Functional characterization of 105 Factor H variants associated with HUS:lessons for variant classification
| Autor: | Emilia Arjona, Malkoa Michelena, Elena Gómez-Rubio, Richard J.H. Smith, Rui-Ru Ji, Renee X. Goodfellow, Yuzhou Zhang, Héctor Martín Merinero, Santiago Rodríguez de Córdoba, Guillermo del Angel |
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| Přispěvatelé: | Ministerio de Economía y Competitividad (España), Comunidad de Madrid, National Institute of Diabetes and Digestive and Kidney Diseases (US), Alexion Pharmaceuticals, Oxford PharmaGenesis, Martín Merinero, Héctor, Arjona, Emilia, Del Ángel, Guillermo, Gomez-Rubio, Elena, Ji, Rui-Ru, Rodríguez de Córdoba, Santiago, Martín Merinero, Héctor [0000-0002-9094-5934], Arjona, Emilia [0000-0002-0753-3657], Del Ángel, Guillermo [0000-0002-0104-1563], Gomez-Rubio, Elena [0000-0002-8037-4007], Ji, Rui-Ru [0000-0003-3795-9840], Rodríguez de Córdoba, Santiago [0000-0001-6401-1874] |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Models
Molecular Thrombotic microangiopathy Immunobiology and Immunotherapy Atypical hemolytic uremic syndrome Immunology Complement Gene Expression Disease Biology urologic and male genital diseases Biochemistry Polymorphism Single Nucleotide medicine Humans Point Mutation Genetic Predisposition to Disease Functional studies Uncertain significance Gene Functional assays Genetics Factor H Robustness (evolution) Genetic Variation Cell Biology Hematology medicine.disease Recombinant Proteins Complement Factor H Pathogenicity prediction Function (biology) |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname Blood Digital.CSIC: Repositorio Institucional del CSIC Consejo Superior de Investigaciones Científicas (CSIC) |
| Popis: | 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. Key Points 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. Visual Abstract 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. |
| Databáze: | OpenAIRE |
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