Chromosomes, Human, Pair 9

染色体,人类,对 9
  • 文章类型: Journal Article
    背景:虽然黑色素瘤通常损失9p21,CDKN2A位于其上,在该位点存在其他肿瘤抑制因子的特征不完全。在这里,我们评估了microRNA-876-3p(miR-876)的表达水平和功能作用,其基因也映射到9p21。
    方法:使用定量miRNA逆转录酶聚合酶链反应(qRT-PCR)在人组织和细胞系中评估miR-876的表达。在癌症基因组图谱(TCGA)黑素瘤队列中确定MIR876拷贝数。miR-876表达的调控对黑色素瘤细胞集落形成的影响进行了评估,迁移,入侵,凋亡,细胞周期进程,和培养中的药物敏感性,以及异种移植模型中的体内肿瘤生长。使用RNA测序(RNA-Seq)测定由miR-876过表达诱导的全基因组转录组变化。
    结果:与痣相比,miR-876在原发性黑色素瘤样本中的表达显着降低,与人类黑素细胞相比,在人类黑素瘤细胞系中。对TCGA队列的分析显示MIR876在>50%的黑素瘤中缺失。miR-876过表达导致黑素瘤细胞集落形成减少,迁移,和入侵,伴随着细胞周期停滞和细胞凋亡增加。肿瘤内注射miR-876显著抑制体内黑色素瘤生长。miR-876处理的肿瘤的RNA-Seq分析揭示了几种生长促进基因的下调,随着肿瘤抑制基因的上调,通过qRT-PCR分析证实。计算分析将MAPK1(或ERK2)鉴定为miR-876作用的可能靶标。miR-876的过表达显著抑制了由MAPK1/ERK23'UTR驱动的荧光素酶表达,并导致黑色素瘤细胞中ERK蛋白表达降低。MAPK1/ERK2cDNA过表达拯救了miR-876对黑色素瘤集落形成的影响。miR-876过表达使黑色素瘤细胞对BRAF抑制剂vemurafenib治疗敏感。
    结论:这些研究确定miR-876是9p21上的一种独特的肿瘤抑制因子,在黑色素瘤中失活,并提示miR-876丢失是激活ERK和促分裂原活化蛋白激酶(MAPK)途径的另一种机制。此外,他们提出了miR-876过表达与BRAF抑制相结合作为黑色素瘤合理治疗策略的治疗潜力.
    BACKGROUND: While melanomas commonly harbor losses of 9p21, on which CDKN2A resides, the presence of additional tumor suppressor elements at this locus is incompletely characterized. Here we assess the expression levels and functional role of microRNA-876-3p (miR-876), whose gene also maps to 9p21.
    METHODS: Expression of miR-876 was assessed in human tissues and cell lines using quantitative miRNA reverse transcriptase polymerase chain reaction (qRT-PCR). MIR876 copy number was determined in The Cancer Genome Atlas (TCGA) melanoma cohort. The consequences of regulation of miR-876 expression were assessed on melanoma cell colony formation, migration, invasion, apoptosis, cell cycle progression, and drug sensitivity in culture, and on in vivo tumor growth in a xenograft model. Genome-wide transcriptomic changes induced by miR-876 overexpression were determined using RNA sequencing (RNA-Seq).
    RESULTS: miR-876 expression was significantly decreased in primary melanoma samples when compared with nevi, and in human melanoma cell lines when compared with human melanocytes. Analysis of the TCGA cohort revealed deletions in MIR876 in > 50% of melanomas. miR-876 overexpression resulted in decreased melanoma cell colony formation, migration, and invasion, which was accompanied by cell cycle arrest and increased apoptosis. Intra-tumoral injections of miR-876 significantly suppressed melanoma growth in vivo. RNA-Seq analysis of miR-876-treated tumors revealed downregulation of several growth-promoting genes, along with upregulation of tumor suppressor genes, which was confirmed by qRT-PCR analysis. Computational analyses identified MAPK1 (or ERK2) as a possible target of miR-876 action. Overexpression of miR-876 significantly suppressed luciferase expression driven by the MAPK1/ERK2 3\' UTR, and resulted in decreased ERK protein expression in melanoma cells. MAPK1/ERK2 cDNA overexpression rescued the effects of miR-876 on melanoma colony formation. miR-876 overexpression sensitized melanoma cells to treatment with the BRAF inhibitor vemurafenib.
    CONCLUSIONS: These studies identify miR-876 as a distinct tumor suppressor on 9p21 that is inactivated in melanoma and suggest miR-876 loss as an additional mechanism to activate ERK and the mitogen activated protein kinase (MAPK) pathway in melanoma. In addition, they suggest the therapeutic potential of combining miR-876 overexpression with BRAF inhibition as a rational therapeutic strategy for melanoma.
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  • 文章类型: Journal Article
    T细胞前淋巴细胞白血病(T-PLL)是一种罕见且侵袭性的成熟T细胞恶性肿瘤,其特征是明显的淋巴细胞增多,B症状,淋巴结病,和肝脾肿大.没有标准的治疗方法,在没有同种异体移植的情况下,预后仍然很差。T-PLL中定义疾病的细胞遗传学异常是TCL1家族癌基因与TCR基因增强子基因座的并置,主要是由于14号染色体的倒置,即inv(14)。下一代测序技术的应用导致在超过70%的T-PLL中发现JAK1/3和STAT5B中的高度复发的功能获得突变,为使用小分子抑制剂进行治疗干预提供了机会。可能导致T-PLL发病的其他遗传机制仍然未知。在这里,我们描述了一种新的基因融合SMCHD1::JAK2的鉴定,该基因融合是由9号和18号染色体之间易位产生的,涉及SMCHD1外显子45和JAK2外显子14(t(9;18)(p24.1;p11.32)(chr9:g.5080171::chr18:g.2793269)),患有T-PLL的患者中先前未描述的遗传事件,该患者患有定义inv(14)的关键疾病,导致TCL1和TRA/D的重排。在这份手稿中,我们描述了使用ruxolitinib和duvelisib治疗后25个月内患者病程的临床和遗传特征.
    T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive mature T-cell malignancy characterized by marked lymphocytosis, B symptoms, lymphadenopathy, and hepatosplenomegaly. There is no standard treatment approach, and in the absence of an allogeneic transplant, the prognosis remains poor. The disease-defining cytogenetic abnormality in T-PLL is the juxtaposition of the TCL1-family oncogene to the TCR gene enhancer locus primarily due to an inversion of chromosome 14, that is, inv(14). The application of next-generation sequencing technologies led to the discovery of highly recurrent gain-of-function mutations in JAK1/3 and STAT5B in over 70% of T-PLL providing opportunities for therapeutic intervention using small molecule inhibitors. Additional genetic mechanisms that may contribute to the pathogenesis of T-PLL remain unknown. Herein we describe the identification of a novel gene fusion SMCHD1::JAK2 resulting from a translocation between chromosome 9 and 18 involving SMCHD1 exon 45 and JAK2 exon 14 (t(9;18)(p24.1;p11.32)(chr9:g.5080171::chr18:g.2793269)), a previously undescribed genetic event in a patient with T-PLL harboring the key disease defining inv(14) resulting in rearrangement of TCL1 and TRA/D. In this manuscript, we describe the clinical and genetic features of the patient\'s disease course over a 25-month post-treatment duration using ruxolitinib and duvelisib.
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  • 文章类型: Case Reports
    四体性9p是一种罕见的遗传综合征,由9号染色体短臂的两个额外拷贝引起。症状通常以先天性异常的形式存在,包括认知障碍,生长迟缓,耳垂异常,先天性心脏病,头骨和面部畸形。目前的文献表明,患有9p四体的患者可能会表现出这些症状的任何组合,或者,在极少数情况下,一点也没有。虽然核型分析,染色体微阵列,和半乳糖-1-磷酸尿嘧啶转移酶活性分析是使用的确定诊断方法,在轻度表型表达的病例中,仍然需要更可靠的临床识别.在这里,我们介绍了一个罕见的马赛克四体9p的长期生存患者,患有多发性和复发性毛曲霉菌瘤,罕见的良性生长更常见于20岁以下的个体。据我们所知,以前只有两份报告指出9p四体与毛曲菌瘤同时发生.我们是第一个在成年四体性9p患者中鉴定这种表型的人。进行皮肤病理学评估以验证我们的诊断。我们的目标是提出一个独特的,另一个病例提示多发性毛囊房瘤是马赛克四体9p的新定义临床表现,并回顾与该综合征相关的遗传变化的文献。
    Tetrasomy 9p is a rare genetic syndrome resulting from two additional copies of the short arm of chromosome 9. Symptoms often present in the form of congenital abnormalities including cognitive disabilities, growth retardation, abnormal earlobes, congenital heart disease, and dysmorphia of the skull and face. Current literature suggests patients with tetrasomy 9p may exhibit any combination of these symptoms or, in rare instances, none at all. Although karyotyping, chromosomal microarray, and galactose-1-phosphate uridyltransferase activity analyses are the definitive diagnostic methods used, there remains a need for more robust clinical recognition in cases of mild phenotypic expression. Herein, we present a rare case of mosaic tetrasomy 9p in a long-term survival patient with multiple and recurrent pilomatrixomas, rare benign growths more commonly found in individuals under the age of 20. To our knowledge, only two previous reports have noted concurrent tetrasomy 9p with pilomatrixomas. We are the first to identify this phenotype in an adult tetrasomy 9p patient. Dermatopathology evaluation was conducted to verify our diagnoses. Our aim is to present a unique, additional case suggesting multiple pilomatrixomas as a new defining clinical presentation of mosaic tetrasomy 9p and to review the literature underlying the genetic changes associated with this syndrome.
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  • 文章类型: Journal Article
    Trithorax相关H3K4甲基转移酶,KMT2C和KMT2D,是关键的表观遗传修饰剂。KMT2C的单倍功能不全最近才被认为是神经发育障碍(NDD)的原因,因此KMT2C相关NDD(现称为Kleefstra综合征2)的临床和分子谱在很大程度上是未知的.我们确定了98例具有罕见KMT2C变体的个体,包括75个蛋白质截短变体(PTV)。值得注意的是,15%的KMT2CPTV是遗传的。尽管最高表达的KMT2C转录物仅由最后四个外显子组成,在这个大基因的几乎所有外显子中都发现了致病性PTV。由于分段重复和克隆性造血引起的伪影,KMT2C变体解释可能具有挑战性。使用来自27个受影响个体的样本,分为发现和验证队列,我们产生了中度强度障碍特异性KMT2CDNA甲基化(DNAm)特征,并证明了其在分类非截短变体中的实用性.基于81名具有致病性/可能的致病性变异的个体,我们证明与KMT2C相关的NDD具有发育迟缓的特征,智力残疾,行为和精神问题,低张力,癫痫发作,身材矮小,和其他合并症。PhenoScore的面部模块,适用于34名受影响个人的照片,揭示了KMT2C相关的面部完形与一般NDD人群有显著差异。最后,使用PhenoScore和DNAM签名,我们证明KMT2C相关NDD在临床和表观遗传上与Kleefstra和Kabuki综合征不同.总的来说,我们定义了临床特征,分子光谱,与KMT2C相关的NDD的DNAm签名,并证明它们与Kleefstra和Kabuki综合征不同,强调需要重命名这种情况。
    Trithorax-related H3K4 methyltransferases, KMT2C and KMT2D, are critical epigenetic modifiers. Haploinsufficiency of KMT2C was only recently recognized as a cause of neurodevelopmental disorder (NDD), so the clinical and molecular spectrums of the KMT2C-related NDD (now designated as Kleefstra syndrome 2) are largely unknown. We ascertained 98 individuals with rare KMT2C variants, including 75 with protein-truncating variants (PTVs). Notably, ∼15% of KMT2C PTVs were inherited. Although the most highly expressed KMT2C transcript consists of only the last four exons, pathogenic PTVs were found in almost all the exons of this large gene. KMT2C variant interpretation can be challenging due to segmental duplications and clonal hematopoesis-induced artifacts. Using samples from 27 affected individuals, divided into discovery and validation cohorts, we generated a moderate strength disorder-specific KMT2C DNA methylation (DNAm) signature and demonstrate its utility in classifying non-truncating variants. Based on 81 individuals with pathogenic/likely pathogenic variants, we demonstrate that the KMT2C-related NDD is characterized by developmental delay, intellectual disability, behavioral and psychiatric problems, hypotonia, seizures, short stature, and other comorbidities. The facial module of PhenoScore, applied to photographs of 34 affected individuals, reveals that the KMT2C-related facial gestalt is significantly different from the general NDD population. Finally, using PhenoScore and DNAm signatures, we demonstrate that the KMT2C-related NDD is clinically and epigenetically distinct from Kleefstra and Kabuki syndromes. Overall, we define the clinical features, molecular spectrum, and DNAm signature of the KMT2C-related NDD and demonstrate they are distinct from Kleefstra and Kabuki syndromes highlighting the need to rename this condition.
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  • 文章类型: Journal Article
    基因诊断向基因型优先的转变彻底改变了我们对神经发育障碍的理解,扩展它们的分子和表型光谱。Kleefstra综合征(KLEFS1)由EHMT1单倍体功能不全引起,并表现出广泛的临床表现。EHMT1编码原色组蛋白甲基转移酶-1-表观遗传机制的关键组成部分。我们招募了209名具有罕见EHMT1变体的个体,并对鉴定的变体进行了全面的分子模拟和体外测试以及DNA甲基化(DNAm)特征分析。我们(重新)将191名个体的变体分类为可能的致病性/致病性(分子确认Kleefstra综合征)。我们提供Kleefstra综合征的最新和更广泛的临床和分子谱,包括智力正常和家族发生的个体。对EHMT1变体的分析揭示了广泛的分子效应及其相关表型,包括不同的基因型-表型关联。值得注意的是,我们表明,蛋白质改变变体(PAV)破坏了锚蛋白重复结构域的“阅读器”功能,导致KLEFS1特异性DNAm签名和较温和的表型,而SET结构域的“写入者”甲基转移酶活性的破坏不会导致KLEFS1DNA标记或典型的KLEFS1表型。同样,N-末端截短变体导致没有DNAm标签的轻度表型。我们展示了全面的变异分析如何提供对疾病发病机理和DNAm特征的见解。总之,本研究对KLEFS1和EHMT1进行了全面概述,揭示了其更广泛的光谱,加深了我们对其分子机制的理解,从而告知准确的变体解释,咨询,和临床管理。
    The shift to a genotype-first approach in genetic diagnostics has revolutionized our understanding of neurodevelopmental disorders, expanding both their molecular and phenotypic spectra. Kleefstra syndrome (KLEFS1) is caused by EHMT1 haploinsufficiency and exhibits broad clinical manifestations. EHMT1 encodes euchromatic histone methyltransferase-1-a pivotal component of the epigenetic machinery. We have recruited 209 individuals with a rare EHMT1 variant and performed comprehensive molecular in silico and in vitro testing alongside DNA methylation (DNAm) signature analysis for the identified variants. We (re)classified the variants as likely pathogenic/pathogenic (molecularly confirming Kleefstra syndrome) in 191 individuals. We provide an updated and broader clinical and molecular spectrum of Kleefstra syndrome, including individuals with normal intelligence and familial occurrence. Analysis of the EHMT1 variants reveals a broad range of molecular effects and their associated phenotypes, including distinct genotype-phenotype associations. Notably, we showed that disruption of the \"reader\" function of the ankyrin repeat domain by a protein altering variant (PAV) results in a KLEFS1-specific DNAm signature and milder phenotype, while disruption of only \"writer\" methyltransferase activity of the SET domain does not result in KLEFS1 DNAm signature or typical KLEFS1 phenotype. Similarly, N-terminal truncating variants result in a mild phenotype without the DNAm signature. We demonstrate how comprehensive variant analysis can provide insights into pathogenesis of the disorder and DNAm signature. In summary, this study presents a comprehensive overview of KLEFS1 and EHMT1, revealing its broader spectrum and deepening our understanding of its molecular mechanisms, thereby informing accurate variant interpretation, counseling, and clinical management.
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  • 文章类型: Case Reports
    目的:我们在产前诊断中提出了与良好胎儿结局相关的妊娠中的马赛克远端9p缺失。
    方法:34岁,由于母亲年龄高,初产妇在妊娠17周时接受了羊膜穿刺术。羊膜穿刺术显示核型为46,XY,del(9)(p23)[8]/46,XY[17]。对从未培养的羊膜细胞提取的DNA进行的同时阵列比较基因组杂交(aCGH)分析显示,9p24.3p23缺失的镶嵌性为43%。产前超声怀疑尿道下裂和回声肠。妊娠23周时,她被推荐接受遗传咨询,重复羊膜穿刺术显示核型为46,XY,del(9)(p23)[10]/46,XY[10]。亲本核型正常。未培养的羊膜细胞的分子遗传学分析显示,通过定量荧光聚合酶链反应(QF-PCR)和aCGH的arr9p24.3p23×1.55(40%-50%镶嵌性)没有单亲二体(UPD)9。妊娠27周时,她接受了第三次羊膜穿刺术,结果显示染色体核型为46,XY,del(9)(p23)[6]/46,XY[14]。从未培养的羊膜细胞中提取的DNA的同时aCGH分析显示了arr9p24.3p23(35%镶嵌性)的结果。产前超声检查正常。建议她继续怀孕,一个3020克表型正常的男婴在妊娠41周时分娩。出生时,脐带血的核型,脐带和胎盘分别为46,XY,del(9)(p23)[7]/46,XY[37],46,XY,del(9)(p23)[17]/46,XY[23]和46,XY在40/40细胞,分别。在三个月的年龄进行随访时,新生儿表型和发育正常。外周血核型为46,XY,del(9)(p23)[3]/46,XY[37],和口腔粘膜细胞的相间荧光原位杂交(FISH)分析显示,远端9p缺失具有13%(13/102个细胞)的镶嵌性。
    结论:产前诊断时正常细胞系的Mosaic远端9p缺失可能与良好的胎儿结局和非整倍体细胞系的围产期进行性减少有关。
    OBJECTIVE: We present mosaic distal 9p deletion at prenatal diagnosis in a pregnancy associated with a favorable fetal outcome.
    METHODS: A 34-year-old, primigravid woman underwent amniocentesis at 17 weeks of gestation because of advanced maternal age. Amniocentesis revealed a karyotype of 46,XY, del(9)(p23)[8]/46,XY[17]. Simultaneous array comparative genomic hybridization (aCGH) analysis on the DNA extracted from uncultured amniocytes showed 43% mosaicism for the 9p24.3p23 deletion. Prenatal ultrasound suspected hypospadias and echogenic bowel. At 23 weeks of gestation, she was referred for genetic counseling, and repeat amniocentesis revealed a karyotype of 46,XY,del(9)(p23)[10]/46,XY[10]. The parental karyotypes were normal. Molecular genetic analysis on uncultured amniocytes revealed no uniparental disomy (UPD) 9 by quantitative fluorescence polymerase chain reaction (QF-PCR) and arr 9p24.3p23 × 1.55 (40%-50% mosaicism) by aCGH. At 27 weeks of gestation, she underwent the third amniocentesis which revealed a karyotype of 46,XY,del(9)(p23)[6]/46,XY[14]. Simultaneous aCGH analysis on the DNA extracted from uncultured amniocytes revealed the result of arr 9p24.3p23 (35% mosaicism). Prenatal ultrasound was normal. She was advised to continue the pregnancy, and a 3020-g phenotypically normal male baby was delivered at 41 weeks of gestation. At birth, the karyotypes of cord blood, umbilical cord and placenta were 46,XY,del(9)(p23)[7]/46,XY[37], 46,XY,del(9)(p23)[17]/46,XY[23] and 46,XY in 40/40 cells, respectively. When follow-up at age three months, the neonate was normal in phenotype and development. The peripheral blood had a karyotype of 46,XY,del(9)(p23)[3]/46,XY[37], and interphase fluorescence in situ hybridization (FISH) analysis on buccal mucosal cells showed 13% (13/102 cells) mosaicism for the distal 9p deletion.
    CONCLUSIONS: Mosaic distal 9p deletion with a normal cell line at prenatal diagnosis can be associated with a favorable fetal outcome and perinatal progressive decrease of the aneuploid cell line.
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  • 文章类型: Journal Article
    9p21.3基因组位点是疾病相关单核苷酸多态性(SNP)的热点,其与冠状动脉疾病(CAD)的相关性最强。疾病相关的SNP位于长链非编码RNAANRIL的序列内,它可能通过调节血管细胞的应激和增殖来促进动脉粥样硬化,但也会影响胰腺β细胞的增殖。改变了邻近基因的表达,CDKN2B,在携带风险SNP的人群中,也已经认识到与肥胖和肝脂肪变性相关。在本研究中,我们研究了在高脂血症Ldlr-/-ApoB100/100背景中9p21.3(Chr4Δ70/Δ70)风险基因座缺失的小鼠中,9p21.3对伴有高脂血症的肥胖的影响。Chr4Δ70/Δ70小鼠在年轻时已经显示出白色脂肪组织中胰岛素受体的mRNA表达降低,随着年龄的增长发展为胰岛素抵抗和肥胖。此外,Sirt1-Ppargc1a-Ucp2通路与Cdkn2b的表达一起下调,特别是在Chr4Δ70/Δ70小鼠的白色脂肪组织中。这些结果表明,9p21.3基因座,ANRILlncRNA,在高胆固醇血症的存在下,它们的鼠直系同源物可能以白色脂肪组织特异性方式调节关键的能量代谢途径,从而促进代谢综合征的发病机制。
    The 9p21.3 genomic locus is a hot spot for disease-associated single-nucleotide polymorphisms (SNPs), and its strongest associations are with coronary artery disease (CAD). The disease-associated SNPs are located within the sequence of a long noncoding RNA ANRIL, which potentially contributes to atherogenesis by regulating vascular cell stress and proliferation, but also affects pancreatic β-cell proliferation. Altered expression of a neighboring gene, CDKN2B, has been also recognized to correlate with obesity and hepatic steatosis in people carrying the risk SNPs. In the present study, we investigated the impact of 9p21.3 on obesity accompanied by hyperlipidemia in mice carrying a deletion of the murine ortholog for the 9p21.3 (Chr4Δ70/Δ70) risk locus in hyperlipidemic Ldlr-/-ApoB100/100 background. The Chr4Δ70/Δ70 mice showed decreased mRNA expression of insulin receptors in white adipose tissue already at a young age, which developed into insulin resistance and obesity by aging. In addition, the Sirt1-Ppargc1a-Ucp2 pathway was downregulated together with the expression of Cdkn2b, specifically in the white adipose tissue in Chr4Δ70/Δ70 mice. These results suggest that the 9p21.3 locus, ANRIL lncRNA, and their murine orthologues may regulate the key energy metabolism pathways in a white adipose tissue-specific manner in the presence of hypercholesterolemia, thus contributing to the pathogenesis of metabolic syndrome.
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  • 文章类型: Journal Article
    软骨-毛发发育不全综合征(CHH)是一种常染色体隐性遗传疾病,通常与n.72A>G(以前称为n.70A>G和n.71A>G)有关,全球最常见的RMRP变体。已经描述了该基因中的130多种致病变体与CHH相关,据报道,芬兰和日本人口中有创始人的改变。我们先前在巴西CHH患者中的研究显示,与其他人群相比,n.197C>T变体(前n.195C>T和n.196C>T)的患病率很高。这项研究的目的是研究在一系列CHH巴西患者中RMRP基因中n.197C>T变体的可能的创始人效应。我们选择了9号染色体内的四个TAGSNP,并对先证者及其父母进行了基因分型(先前描述的23例患者和9例新颖患者)。鉴定了n.197C>T变异携带者的常见单倍型。患者的特征还包括46个常染色体祖先信息标记(AIM)。欧洲血统是最普遍的(58%),其次是非洲(24%)和美洲原住民(18%)。我们的结果加强了巴西n.197C>T变体的基础效应的假设,并表明RMRP基因中的该变体起源于9号染色体上的单个事件,可能是欧洲起源。
    Cartilage-hair hypoplasia syndrome (CHH) is an autosomal recessive disorder frequently linked to n.72A>G (previously known as n.70A>G and n.71A>G), the most common RMRP variant worldwide. More than 130 pathogenic variants in this gene have already been described associated with CHH, and founder alterations were reported in the Finnish and Japanese populations. Our previous study in Brazilian CHH patients showed a high prevalence of n.197C>T variant (former n.195C>T and n.196C>T) when compared to other populations. The aim of this study was to investigate a possible founder effect of the n.197C>T variant in the RMRP gene in a series of CHH Brazilian patients. We have selected four TAG SNPs within chromosome 9 and genotyped the probands and their parents (23 patients previously described and nine novel). A common haplotype to the n.197C>T variant carriers was identified. Patients were also characterized for 46 autosomal Ancestry Informative Markers (AIMs). European ancestry was the most prevalent (58%), followed by African (24%) and Native American (18%). Our results strengthen the hypothesis of a founder effect for the n.197C>T variant in Brazil and indicate that this variant in the RMRP gene originated from a single event on chromosome 9 with a possible European origin.
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  • 文章类型: Journal Article
    急性髓性白血病(AML),t(9;22)(q34.1;q11.2)/BCR::ABL1,AML组中具有定义遗传异常的独特实体,属于2022年ELN分类的不利风险组。然而,自酪氨酸激酶抑制剂时代以来,关于结果的数据很少。在DATAML注册表中的5819起AML案件中,鉴定出20例患者从头BCR::ABL1+AML(0.3%)。在这项研究中分析了18例接受标准诱导化疗的患者。16例患者化疗中加入了伊马替尼。男女比例为1.25,中位年龄为54岁。t(9;22)易位是12例患者中唯一的染色体异常。NGS检测到的主要基因突变为ASXL1、RUNX1和NPM1。与慢性粒细胞白血病(CML-BP)的髓细胞母细胞期患者相比,从头BCR::ABL1+AML有较高的白细胞,减少额外的染色体异常,CD36或CD7表达较低,无ABL1突变。17例患者(94.4%)达到完全缓解(CR)或CR,血液学恢复不完全。12例患者在首次缓解时进行了同种异体移植。中位随访时间为6.3年,未达到中位OS,2年OS为77%(95%CI:50~91).五分之四的未移植患者没有复发。BCR::ABL1+AML的比较,CML-BP,2017年ELN中间(n=643)和不良风险患者(n=863)显示,BCR::ABL1AML患者的预后明显优于中间和不良风险患者。BCR::用伊马替尼和强化化疗治疗的ABL1+AML患者不应包括在当前AML分类的不良风险组中。
    Acute myeloid leukemia (AML) with t(9;22) (q34.1; q11.2)/BCR::ABL1, a distinct entity within the group of AML with defining genetic abnormalities, belong to the adverse-risk group of the 2022 ELN classification. However, there is little data on outcome since the era of tyrosine kinase inhibitors. Among 5819 AML cases included in the DATAML registry, 20 patients with de novo BCR::ABL1+AML (0.3%) were identified. Eighteen patients treated with standard induction chemotherapy were analyzed in this study. Imatinib was added to chemotherapy in 16 patients. The female-to-male ratio was 1.25 and median age was 54 years. The t(9;22) translocation was the sole chromosomal abnormality in 12 patients. Main gene mutations detected by NGS were ASXL1, RUNX1 and NPM1. Compared with patients with myeloid blast phase of chronic myeloid leukemia (CML-BP), de novo BCR::ABL1+AML had higher WBC, fewer additional chromosomal abnormalities, lower CD36 or CD7 expression and no ABL1 mutations. Seventeen patients (94.4%) achieved complete remission (CR) or CR with incomplete hematologic recovery. Twelve patients were allografted in first remission. With a median follow-up of 6.3 years, the median OS was not reached and 2-year OS was 77% (95% CI: 50-91). Four out of five patients who were not transplanted did not relapse. Comparison of BCR::ABL1+AML, CML-BP, 2017 ELN intermediate (n = 643) and adverse-risk patients (n = 863) showed that patients with BCR::ABL1+AML had a significant better outcome than intermediate and adverse-risk patients. BCR::ABL1+AML patients treated with imatinib and intensive chemotherapy should not be included in the adverse-risk group of current AML classifications.
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  • 文章类型: Journal Article
    细胞遗传学研究表明,人类染色体1,9和16,具有高度甲基化的经典卫星DNA的大异色区域,丝裂霉素C(MMC)容易诱导染色单体断裂和互换。几项研究表明,来自9号染色体以及可能来自1号和16号染色体的物质优先被MMC微核化。这里,我们进一步检查了MMC对微核(MN;有或没有细胞松弛素B)和染色体畸变(CA)的染色体特异性诱导。处理来自两名男性供体的分离的人淋巴细胞的培养物(在培养48小时时,24小时)与MMC(500ng/ml),并通过9号染色体的pancentromericDNA探针和油漆探针以及1号和16号染色体的油漆探针检查诱导的MN。MMC使MN的总频率增加了6-8倍,但9号染色体阳性(9)MN的频率增加了29-30倍,1号染色体阳性(1)MN和16号染色体阳性(16)MN的频率增加了12-16倍和10-17倍,分别。用MMC治疗后,所有MN的34-47%为9+,17-20%1+,和3-4%16+。9MN中的大多数(94-96%)不含着丝粒,因此带有无心片段。当MMC诱导的CAs畸变通过使用9号染色体的经典卫星区域和长臂和短臂端粒的探针和探针来表征时,染色体断裂的比例很高(31%)和互换(41%)涉及9号染色体。在83%的案例中,9号染色体上的断点正好在经典卫星探针标记的区域(9cen-q12)下方。我们的结果表明,MMC特异性诱导携带9号、1号和16号染色体片段的MN。9号染色体的CA在MMC处理的淋巴细胞的中期中高度过量。优先断点低于9q12区域。
    Cytogenetic studies have shown that human chromosomes 1, 9, and 16, with a large heterochromatic region of highly methylated classical satellite DNA, are prone to induction of chromatid breaks and interchanges by mitomycin C (MMC). A couple of studies have indicated that material from chromosome 9, and possibly also from chromosomes 1 and 16, are preferentially micronucleated by MMC. Here, we further examined the chromosome-specific induction of micronuclei (MN; with and without cytochalasin B) and chromosomal aberrations (CAs) by MMC. Cultures of isolated human lymphocytes from two male donors were treated (at 48 h of culture, for 24 h) with MMC (500 ng/ml), and the induced MN were examined by a pancentromeric DNA probe and paint probe for chromosome 9, and by paint probes for chromosomes 1 and 16. MMC increased the total frequency of MN by 6-8-fold but the frequency of chromosome 9 -positive (9+) MN by 29-30-fold and the frequency of chromosome 1 -positive (1+) MN and chromosome 16 -positive (16+) MN by 12-16-fold and 10-17-fold, respectively. After treatment with MMC, 34-47 % of all MN were 9+, 17-20 % 1+, and 3-4 % 16+. The majority (94-96 %) of the 9+ MN contained no centromere and thus harboured acentric fragments. When MMC-induced CAs aberrations were characterized by using the pancentromeric DNA probe and probes for the classical satellite region and long- and short- arm telomeres of chromosome 9, a high proportion of chromosomal breaks (31 %) and interchanges (41 %) concerned chromosome 9. In 83 % of cases, the breakpoint in chromosome 9 was just below the region (9cen-q12) labelled by the classical satellite probe. Our results indicate that MMC specifically induces MN harbouring fragments of chromosome 9, 1, and 16. CAs of chromosome 9 are highly overrepresented in metaphases of MMC-treated lymphocytes. The preferential breakpoint is below the region 9q12.
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