Journal article
Comprehensive genetic analysis of complement and coagulation genes in atypical hemolytic uremic syndrome
Journal of the American Society of Nephrology, Vol.25(1), pp.55-64
01/2014
DOI: 10.1681/ASN.2013050453
PMCID: PMC3871781
PMID: 24029428
Abstract
Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy caused by uncontrolled activation of the alternative pathway of complement at the cell surface level that leads to microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney failure. In approximately one half of affected patients, pathogenic loss-of-function variants in regulators of complement or gain-of-function variants in effectors of complement are identified, clearly implicating complement in aHUS. However, there are strong lines of evidence supporting the presence of additional genetic contributions to this disease. To identify novel aHUS-associated genes, we completed a comprehensive screen of the complement and coagulation pathways in 36 patients with sporadic aHUS using targeted genomic enrichment and massively parallel sequencing. After variant calling, quality control, and hard filtering, we identified 84 reported or novel nonsynonymous variants, 22 of which have been previously associated with disease. Using computational prediction methods, 20 of the remaining 62 variants were predicted to be deleterious. Consistent with published data, nearly one half of these 42 variants (19; 45%) were found in genes implicated in the pathogenesis of aHUS. Several genes in the coagulation pathway were also identified as important in the pathogenesis of aHUS. PLG, in particular, carried more pathogenic variants than any other coagulation gene, including three known plasminogen deficiency mutations and a predicted pathogenic variant. These data suggest that mutation screening in patients with aHUS should be broadened to include genes in the coagulation pathway.
Details
- Title: Subtitle
- Comprehensive genetic analysis of complement and coagulation genes in atypical hemolytic uremic syndrome
- Creators
- Fengxiao Bu - Interdisciplinary PhD Program in GeneticsTara MagaNicole C MeyerKai WangChristie P ThomasCarla M NesterRichard J H Smith
- Resource Type
- Journal article
- Publication Details
- Journal of the American Society of Nephrology, Vol.25(1), pp.55-64
- DOI
- 10.1681/ASN.2013050453
- PMID
- 24029428
- PMCID
- PMC3871781
- NLM abbreviation
- J Am Soc Nephrol
- ISSN
- 1046-6673
- eISSN
- 1533-3450
- Publisher
- United States
- Grant note
- T32 GM008629 / NIGMS NIH HHS
- Language
- English
- Date published
- 01/2014
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Molecular Physiology and Biophysics; Anatomy and Cell Biology; Nephrology, Dialysis and Transplantation; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Biostatistics; Obstetrics and Gynecology; Otolaryngology; Internal Medicine
- Record Identifier
- 9983986084002771
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