Studying the pathogenicity of 26 variants characterized in the first molecular analyses of Egyptian aplastic anemia patients.

IF 3.6 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Journal, genetic engineering & biotechnology Pub Date : 2023-11-29 DOI:10.1186/s43141-023-00585-8
Mona F Sokkar, Mona Hamdy, Peter Sf Erian, Rehab M Mosaad, Nesma M Elaraby, Mohamed B Taher, Heba El-Sayed, Mohammed Al Komy, Maha M Eid, Amal M Mohamed, Khalda S Amr, Ghada Y El-Kamah
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Abstract

Background: Aplastic anemia (AA) is a bone marrow disorder characterized by peripheral pancytopenia and marrow hypoplasia which can lead to life-threatening complications. Our objective was to study the telomerase genes (TERT and TERC) variants, explore their relationship to telomere shortening and TERT gene expression, and to identify variants in the MPL gene within Egyptian AA patients.

Methods: Forty AA patients and 40 sex- and age-matched healthy individuals as the control group were studied through sequencing of TERT, TERC, and MPL genes. Quantitative real-time PCR (qRT-PCR) was used for measuring TERT gene expression. Telomere length (TL) was measured using the Quantitative Fluorescence In Situ Hybridization (Q-FISH) technique. In silico analysis was performed for the prediction of the pathogenicity of resultant variants.

Results: Sequencing of MPL, TERT, and TERC genes identified 26 variants. Eleven variants were identified in the MPL gene. Three of them are pathogenic: two missense [c.305 G>A, c.1589 C>T] and one splice site [g.9130T>G]. TERT gene sequencing showed thirteen variants, among them, four novel [c.484G>A, c.499G>A, c.512G>A, c.3164C>G] and two previously reported [c.835G>A, c.2031C>T] were predicted to be pathogenic. Two variants were characterized within the TERC gene; n.514A>G and n.463 C>T. TERT gene expression was downregulated in 70% of studied patients and the Q-FISH technique detected telomere shortening in 82.5% of patients.

Conclusions: Twenty-six pathogenic and benign variants within the TERC, TERT, and MPL genes were identified among the studied AA patients that were in several cases associated with shortened telomeres and/or lower TERT gene expression. Genotype/phenotype correlation in AA patients is of great importance in explaining the disease severity and guiding therapeutic decisions.

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研究埃及再生障碍性贫血患者首次分子分析中26个变异的致病性。
背景:再生障碍性贫血(AA)是一种以外周血全血细胞减少和骨髓发育不全为特征的骨髓疾病,可导致危及生命的并发症。我们的目的是研究端粒酶基因(TERT和TERC)变异,探索它们与端粒缩短和TERT基因表达的关系,并在埃及AA患者中鉴定MPL基因变异。方法:对40例AA患者和40例性别、年龄相匹配的健康人进行TERT、TERC和MPL基因测序,作为对照组。采用实时荧光定量PCR (qRT-PCR)检测TERT基因表达。采用定量荧光原位杂交(Q-FISH)技术测定端粒长度(TL)。计算机分析用于预测产生的变异的致病性。结果:MPL、TERT和TERC基因测序鉴定出26个变异。在MPL基因中鉴定出11个变体。其中三个是致病的:两个是错义的[c.305]c.1589 G >C>T]和一个剪接位点[G . 9130t >G]。TERT基因测序显示13个变异,其中4个为新变异[c]。484G>A, c.499G>A, c. 512g >A, c. 3164c >G]和之前报道的两篇[c. 3164c]。835G>A, c.2031C>T]预测具有致病性。在TERC基因中发现了两个变异;n.514A>G和n.463C > T。研究中70%的患者TERT基因表达下调,Q-FISH技术检测到82.5%的患者端粒缩短。结论:在研究的AA患者中,发现了TERC、TERT和MPL基因中的26个致病和良性变异,这些变异在一些病例中与端粒缩短和/或TERT基因表达降低有关。AA患者的基因型/表型相关性对解释疾病严重程度和指导治疗决策具有重要意义。
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