's instructions (MRC Holland, Amsterdam, the Netherlands). Gap-PCR and sequence analysis using respective flanking primers were performed to determine deletional breakpoints. Sanger sequencing was applied to examine the promoter regions of γ-globin genes (including Aγ- and Gγ-globin genes) for all subjects with HbF levels ≥5%.

Statistical analysis

The hematological parameters of subjects with different genotypes are to described using the mean and standard deviation. Differences in hematological parameters between groups were compared by the nonparametric Mann-Whitney U test. A p-value of less than 0.05 was considered to indicate to a significant difference.

A total of 654 individuals, including 277 men and 377 women aged 21 to 49 years from eleven districts of Guangzhou, were found to have a high percentage of HbF (>5% ). None of these subjects was from the same family. The most common β-globin gene cluster deletion was Chinese ^Gγ(^Aγδβ)⁰ thalassemia, followed by SEA-HPFH. One hundred forty-two (142/654 21.71%) had one of those two types mentioned above. We detected 5 cases of Taiwanese deletion (5/654, 0.76%) and one case of Hb Lepore. Three cases of β-globin gene cluster deletions(3/654, 0.46) not reported to date were identified by MLPA. We also identified 53 cases as nondeletional HPFH, including 52 samples with the ^Aγ-196 C-T mutation (52/654,7.95%), named Italian nd-HPFH, and one sample with ^Aγ-197 C-T. The spectra of HPFH/δβ-thalassemia were shown in Fig. 1. The familial prevalences of Chinese ^Gγ(^Aγδβ)⁰ thalassemia and SEA-HPFH were 0.071% (89/125661) and 0.042% (53/125661), respectively. Two of the 125,661 couples were identified as being at risk of having a baby with thalassemia intermedia. The carrier rate of these two disorders in eleven districts of Guangzhou is shown in Fig. 2, with a significant difference in the prevalence of deletional HPFH/δβ-thalassemia among the districts due to the composition of the population.

Among 89 Chinese Gγ(Aγδβ)0 thalassemia mutations, 77 were in the heterozygous state; 11 were combined with α-thal and one with β-thal. Three cases of coinheritance of SEA-HPFH and Southern Asian α-thal deletion (--SEA/αα) were detected. We also observed 14 individuals with coinherited Southern Asian sithal and ^Aγ-196C-T mutations. The hematological data are shown in Fig. 3. For the first time, we describe a homozygous carrier of the ^Aγ-196 C-T mutation and one with coexistence of α⁰β-thal and ^Aγ-196C-T mutation. (Fig. 4A). Another nondeletional HPFH variant named Cretan HPFH (^Aγ-197 C-T mutation) was detected for the first time in China. This individual was also a carrier of the South-East Asian (SEA)-type deletion (--^SEA/αα) (Fig. 4B). The hematological analysis showed high HbF levels and hypochromic microcytic parameters (MCV72.4 fL, MCH 23.1 pg, Hb 148 g/L, Hb A 88.8%, Hb A2 2.1%, HbF 9.1%).

The individual with Hb Lepore showed an Hb variant in Zone 6, for a level of 8.6% by CE (Supplementary File 1 A). Gap-PCR and MLPA were employed to confirm Hb Lepore–Boston–Washington (Supplementary Files 1 B and C).

Three cases of deletions in the β-globin gene cluster were found by MLPA, which has never been never reported so far. Case 1, a 30-year-old male, had a low MCV and MCH but a normal hemoglobin level (Hb 162 g/L, MCV 79.1 fL, MCH 28.9 pg). Hb analysis showed increased HbF (9.8%) and low HbA2 (2.7%) levels. MLPA analysis revealed half dosages for three probes targeting exons 2-3 of HBG2 and the region between HBG2 and HBG1. We designed primers around probes for which normal dosages were observed and obtained a PCR product of 1.7 kb (Fig. 5 A). Sequencing indicated a novel deletion from HBG2 exon 2 to the HBG1 intervening sequence (IVS2). A fusion gene from HBG2 and HBG1 was found based on specific polymorphisms, but the exact breakpoint could not be determined because of the high homology between HBG2 and HBG (Fig. 5 B and C). Case 2, a 31-year-old female with increased HbF (21%) and lower HbA2 (1.8%) levels, had hypochromia and microcytosis (Hb 123 g/L, MCV 76.5 fL, MCH 24.9 pg). MLPA analysis showed half dosages for 13 consecutive MLPA probes with targets ranging from exon 1 of HBD to the 3’-UTR of HBB, indicating δβ-thal (Fig. 6 A). Case 3 was a 43-year-old female without other clinical or hematological abnormalities except for a markedly high level of HbF (5.8%), the clinical presentation of which was consistent with HPFH. MLPA analysis indicated reduced dosages for two MLPA probes located in the HBG1 region. All these breakpoints should be further identified by gap-PCR (Fig. 6 B).

δβ-Thalassemia/deletional HPFH compounded with β-thalassemia can cause intermedia thalassemia or thalassemia major, though clinical phenotypes vary [11-14]. More than 50 HPFH/δβ-thalassemia deletions have been reported to date, which are related to different ethnic backgrounds (http://globin.cse.psu.edu/hbvar/menu.html). In general, determining the prevalence and molecular characteristics of HPFH/δβ-thalassemias is important for thalassemia prevention. Guangzhou is the center of Southern China and consists of eleven districts. Although the population composition changed constantly due to the frequent migration from other provinces to this place, people with local residential registration were the main body of the population in our investigation for a good representation. This is the first report on the prevalence of (δβ)⁰-thal/HPFH in Guangzhou. Chinese ^Gγ(^Aγδβ)⁰ thalassemia and SEA-HPFH are the most common (δβ)⁰-thal/HPFH disorders in this region, the prevalences of which were lower than in the Chinese Zhuang population but higher than in the Chinese Hakka population and Yunnan population [15-17]. These differences may be caused by the population composition, which is rather homogeneous in those regions. This situation is similar in most districts except for Huadu and Nansha , possibly due to differences in population migration. The Nansha district was established in 2005, with immigrants predominating. Hudu is a district with a long history. There are a large number of ethnic minorities, including Zhuang, Tujia and others. It is also the district in which most Hakka people reside.

Chinese ^Gγ(^Aγδβ)⁰ -thal, SEA-HPFH, the Taiwanese deletion and the^Aγ-196C-T mutation are common genetic factors related to high Hb F levels in Guangzhou. Only individuals with the ^Aγ-196C-T mutation had normal values of MCV and MCH. The Taiwanese deletion and Chinese ^Gγ(^Aγδβ)⁰ -thal manifested the phenotype of beta0-thalassemia, and the values of Hb, MCH and MCV were much lower in the former. The HbA2 level was lower than 3.5% for heterozygous carriers of Chinese ^Gγ(^Aγδβ)⁰ thal or the ^Aγ-196 C-T mutation, whereas the latter carriers had much

lower HbA2 levels, regardless of coinheritance with α⁰-thalassaemia(southeast Asian type deletion) heterozygosity. The mechanism is not clear because the ^Aγ-196C-T mutation only involves a point mutation in HBG1. It is difficult to discriminate among carriers with Southern Asian α-thal deletion (--SEA/αα) coexistence. The HbA2 level was higher than 3.5% for cases of heterozygous SEA-HPFH mutation or Taiwanese deletion, and individuals with SEA-HPFH deletion had normal, hypochromic or borderline red blood cell indices. To date, the Taiwanese deletion has only been reported as the case study^,[10, 18]. Compared to the three types that caused higher HbF, the individual with the Taiwanese deletion showed higher HbA2 levels than 6% of our study cohort. This higher HbA2 level may be due to deletion of the β-globin gene promoter because a competitive relationship exists among the β, γ and δ chains in the HS region. ^Aγ-globin gene triplication was observed among our cases, as has been described before. All of these four cases exhibited a high HbF level of more than 8%; in contrast, the HbF level of the case without g-globin gene triplication was only 3.4%, which was lower than that of the other cases. Whether the g-globin gene triplication might contribute to the elevated level of Hb F in the presence of the Taiwan deletion should be studied further. It has been previously described that compound Taiwan deletion with a mutant allele with β-thal generates the β-TI phenotype. Thus, it is necessary to identify Taiwanese deletion carriers. The Taiwanese deletion may constitute the best possibility when no β-globin gene mutation is found in a case of increased HbF and Hb A2 (>6%).

Only one type of Hb Lepore variant named Hb Lepore-Boston/Washington has been reported in China [19]. Fusion between the HBD gene and the HBB gene occurs due to their high sequence homology. Homozygotes for Hb Lepore or compound heterozygous for Hb Lepore and β-thalassemia can present with thalassemia major or intermedia. Hb Lepore is very important for diagnosis, with level ranging from 5%–15%. Compared to HPLC, the capillary electrophoresis system is a better method for identifying a peak in Zone 6. Hb Lepore-Boston/Washington has been described in Thailand [20]. It was reported that carriers with Hb Lepore-Boston/Washington showed slightly elevated Hb F levels, which was different from our observation. More cases are needed to illustrate the molecular and hematological characteristics of this disease.

We found a case with the β^-28/β Chinese ^Gγ(^Aγδβ)⁰ genotype, a high level of HbF and mild anemia. CC [21] described a patient with the same genotype who presented moderate anemia. The phenotype of patients with the β⁺/β^{Chinese Gγ(Aγδβ)0} genotype or β⁰/β^{Chinese Gγ(Aγδβ)0} genotype varies, making genetic counseling difficult. There is also some dispute about pregnancy termination in the case of a fetus with those genotypes.

Three cases of β-globin gene cluster deletions in were found by MLPA. Case 1 with the HBG2-HBG1 fusion gene was similar to a case reported by Seung-Tae Lee, but the breakpoint may be different [22]. The fusion occurred between HBG2 exon 2 and HBG1 IVS2 in our study. The HBG2–HBG1 fusion can cause γ-thalassemia, which has been described [23]. The breakpoints displayed heterogeneity because the HBG2 and HBG1 genes are highly homologous. The mechanism of γ-thalassemia caused by HBG2–HBG1 gene fusion should be further explored.

Nondeletional-HPFH has not been described systematically in China. Italian nd-HPFH(Aγ-196 C-T mutation) was first described in 1984 [24] but seldom reported since. Our study found that it was the most common nondeletional HPFH in Guangzhou, of which the familial prevalence was 0.042%. Because Italian nd-HPFH and Chinese ^Gγ(^Aγδβ)⁰-thal carriers have similar HbF and HbA2 levels, the red blood cell count is the only difference used for discrimination during initial screening for thalassemia. We first detected one Italian nd-HPFH heterozygous condition coexisting α-thal and β-thal, with high Hb A2 and HbF levels detected (HbA2:4.1%, HbF: 25.9%), similar to SEA-HPFH carriers. Overall, the phenotypic characteristics of Italian nd-HPFH are useful for genetic counseling for individuals with increased HbF. We also found another nd-HPFH named Cretan HPFH (^Aγ-197 C-T), which was described in 2014 [8]. The two types of nd-HPFH are related to point mutations at approximately -200 relative to the transcriptional start site of the fetal γ-globin gene. Using K562 cells and HUDEP-2 cells, Gabriella E revealed that mutations at -200 of the γ-globin promotor disrupt ZBTB7A for HbF repressor binding. It was indicated that introducing naturally occurring variants in this region may be regarded as an attractive gene therapy strategy. Coincidentally, we detected two homozygotes for the ^Aγ-196 C-T mutation never reported before, raising the question that the HbF levels of homozygotes can be similar to those of heterozygotes. Our study suggests a natural model for disrupting ZBTB7A binding. More research is needed to estimate the degree of influence of mutations in the -200 site of the γ-globin promotor on HbF levels, especially when coexisting with major β-thal. Such studies may provide information for β-thal treatment.

In summary, our study systematically demonstrated the prevalence and molecular epidemiological characteristics of the hereditary persistence of fetal hemoglobin and δβ-thalassemia in the Greater Guangzhou Area, the capital of Southern China. This is the first report that Italian nd-HPFH (Aγ-196 C-T mutation) is not rare but in fact the most common nd-HPFH in China. Characterizing phenotypes and genetic mechanisms is very useful for understanding the globin switch and genetic therapy.

Hb:Hemoglobin; HPFH:Hereditary Persistence of Fetal Hemoglobin; nd-HPFH: nondeletional HPFH; Gap-PCR: gap polymerase chain reaction; Hb A2: Hemoglobin A2 ; Hb F:Hemoglobin F; MCV: mean corpuscular volume;Hb CS: Hb Constant Spring; Hb QS:Hb Quong Sze; Hb WS: Hb Westmead; MLPA: Multiplex ligation-dependent probe amplification; IVS: Intervening sequences; SEA:Southeast Asian; THAI, Thailand; β^N, β^Normal

Ethics approval and consent to participate

Ethical approval for the study was given by the the Ethics Committee of the Guangzhou Women & Children Medical Center, and informed consent was obtained from all subjects participating in the study.

Consent for publication

Based on the Declaration of Helsinki, informed consent was obtained from all subjects participating in the study. The study was approved by the the Ethics Committee of the Guangzhou Women & Children Medical Center ethics committee. This article does not include any studies with animals performed by any of the authors.

Availability of data and materials

The datasets used or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors in our study announce that they have no competing interests

Funding

This study was supported by grants from the Science and Technology Foundation of Guangzhou [20171A011257] and the Science and Technology Foundation of Guangdong Province [2017A030223003] which Fan Jiang received.

Authors’ contributions

LC contributed the central idea; JF analyzed most of the data and wrote the initial draft of the paper; LDZ contributed to revisions; TXW, CGL ,LH and ZJY collected the clinical data; ZLD and LJ interpreted the results and depicted the figures; All authors discussed the results and revised the manuscript.

Acknowledgements

The authors would like to acknowledge all patients for their cooperation with our study.

Author details

¹Southern Medical University, Guangzhou, Guangdong Province, People’s Republic of China; ²Prenatal Diagnostic Center, Guangzhou Women and Children’s Medical Center affiliated with Guangzhou Medical University, Guangzhou, Guangdong Province, People’s Republic of China

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Supplementary File 1 (A) Hb analysis showing Hb Lepore variant using capillary electrophoresis; (B) MLPA analysis showing half dosages for probes located in the region ranging from exon 3 of HBD to intron 1 of HBB; (C) A representative gel electrophoresis for Hb Lepore-Boston carrier: 915 bp Hb Lepore-Boston specific and 775 bp internal control

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Molecular Epidemiology and Hematologic Characterizationof δβ-thalassemia and Hereditary Persistence of Fetal Hemoglobin in 125661 Families of Greater Guangzhou Area, the metropolis of Southern China

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