Functional characterization of 105 factor H variants associated with aHUS: lessons for variant classification.
Functional characterization of 105 factor H variants associated with aHUS: lessons for variant classification.
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与阿胡斯相关的105种H因子变异体的功能特征：变异体分类的经验教训
DOI：
10.1182/blood.2021012037
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发表时间：
2021-12-02
期刊：
影响因子：
20.3
通讯作者：
Rodríguez de Córdoba S
中科院分区：
文献类型：
--
作者：
Martín Merinero H;Zhang Y;Arjona E;Del Angel G;Goodfellow R;Gomez-Rubio E;Ji RR;Michelena M;Smith RJH;Rodríguez de Córdoba S
非典型溶血性尿毒症综合征（aHUS）是一种危及生命的血栓性微血管疾病，由H因子（FH）致病变异引起的补体失调是公认的病因。基因检测在aHUS中的临床应用受到FH基因大量变异报道为“意义不确定的变异”的限制。Martin Merinero及其同事对105个FH变异进行了功能表征，并提供了关键数据，提高了对其临床意义的理解，并应更好地为临床实践提供信息。105个ahus相关FH变异的功能特征揭示了常规变异分类方法的局限性。将预测算法应用于FH域可以显著提高变异分类，而控制数据库中的稀缺性可能会产生误导。非典型溶血性尿毒症综合征（aHUS）是一种危及生命的血栓性微血管疾病，如果不及时治疗，可发展为终末期肾脏疾病。最常见的是，aHUS是由编码补体成分和调节因子的基因的致病性变异引起的补体失调引起的。在这些基因中，因子H （FH）基因CFH出现变异的频率最高（15%至20%），并与最差预后相关。将CFH变异正确分类为致病性或良性对临床护理至关重要，但由于缺乏功能性研究，仍然具有挑战性。结果，大量的变异被报告为不确定意义的变异。为了解决这一知识差距，我们表达了105个ahus相关的FH变异并对其进行了功能表征。所有的FH变异都被分类为致病性或良性，对于每一种，我们都充分记录了致病性的性质。使用26个先前表征的FH变体作为对照，以验证和确认所使用的功能分析的稳健性。在剩下的79个未表征的变异中，只有29个（36.7%）在体外改变FH的表达或功能，因此被认为是致病的。研究表明，对照数据库中的罕见度不能作为变异分类的信息，并确定了将预测算法应用于FH变异的重要限制。基于结构和功能数据，我们提出了克服这些困难的方法，从而改进变异分类。我们的工作强调，如果要个体化和优化aHUS患者的临床护理，需要功能分析来准确解释FH变异。
Atypical hemolytic uremic syndrome (aHUS) is a life-threatening thrombotic microangiopathy, and complement dysregulation due to pathogenic variants in factor H (FH) is a recognized cause. The clinical utility of genetic testing in aHUS is limited by the large number of variants reported as “variants of uncertain significance” for the FH gene. Martin Merinero and colleagues functionally characterized 105 FH variants and provide critical data that improve understanding of their clinical significance and should better informclinical practice. Functional characterization of 105 aHUS-associated FH variants reveals limitations of routinely used variant-classification methods. Adapting prediction algorithms to FH domains markedly improves variant classification, and rarity in control databases can be misleading. Atypical hemolytic uremic syndrome (aHUS) is a life-threatening thrombotic microangiopathy that can progress, when untreated, to end-stage renal disease. Most frequently, aHUS is caused by complement dysregulation due to pathogenic variants in genes that encode complement components and regulators. Among these genes, the factor H (FH) gene, CFH, presents with the highest frequency (15% to 20%) of variants and is associated with the poorest prognosis. Correct classification of CFH variants as pathogenic or benign is essential to clinical care but remains challenging owing to the dearth of functional studies. As a result, significant numbers of variants are reported as variants of uncertain significance. To address this knowledge gap, we expressed and functionally characterized 105 aHUS-associated FH variants. All FH variants were categorized as pathogenic or benign and, for each, we fully documented the nature of the pathogenicity. Twenty-six previously characterized FH variants were used as controls to validate and confirm the robustness of the functional assays used. Of the remaining 79 uncharacterized variants, only 29 (36.7%) alter FH expression or function in vitro and, therefore, are proposed to be pathogenic. We show that rarity in control databases is not informative for variant classification, and we identify important limitations in applying prediction algorithms to FH variants. Based on structural and functional data, we suggest ways to circumvent these difficulties and, thereby, improve variant classification. Our work highlights the need for functional assays to interpret FH variants accurately if clinical care of patients with aHUS is to be individualized and optimized.
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DOI：
10.4049/jimmunol.0804031
发表时间：
2009-06-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Ferreira VP;Herbert AP;Cortés C;McKee KA;Blaum BS;Esswein ST;Uhrín D;Barlow PN;Pangburn MK;Kavanagh D
通讯作者：
Kavanagh D
影响因子：
20.3
作者：
Martin Merinero H;Subías M;Pereda A;Gómez-Rubio E;Juana Lopez L;Fernandez C;Goicoechea de Jorge E;Martin-Santamaria S;Cañada FJ;Rodríguez de Córdoba S
通讯作者：
Rodríguez de Córdoba S
影响因子：
13.6
作者：
de Jorge, Elena Goicoechea;Tortajada, Agustin;de Cordoba, Santiago Rodriguez
通讯作者：
de Cordoba, Santiago Rodriguez
影响因子：
3.6
作者：
Montes, Tamara;Goicoechea de Jorge, Elena;Rodriguez de Cordoba, Santiago
通讯作者：
Rodriguez de Cordoba, Santiago
影响因子：
30.8
作者：
Kircher, Martin;Witten, Daniela M.;Jain, Preti;O'Roak, Brian J.;Cooper, Gregory M.;Shendure, Jay
通讯作者：
Shendure, Jay