Abstract：
UNASSIGNED: Clinical manifestations of patients with Hemoglobin E/beta-thalassemia vary from mild to severe phenotypes despite exhibiting the same genotype. Studies have partially identified genetic modifiers. We aimed to study the association between rare variants in protein-coding regions and clinical severity in Thai patients.
UNASSIGNED: From April to November 2018, a case-control study was conducted based on clinical information and DNA samples collected from Thai patients with hemoglobin E/beta-thalassemia over the age of four years. Cases were patients with severe symptoms, while patients with mild symptoms acted as controls. Whole exome sequencing and rare variant association study were used to analyze the data.
UNASSIGNED: All 338 unrelated patients were classified into 165 severe and 173 mild cases. Genotypes comprised 81.4% of hemoglobin E/beta-thalassemia, 2.7% of homozygous or compound heterozygous beta-thalassemia, and 0.3% of (δβ)0 thalassemia Hb E while 15.7% of samples were not classified as beta-thalassemia. A novel cis heterozygotes of IVS I-7 (A > T) and codon 26 (G > A) was identified. Six genes (COL4A3, DLK1, FAM186A, PZP, THPO, and TRIM51) showed the strongest associations with severity (observed p-values of <0.05; significance lost after correction for multiplicity). Among known modifiers, KLF1 variants were found in four mild patients and one severe patient.
UNASSIGNED: No rare variants were identified as contributors to the clinical heterogeneity of hemoglobin E/beta-thalassemia. KLF1 mutations are potential genetic modifiers. Studies to identify genetic factors are still important and helpful for predicting severity and developing targeted therapy.
UNASSIGNED: From April to November 2018, a case-control study was conducted based on clinical information and DNA samples collected from Thai patients with hemoglobin E/beta-thalassemia over the age of four years. Cases were patients with severe symptoms, while patients with mild symptoms acted as controls. Whole exome sequencing and rare variant association study were used to analyze the data.
UNASSIGNED: All 338 unrelated patients were classified into 165 severe and 173 mild cases. Genotypes comprised 81.4% of hemoglobin E/beta-thalassemia, 2.7% of homozygous or compound heterozygous beta-thalassemia, and 0.3% of (δβ)0 thalassemia Hb E while 15.7% of samples were not classified as beta-thalassemia. A novel cis heterozygotes of IVS I-7 (A > T) and codon 26 (G > A) was identified. Six genes (COL4A3, DLK1, FAM186A, PZP, THPO, and TRIM51) showed the strongest associations with severity (observed p-values of <0.05; significance lost after correction for multiplicity). Among known modifiers, KLF1 variants were found in four mild patients and one severe patient.
UNASSIGNED: No rare variants were identified as contributors to the clinical heterogeneity of hemoglobin E/beta-thalassemia. KLF1 mutations are potential genetic modifiers. Studies to identify genetic factors are still important and helpful for predicting severity and developing targeted therapy.
摘要：
未经证实：尽管具有相同的基因型，但血红蛋白E/β地中海贫血患者的临床表现从轻度到重度不等。研究已经部分确定了遗传修饰剂。我们旨在研究泰国患者中蛋白质编码区的罕见变异与临床严重程度之间的关系。
UNASSIGNED：从2018年4月至11月，根据从4岁以上的泰国血红蛋白E/β-地中海贫血患者收集的临床信息和DNA样本进行了病例对照研究。病例为症状严重的患者，而症状轻微的患者作为对照。使用全外显子组测序和罕见变异关联研究来分析数据。
UNASSIGNED：所有338例无关患者分为165例重度和173例轻度。基因型占血红蛋白E/β-地中海贫血的81.4%，2.7%的纯合或复合杂合β-地中海贫血，（δβ）0地中海贫血HbE占0.3％，而15.7％的样品未归类为β-地中海贫血。鉴定了IVS1-7(A>T)和密码子26(G>A)的新顺式杂合子。六个基因（COL4A3，DLK1，FAM186A，PZP,THPO,和TRIM51）显示出与严重程度的最强关联（观察到的p值<0.05；校正多重性后失去了显著性）。在已知的修饰符中，在四名轻度患者和一名重度患者中发现了KLF1变体。
未经证实：没有发现罕见变异是导致血红蛋白E/β-地中海贫血临床异质性的因素。KLF1突变是潜在的遗传修饰因子。识别遗传因素的研究对于预测严重程度和开发靶向治疗仍然很重要。
UNASSIGNED：从2018年4月至11月，根据从4岁以上的泰国血红蛋白E/β-地中海贫血患者收集的临床信息和DNA样本进行了病例对照研究。病例为症状严重的患者，而症状轻微的患者作为对照。使用全外显子组测序和罕见变异关联研究来分析数据。
UNASSIGNED：所有338例无关患者分为165例重度和173例轻度。基因型占血红蛋白E/β-地中海贫血的81.4%，2.7%的纯合或复合杂合β-地中海贫血，（δβ）0地中海贫血HbE占0.3％，而15.7％的样品未归类为β-地中海贫血。鉴定了IVS1-7(A>T)和密码子26(G>A)的新顺式杂合子。六个基因（COL4A3，DLK1，FAM186A，PZP,THPO,和TRIM51）显示出与严重程度的最强关联（观察到的p值<0.05；校正多重性后失去了显著性）。在已知的修饰符中，在四名轻度患者和一名重度患者中发现了KLF1变体。
未经证实：没有发现罕见变异是导致血红蛋白E/β-地中海贫血临床异质性的因素。KLF1突变是潜在的遗传修饰因子。识别遗传因素的研究对于预测严重程度和开发靶向治疗仍然很重要。
