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respectively, analyzed by quantitative reverse transcrip-
tase PCR [qRT-PCR]) (Figure 1E). Meantime the qRT-PCR
analysis of the mRNA level in II1’s blood showed a
1Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University; 2Guangdong Genetics Testing Engineering Research Center; 3Guangdong Provincial Key Laboratory of Single Cell Technology and Application and 4Center of Prenatal Diagnosis, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
#
DP and XS contributed equally as co-first authors.
Correspondence: XIANGMIN XU - xixm@smu.edu.cn doi:10.3324/haematol.2020.262600
Received: June 29, 2020.
Accepted: October 12, 2020.
Pre-published: October 29, 2020.
Disclosures: no conflicts of interest to disclose.
Contributions: DP, DC, YC, XW and FH collected samples and performed the research; DP, FY and HL analysed the data; DP, XS and XX designed the study and wrote the paper; XX supervised the research and all authors reviewed, edited and approved the manuscript.
Funding: this research was supported by research funding from the National Key R&D Program of China (2018YFA0507800; 2018YFA0507803), National Natural Science Foundation of China (81870148) and Guangdong Basic and Applied Basic Research Foundation (2019A1515011545).
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3.16±0.48% expression level of this residual
α-globin gene (Figure 1F), and a low expression level of
z-globin (embryonic α-like globin) gene comparing with 0
other homozygous α -thalassemia patient (Figure 1G). In addition, the haplotype analysis also confirmed that this residual α-globin gene was inherited from his mother (Figure 1H). Therefore, II1 was assumed to be a chimera with two genotypes: --SEA/--SEA (major) and --SEA/αα (minor), which is the same as analysis result of six short tandem repeat (STR) loci showing a low degree of chimerism in II1’s blood, hair follicle and oral mucosa samples (5.22±0.83%, 19.32±1.03% and 6.70±0.28% in cells with the --SEA/αα genotype, respectively) (Figure 2).
An international registry of homozygous α0-tha- lassemia survivors has proved that intrauterine transfu- sion increases the chance of survival in utero.3 In addition, the persistent expression of the z-globin gene was assumed to be one explanation for the phenotypic diver- sity in homozygous α0-thalassemia survivors. However, the II1 survived naturally, until birth, without intrauter- ine treatment, and the expression level of the z-globin gene does not increase comparing with other homozy- gous α0-thalassemia patient (Figure 1G). Previous research had shown that even a very small amount of chimerism of the Y chromosome can make girls appear with ambiguous genitalia or hermaphroditism.10,11 Therefore, we considered a low level of expression (approximately 3% of that of normal individuals, Figure 1F) of α-globin, originating from approximately 5% chimerism of --SEA/αα in blood cells (Figure 2), can ensure a natural birth and significant improvement in growth and neurodevelopment.
We have further considered the generation of chimerism. The II1 and II2 patients were monochorionic dizygotic twins, based on the ultrasound findings and STR loci analysis. Previous research12 indicated that there are three hypotheses to explain the generation of chimeric monochorionic dizygotic twins. Hypothesis 1: placental anastomoses result in inter twin transfer of blood cells, with subsequent blood cell chimerism. However, the STR analysis of II1 indicated that the chimeric ratio of hair follicle cells is higher than that of blood cells (Figure 2). Hypothesis 2: fusion of elements of two genetically distinct zygotes. This is more normal in an assisted reproductive technologies pregnancy, whilst our case was a natural pregnancy. Therefore, we propose a model (Figure 3) based on hypothesis 3: “fertilization of a binovular follicle”, were two oocytes arising in a single zona pellucida are fertilized by two individual sperm and form two inner cell masses by division, fusion and migra- tion. The cell mass then differentiates into two fetuses: II1 (chimera, survives) and II2 (non-chimera, deceased).
In summary, this is the first report of a homozygous α0- thalassemia patient who survived, without intrauterine intervention, due to chimerism. This data may be valu- able in providing accurate diagnosis and genetic counsel- ing in similar cases.
Dejian Pang,1# Xuan Shang,1,2,3# Decheng Cai,1 Fang Yang,4 Huijie Lu,1 Yi Cheng,1 Xiaofeng Wei,1 Fei He1
and Xiangmin Xu1,2,3
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