Clinical implications of systematic phenotyping and exome sequencing in patients with primary antibody deficiency
Clinical implications of systematic phenotyping and exome sequencing in patients with primary antibody deficiency
复制标题
对原发性抗体缺乏症患者进行系统表型分析和外显子测序的临床意义
DOI：
10.1038/s41436-018-0012-x
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发表时间：
2019-01-01
影响因子：
8.8
通讯作者：
Hammarstrom, Lennart
中科院分区：
文献类型：
--
作者：
Abolhassani, Hassan;Aghamohammadi, Asghar;Hammarstrom, Lennart
目的：80%的原发性抗体缺乏症（PAD）患者的病因尚不清楚，PAD是人类免疫缺陷病毒感染后第二种最常见的人类免疫系统疾病。126例PAD患者的临床/免疫学表型和外显子组测序（55.5%男性，95.2%儿童期发病）出生的主要近亲的父母（82.5%）未知的遗传缺陷进行。美国医学遗传学和基因组学标准用于验证致病性的变种。结果：这种遗传方法和随后的免疫学调查确定了潜在的致病变异86例（68.2%），然而，27这些患者（31.4%）携带常染色体显性（24.4%）和X连锁（7%）基因缺陷。这种遗传学方法导致在19个已知基因（38名患者）中鉴定出新的表型，并发现了新的遗传缺陷（2名患者中的CD 70致病性变体）。一个明确的基因诊断的医学意义的报道，在类似的50%的patient.Conclusion：由于错误的传统方法的靶向测序分类，采用新一代测序作为分子诊断方法的初步步骤，以PAD患者是至关重要的管理和治疗的患者及其家属。
Purpose: The etiology of 80% of patients with primary antibody deficiency (PAD), the second most common type of human immune system disorder after human immunodeficiency virus infection, is yet unknown.Methods: Clinical/immunological phenotyping and exome sequencing of a cohort of 126 PAD patients (55.5% male, 95.2% childhood onset) born to predominantly consanguineous parents (82.5%) with unknown genetic defects were performed. The American College of Medical Genetics and Genomics criteria were used for validation of pathogenicity of the variants.Results: This genetic approach and subsequent immunological investigations identified potential disease-causing variants in 86 patients (68.2%); however, 27 of these patients (31.4%) carried autosomal dominant (24.4%) and X-linked (7%) gene defects. This genetic approach led to the identification of new phenotypes in 19 known genes (38 patients) and the discovery of a new genetic defect (CD70 pathogenic variants in 2 patients). Medical implications of a definite genetic diagnosis were reported in similar to 50% of the patients.Conclusion: Due to misclassification of the conventional approach for targeted sequencing, employing next-generation sequencing as a preliminary step of molecular diagnostic approach to patients with PAD is crucial for management and treatment of the patients and their family members.