Identification of a novel ATR-X mutation causative of acquired α-thalassemia in a myelofibrosis patient,Egyptian Journal of Medical Human Genetics

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Identification of a novel ATR-X mutation causative of acquired α-thalassemia in a myelofibrosis patient
Egyptian Journal of Medical Human Genetics Pub Date : 2024-02-28 , DOI: 10.1186/s43042-024-00497-3
Rosa Catapano , Filippo Russo , Marco Rosetti , Giovanni Poletti , Silvia Trombetti , Raffaele Sessa , Tommaso Fasano , Sauro Maoggi , Sante Roperto , Michela Grosso

Dear Editor,

Acquired alpha-thalassemia mental retardation X-linked (ATRX) mutations are associated with the onset of α-thalassemia in several hematological malignancies including myelodysplasia, acute lymphoblastic leukemia, myelofibrosis, essential thrombocythemia, and acute myeloid leukemia (acquired α-thalassemia myelodisplastic syndrome, ATMDS) [1]. The ATRX gene (NM_000489.6) is located at Xq21.1 and encodes a chromatin remodeling protein which contributes to regulate the structure and function of chromatin in centromeric heterochromatin and telomeric domains to control different cellular pathways including DNA damage response and senescence mechanisms [2, 3]. ATRX is also involved in the epigenetic regulation of α-globin genes: loss-of-function mutations in the ATRX gene cause the transcriptional repression of the α-globin gene (HBA), thus resulting in a decreasing production of α-globin chains [4]. In this regard, mutations of the ATRX gene have been reported in association with a rare inherited pathology called X-linked α-thalassemia and mental retardation syndrome (or ATR-X syndrome) characterized by mental retardation, facial and urogenital abnormalities along with an α-thalassemia trait with elevated levels of β-globin or γ-globin tetramers (HbH or Barts' hemoglobin), the amount of which is directly related to the severity of the α-globin chain deficiency [5].

Here we report a novel single-nucleotide variant (SNV) in the ATRX gene, found by Next-Generation Sequencing (NGS) analysis in a 77-year-old Italian man previously healthy who had been hospitalized for myelofibrosis and was referred to our Centre to investigate the possible genetic cause of an acquired form of α-thalassemia with elevated levels of HbH. The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of the University of Naples Federico II (project approval number 443/21). Genomic DNA was extracted using the Nucleon BACC3 kit (GE Healthcare, Life Sciences, Chicago, IL, USA) and analyzed by a customized NGS gene panel recently developed by our group to identify acquired or inherited mutations associated with thalassemic disorders. The DNA libraries were prepared with the SureSelect^{XT HS} Target Enrichment System kit (Agilent Technologies, Santa Clara, CA, USA) after enzymatic fragmentation and according to the manufacturer’s protocol. Library quality and quantity were checked with the TapeStation system (Agilent Technologies) and Qubit dsDNA High Sensitivity assay kit on Qubit Fluorometer (Thermo Fisher Scientific, Waltham, MA, USA), respectively. Libraries were sequenced with MiSeq Reagent Kit v2 (300-cycles) by loading a concentrated pool (9 pM) and 1% Phix on a MiSeq Illumina® instrument (Illumina; San Diego, CA, USA). To exclude any kind of contamination, a blank negative control was included, and it followed all procedure’s steps, from DNA extraction to sequencing. Data analysis was performed using Alissa Report v1.1.6–2023-03 and Alissa Interpret v5.4.2 software (Agilent Technologies) and revealed the presence of a T > G transition at codon 520 in exon 7 of the ATRX gene (c.520T > G) with a variant allele frequency of 89.9% (179/199 variant coverage) which deviates from the expected values for germline mutations, thereby in agreement with the acquired origin of the variant. This SNV leads to a missense p.Cys174Gly mutation in the PHD-like domain, a hot-spot region for ATMDS defects [1, 6]. The mutation was confirmed by Sanger sequencing (Fig. 1A). NGS and MLPA analysis also excluded the presence of point mutations or large deletions in the α-globin gene cluster that are responsible of inherited α-thalassemia (Fig. 1B) [7].

To our best knowledge and according to GnomAD exome, GnomAD genome, and ClinVar databases, this SNV is an unreported variant in the ATRX gene. Thirteen out of 18 in-silico prediction tools (CADD, Polyphen2 HVAR, Polyphen2 HDIV, FATHMM, M-CAP, MutPred, MVP, FATHMM-MKL, LRT, PrimateAI, PROVEAN, SIFT, SIFT4G) supported the possible pathogenicity of this SNV, whereas other five tools (BLOSUM, DANN, DEOGEN2, LIST-S2, MutationTaster) classified it as of uncertain significance (Table 1). In addition, six different meta-scores for in-silico pathogenicity assessment determined a very strong, strong, or moderate pathogenic prediction, basing on multiple tools as reported in Table 1. Furthermore, an analysis of base conservation scores on 99 vertebrate genome sequences aligned to the human genome (represented by PhyloP100way scores provided by the VarSome platform, https://varsome.com/about/resources/acmg-implementation) revealed that c.520T is a highly conserved nucleotide in the human genome, as represented in Fig. 1C. Indeed, this mutation falls in the PHD-like region of the protein, a functional domain where several other ATMDS mutations have been identified so far [8]. Based on this information, we classified this mutation as potentially pathogenic. In fact, according to the criteria of the American College of Medical Genetics and Genomics (ACMG), the detected SNV met three criteria which allow to establish its pathogenicity [9]: first, there are several computational systems supporting a possible deleterious effect of this mutation (PP1 rule); secondly, this mutation is located in a mutational hot-spot genomic area (PM1 rule); finally, no frequency data for this sequence variation are reported in the main genetic databases, such as the Exome Sequencing Project, 1000 Genome Project, or the Exome Aggregation Consortium (PM2 rule).

Table 1 Pathogenicity prediction meta-score

Full size table

In conclusion, here we report a novel ATRX mutation in a patient with myelofibrosis in which the onset of HbH disease can be explained by impaired ATRX functions leading to altered expression of the α-globin genes. This report contributes to better define the ATRX gene mutational spectrum, with the purpose of improving genetic screening and diagnosis of rare diseases.

The data supporting the findings of this study are available from the corresponding author upon request.

ATRX:: Alpha-thalassemia mental retardation X-linked
ATMDS:: Acquired α-thalassemia myelodisplastic syndrome
HBA:: α-globin gene
SNV:: Novel single-nucleotide variant
NGS:: Next-generation sequencing
MLPA:: Multiplex ligation-dependent probe amplification
ACMG:: American College of Medical Genetics and Genomics

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Authors and Affiliations

Ceinge-Biotecnologie Avanzate “Franco Salvatore”, 80131, Naples, Italy
Rosa Catapano, Filippo Russo & Michela Grosso
Clinical Pathology Unit, Hub Laboratory, AUSL Romagna, 47522, Cesena, Italy
Marco Rosetti, Giovanni Poletti & Tommaso Fasano
Sebia Italia Srl, 50012, Bagno a Ripoli, FI, Italy
Sauro Maoggi
Department of Veterinary Medicine and Animal Productions, University of Naples Federico II, 80137, Naples, Italy
Silvia Trombetti & Sante Roperto
Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131, Naples, Italy
Rosa Catapano, Filippo Russo, Silvia Trombetti, Raffaele Sessa & Michela Grosso

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Contributions

Conceptualization was performed by MG; methodology by RC and RS; software by FR; validation by RC, RS, and ST; investigation by RC, RS, and ST; data curation by RC and FR; writing—original draft preparation by RC and FR; writing—review and editing by MG, MR, GP, TF, and SM; visualization by SM and SR; supervision by MG. All authors have read and agreed to the published version of the manuscript.

Corresponding author

Correspondence to Michela Grosso.

Ethics approval and consent to participate

The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Institutional Ethics Committee of University of Naples Federico II (protocol code 443/21; date of approval: 24/02/2022).

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Catapano, R., Russo, F., Rosetti, M. et al. Identification of a novel ATR-X mutation causative of acquired α-thalassemia in a myelofibrosis patient. Egypt J Med Hum Genet 25, 25 (2024). https://doi.org/10.1186/s43042-024-00497-3

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Received: 11 January 2024
Accepted: 21 February 2024
Published: 28 February 2024
DOI: https://doi.org/10.1186/s43042-024-00497-3

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中文翻译：

鉴定导致骨髓纤维化患者获得性 α-地中海贫血的新型 ATR-X 突变

亲爱的编辑，

获得性 α 地中海贫血精神发育迟滞 X 连锁 (ATRX) 突变与多种血液系统恶性肿瘤中 α 地中海贫血的发病相关，包括骨髓增生异常、急性淋巴细胞白血病、骨髓纤维化、原发性血小板增多症和急性髓性白血病（获得性 α 地中海贫血骨髓增生异常综合征、空中交通管理系统）[1]。ATRX 基因 (NM_000489.6) 位于 Xq21.1，编码染色质重塑蛋白，有助于调节着丝粒异染色质和端粒结构域中染色质的结构和功能，以控制不同的细胞途径，包括 DNA 损伤反应和衰老机制 [2 ，3]。ATRX 还参与 α-珠蛋白基因的表观遗传调控：ATRX 基因的功能丧失突变会导致 α-珠蛋白基因 (HBA) 的转录抑制，从而导致 α-珠蛋白链的产量减少。 4]。在这方面，据报道 ATRX 基因的突变与一种罕见的遗传性疾病有关，称为 X 连锁 α 地中海贫血和智力低下综合征（或 ATR-X 综合征），其特征是智力低下、面部和泌尿生殖系统异常以及 α -β-珠蛋白或γ-珠蛋白四聚体（HbH 或 Barts 血红蛋白）水平升高的地中海贫血特征，其数量与 α-珠蛋白链缺陷的严重程度直接相关[5]。

在这里，我们报告了ATRX基因中的一个新的单核苷酸变异 (SNV) ，通过下一代测序 (NGS) 分析在一名先前健康的 77 岁意大利男子中发现，他因骨髓纤维化住院并被转诊到我们的中心调查 HbH 水平升高的获得性 α-地中海贫血的可能遗传原因。该研究是根据赫尔辛基宣言进行的，并得到那不勒斯费德里科二世大学伦理委员会的批准（项目批准号443/21）。使用 Nucleon BACC3 试剂盒（GE Healthcare，生命科学，芝加哥，伊利诺伊州，美国）提取基因组 DNA，并通过我们小组最近开发的定制 NGS 基因组进行分析，以识别与地中海贫血相关的获得性或遗传性突变。DNA 文库是在酶裂解后使用 SureSelect ^{XT HS}靶标富集系统试剂盒（Agilent Technologies，Santa Clara，CA，USA）根据制造商的方案制备的。分别使用 TapeStation 系统 (Agilent Technologies) 和 Qubit 荧光计 (Thermo Fisher Scientific, Waltham, MA, USA) 上的 Qubit dsDNA 高灵敏度检测试剂盒检查文库质量和数量。通过在 MiSeq Illumina® 仪器（Illumina；圣地亚哥，加利福尼亚州，美国）上加载浓缩池 (9 pM) 和 1% Phix，使用 MiSeq Reagent Kit v2（300 个循环）对文库进行测序。为了排除任何类型的污染，添加了空白阴性对照，并遵循从 DNA 提取到测序的所有程序步骤。使用 Alissa Report v1.1.6–2023-03 和 Alissa Interpret v5.4.2 软件 (Agilent Technologies) 进行数据分析，结果显示ATRX基因外显子 7 的密码子 520 处存在 T > G 转变(c.520T > G) 变异等位基因频率为 89.9%（179/199 变异覆盖率），这偏离了种系突变的预期值，因此与变异的获得性起源一致。该 SNV 导致 PHD 样结构域中出现错义 p.Cys174Gly 突变，该结构域是 ATMDS 缺陷的热点区域 [1, 6]。该突变通过桑格测序得到证实（图1A）。NGS 和 MLPA 分析还排除了 α-珠蛋白基因簇中导致遗传性 α-地中海贫血的点突变或大缺失的存在（图 1B）[7]。

据我们所知，根据 GnomAD 外显子组、GnomAD 基因组和 ClinVar 数据库，该 SNV 是ATRX基因中未报告的变体。18 个计算机预测工具（CADD、Polyphen2 HVAR、Polyphen2 HDIV、FATHMM、M-CAP、MutPred、MVP、FATHMM-MKL、LRT、PrimateAI、PROVEAN、SIFT、SIFT4G）中的 13 个支持该 SNV 的可能致病性，而其他五个工具（BLOSUM、DANN、DEOGEN2、LIST-S2、MutationTaster）将其分类为意义不确定（表 1）。此外，根据表 1 中报告的多种工具，用于计算机致病性评估的六种不同元评分确定了非常强、强或中等致病性预测。此外，对 99 个脊椎动物基因组序列的碱基保守评分进行了分析对人类基因组（由 VarSome 平台提供的 PhyloP100way 分数表示，https://varsome.com/about/resources/acmg-implementation）揭示，c.520T 是人类基因组中高度保守的核苷酸，如图所示.1C. 事实上，这种突变属于蛋白质的 PHD 样区域，这是一个功能域，迄今为止已经发现了其他几个 ATMDS 突变 [8]。根据这些信息，我们将这种突变归类为潜在致病性。事实上，根据美国医学遗传学和基因组学学院 (ACMG) 的标准，检测到的 SNV 满足三个标准，可以确定其致病性 [9]：首先，有几个计算系统支持这种可能的有害影响。突变（PP1规则）；其次，该突变位于突变热点基因组区域（PM1规则）；最后，主要遗传数据库（例如外显子组测序计划、千人基因组计划或外显子组聚合联盟（PM2 规则））中没有报告此序列变异的频率数据。

表1 致病性预测元评分

全尺寸桌子

总之，我们在这里报告了骨髓纤维化患者的一种新的 ATRX 突变，其中 HbH 疾病的发作可以通过 ATRX 功能受损导致 α-珠蛋白基因表达改变来解释。该报告有助于更好地定义ATRX基因突变谱，旨在改善罕见疾病的基因筛查和诊断。

支持本研究结果的数据可根据要求向通讯作者提供。

ATRX：: X连锁α-地中海贫血精神发育迟滞
空中交通管理系统：: 获得性α-地中海贫血骨髓增生异常综合征
主机总线适配器：: α珠蛋白基因
序列号：: 新型单核苷酸变体
NGS：: 新一代测序
MLPA：: 多重连接依赖性探针扩增
ACMG：: 美国医学遗传学与基因组学院

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作者和单位

Ceinge-Biotecnologie Avanzate“Franco Salvatore”，80131，那不勒斯，意大利
罗莎·卡塔帕诺、菲利波·罗素和米凯拉·格罗索
临床病理科，中心实验室，AUSL Romagna，47522，切塞纳，意大利
马可·罗塞蒂、乔瓦尼·波莱蒂和托马索·法萨诺
Sebia Italia Srl, 50012, 巴尼奥阿里波利, FI, 意大利
绍罗·毛吉
那不勒斯费德里科二世大学兽医和动物生产系，80137，那不勒斯，意大利
西尔维娅·特罗姆贝蒂和桑特·罗佩托
分子医学和医学生物技术系，那不勒斯大学费德里科二世，80131，那不勒斯，意大利
罗莎·卡塔帕诺、菲利波·罗素、西尔维娅·特罗姆贝蒂、拉斐尔·塞萨和米凯拉·格罗索

作者

罗莎·卡塔帕诺查看作者出版物
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Filippo Russo查看作者出版物
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Marco Rosetti查看作者出版物
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乔瓦尼·波莱蒂查看作者出版物
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Silvia Trombetti查看作者出版物
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Raffaele Sessa查看作者出版物
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托马索·法萨诺查看作者出版物
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Sauro Maoggi查看作者出版物
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Sante Roperto查看作者出版物
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米凯拉·格罗索查看作者出版物
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贡献

概念化由 MG 进行；RC 和 RS 方法；软件由 FR 提供；通过 RC、RS 和 ST 进行验证；通过 RC、RS 和 ST 进行调查；由 RC 和 FR 进行数据管理；写作——由 RC 和 FR 准备初稿；写作—由 MG、MR、GP、TF 和 SM 审阅和编辑；通过 SM 和 SR 进行可视化；由MG监督。所有作者均已阅读并同意稿件的出版版本。

通讯作者

米凯拉·格罗索的通讯。

道德批准并同意参与

该研究是根据赫尔辛基宣言的指导方针进行的，并得到那不勒斯费德里科二世大学机构伦理委员会的批准（方案代码443/21；批准日期：24/02/2022）。

同意发表

不适用。

利益争夺

作者声明他们没有利益冲突。

出版商备注

施普林格·自然对于已出版的地图和机构隶属关系中的管辖权主张保持中立。

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