Primary immunodeficiency diseases: Genomic approaches delineate heterogeneous Mendelian disorders.
Primary immunodeficiency diseases: Genomic approaches delineate heterogeneous Mendelian disorders.
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原发性免疫缺陷疾病：基因组方法描述了异质的孟德尔疾病。
DOI：
10.1016/j.jaci.2016.05.042
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发表时间：
2017-01
期刊：
影响因子：
--
通讯作者：
Lupski JR
中科院分区：
文献类型：
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作者：
Stray-Pedersen A;Sorte HS;Samarakoon P;Gambin T;Chinn IK;Coban Akdemir ZH;Erichsen HC;Forbes LR;Gu S;Yuan B;Jhangiani SN;Muzny DM;Rødningen OK;Sheng Y;Nicholas SK;Noroski LM;Seeborg FO;Davis CM;Canter DL;Mace EM;Vece TJ;Allen CE;Abhyankar HA;Boone PM;Beck CR;Wiszniewski W;Fevang B;Aukrust P;Tjønnfjord GE;Gedde-Dahl T;Hjorth-Hansen H;Dybedal I;Nordøy I;Jørgensen SF;Abrahamsen TG;Øverland T;Bechensteen AG;Skogen V;Osnes LTN;Kulseth MA;Prescott TE;Rustad CF;Heimdal KR;Belmont JW;Rider NL;Chinen J;Cao TN;Smith EA;Caldirola MS;Bezrodnik L;Lugo Reyes SO;Espinosa Rosales FJ;Guerrero-Cursaru ND;Pedroza LA;Poli CM;Franco JL;Trujillo Vargas CM;Aldave Becerra JC;Wright N;Issekutz TB;Issekutz AC;Abbott J;Caldwell JW;Bayer DK;Chan AY;Aiuti A;Cancrini C;Holmberg E;West C;Burstedt M;Karaca E;Yesil G;Artac H;Bayram Y;Atik MM;Eldomery MK;Ehlayel MS;Jolles S;Flatø B;Bertuch AA;Hanson IC;Zhang VW;Wong LJ;Hu J;Walkiewicz M;Yang Y;Eng CM;Boerwinkle E;Gibbs RA;Shearer WT;Lyle R;Orange JS;Lupski JR
原发性免疫缺陷病（PIDDs）是迄今为止与300多个基因突变相关的临床和遗传异质性疾病。来自不同基因型的临床表型可能重叠。遗传病因学可以作为疾病严重程度的预后指标，并可影响治疗决策。研究全外显子组筛查方法检测PIDDs患者致病变异的能力。来自22个国家的278个家庭的PIDDs个体使用全外显子组测序（WES）进行了调查。计算CNV预测管道和外切镶嵌染色体微阵列也被应用于识别基因内拷贝数变异（CNVs）。分析方法最初集中在475个已知或候选的PIDD基因，但不是排他性的，并根据临床数据，家族史和免疫表型进一步定制。110名（40%）不相关的先证者获得了可能的分子诊断。根据分子学结果，约一半（60/110）的家庭修改了临床诊断，近四分之一（26/110）的家庭直接改变了管理。检测到12个引起PIDD的CNV，包括7个小于30 Kb的CNV，这些CNV不能用常规诊断CNV阵列检测到。这种高通量基因组方法能够检测到意外基因中的疾病相关变异，允许检测低级体质，体细胞和回复突变嵌合体，并提供混合PIDD免疫表型突变负担的证据。
Primary immunodeficiency diseases (PIDDs) are clinically and genetically heterogeneous disorders thus far associated with mutations in more than 300 genes. The clinical phenotypes derived from distinct genotypes may overlap. Genetic etiology can be a prognostic indicator of disease severity and can influence treatment decisions. To investigate the ability of whole-exome screening methods to detect disease-causing variants in individuals with PIDDs. Individuals with PIDDs from 278 families from 22 countries were investigated using whole-exome sequencing (WES). Computational CNV prediction pipelines and an exome-tiling chromosomal microarray were also applied to identify intragenic copy number variants (CNVs). Analytic approaches initially focused on 475 known or candidate PIDD genes, but were non-exclusive and were further tailored based upon clinical data, family history and immunophenotyping. A likely molecular diagnosis was achieved in 110 (40%) unrelated probands. Clinical diagnosis was revised in about half (60/110) and management was directly altered in nearly a quarter (26/110) of families based on the molecular findings. Twelve PIDD-causing CNVs were detected, including seven smaller than 30 Kb that would not have been detected with conventional diagnostic CNV arrays. This high-throughput genomic approach enabled detection of disease-related variants in unexpected genes, permitted detection of low-grade constitutional, somatic and revertant mosaicism, and provided evidence of a mutational burden in mixed PIDD immunophenotypes.