■先前的研究已经确定,高达6%的阿司匹林加重呼吸道疾病(AERD)患者有AERD家族史,表明与遗传多态性的可能联系。然而,目前缺乏此类关联的全外显子组测序(WES)研究.
■我们试图检查WES是否可以识别与AERD相关的致病变异。
■在鼻息肉和哮喘患者中证实了AERD的诊断。使用Illumina测序平台进行WES。人类表型本体论术语用于定义患者的表型。Exomiser被用来注释,过滤器,并优先考虑可能引起疾病的遗传变异。
■在39例AERD患者中,41%报告有哮喘家族史,5%报告有AERD家族史。在2例患者(5%)中发现了丝聚蛋白基因(FLG)中的致病性外显子组变异。在另外16名患者(41%)中检测到与上皮完整性和细胞相互作用相关的基因,包括编码桥粒蛋白3(DSG3)的基因,动力蛋白轴突重链9(DNAH9),VII型胶原α1链(COL7A1),胶原XVII型α1链(COL17A1),色域解旋酶DNA结合蛋白-7(CHD7),TSC复合物亚基2/结节性硬化症2蛋白(TSC2),P-选择素(SELP),和血小板衍生生长因子受体-α(PDGFRA)。
■WES在5%的FLG致病变异患者中发现了对AERD的单基因易感性。在与上皮完整性和细胞相互作用相关的基因中发现了先前未被鉴定为致病性的其他变体,并且可能进一步揭示了导致这种状况的遗传因素。
UNASSIGNED: Previous studies have determined that up to 6% of patients with aspirin-exacerbated respiratory disease (AERD) have family history of AERD, indicating a possible link with genetic polymorphisms. However, whole exome sequencing (WES) studies of such associations are currently lacking.
UNASSIGNED: We sought to examine whether WES can identify pathogenic variants associated with AERD.
UNASSIGNED: Diagnoses of AERD were confirmed in patients with nasal polyps and asthma. WES was performed using an Illumina sequencing platform. Human Phenotype Ontology terms were used to define the patients\' phenotypes. Exomiser was used to annotate, filter, and prioritize possible disease-causing genetic variants.
UNASSIGNED: Of 39 patients with AERD, 41% reported a family history of asthma and 5% reported a family history of AERD. Pathogenic exome variants in the filaggrin gene (FLG) were found in 2 patients (5%). Other variants not known to be pathogenic were detected in an additional 16 patients (41%) in genes related to epithelial integrity and cellular interactions, including genes encoding desmoglein 3 (DSG3), dynein axonemal heavy chain 9 (DNAH9), collagen type VII alpha 1 chain (COL7A1), collagen type XVII alpha 1 chain (COL17A1), chromodomain helicase DNA binding protein-7 (CHD7), TSC complex subunit 2/tuberous sclerosis-2 protein (TSC2), P-selectin (SELP), and platelet-derived growth factor receptor-alpha (PDGFRA).
UNASSIGNED: WES identified a monogenic susceptibility to AERD in 5% of patients with FLG pathogenic variants. Other variants not previously identified as pathogenic were found in genes relevant to epithelial integrity and cellular interactions and may further reveal genetic factors that contribute to this condition.