Journal article
Functional characterization of 105 factor H variants associated with aHUS: lessons for variant classification
Blood, Vol.138(22), pp.2185-2201
12/02/2021
DOI: 10.1182/blood.2021012037
PMCID: PMC8641096
PMID: 34189567
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.
Details
- Title: Subtitle
- Functional characterization of 105 factor H variants associated with aHUS: lessons for variant classification
- Creators
- Hector Martín Merinero - Centro de Investigaciones Biológicas Margarita SalasYuzhou Zhang - Roy J. and Lucille A. Carver College of MedicineEmilia Arjona - Consejo Superior de Investigaciones CientíficasGuillermo Del Angel - Alexion PharmaRenee Goodfellow - University of IowaElena Gomez-Rubio - Consejo Superior de Investigaciones CientíficasRui-Ru Ji - Alexion PharmaMalkoa Michelena - Consejo Superior de Investigaciones CientíficasRichard J H Smith - University of IowaSantiago Rodriguez de Cordoba - Centro de Investigaciones Biológicas Margarita Salas
- Resource Type
- Journal article
- Publication Details
- Blood, Vol.138(22), pp.2185-2201
- DOI
- 10.1182/blood.2021012037
- PMID
- 34189567
- PMCID
- PMC8641096
- ISSN
- 0006-4971
- eISSN
- 1528-0020
- Grant note
- R01 DK110023 / NIDDK NIH HHS
- Language
- English
- Date published
- 12/02/2021
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Molecular Physiology and Biophysics; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Otolaryngology; Internal Medicine
- Record Identifier
- 9984256929002771
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