title: Comprehensive genetic analysis of complement and coagulation genes in atypical hemolytic uremic syndrome.
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.
authors.affiliation: Interdisciplinary PhD Program in Genetics.
authors.forename: Fengxiao
authors.initials: F
authors.lastname: Bu
authors.forename: Tara
authors.initials: T
authors.lastname: Maga
authors.forename: Nicole C
authors.initials: NC
authors.lastname: Meyer
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.forename: Christie P
authors.initials: CP
authors.lastname: Thomas
authors.forename: Carla M
authors.initials: CM
authors.lastname: Nester
authors.forename: Richard J H
authors.initials: RJ
authors.lastname: Smith
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D065766:Atypical Hemolytic Uremic Syndrome; D001777:Blood Coagulation / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D003170:Complement Pathway, Alternative / Q000235:genetics; D003165:Complement System Proteins / Q000235:genetics*; D017124:Conserved Sequence; D056915:DNA Copy Number Variations; D005260:Female; D005820:Genetic Testing; D014644:Genetic Variation; D006463:Hemolytic-Uremic Syndrome / Q000097:blood* / Q000209:etiology / Q000235:genetics*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010958:Plasminogen / Q000172:deficiency* / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D057049:Thrombotic Microangiopathies / Q000097:blood / Q000235:genetics / Q000276:immunology; D055815:Young Adult
chemical_list: D010958:Plasminogen; D003165:Complement System Proteins
references.citation: Thromb Res. 2011 Feb;127(2):161-6
references.pmid: 21094983
references.citation: Invest Ophthalmol Vis Sci. 2009 Nov;50(11):5070-9
references.pmid: 19553609
references.citation: Br J Haematol. 1991 Aug;78(4):506-14
references.pmid: 1832934
references.citation: Orphanet J Rare Dis. 2011 Sep 08;6:60
references.pmid: 21902819
references.citation: Proc Natl Acad Sci U S A. 2007 Jan 2;104(1):240-5
references.pmid: 17182750
references.citation: Lancet. 1993 Jun 26;341(8861):1665-6
references.pmid: 8100032
references.citation: J Am Soc Nephrol. 2007 Sep;18(9):2457-60
references.pmid: 17687074
references.citation: J Am Soc Nephrol. 2013 Feb;24(3):475-86
references.pmid: 23431077
references.citation: N Engl J Med. 2009 Oct 22;361(17):1676-87
references.pmid: 19846853
references.citation: N Engl J Med. 1992 Sep 10;327(11):755-9
references.pmid: 1501651
references.citation: Hum Mol Genet. 2005 Mar 1;14(5):703-12
references.pmid: 15661753
references.citation: J Med Genet. 2004 Jun;41(6):e84
references.pmid: 15173250
references.citation: Thromb Haemost. 1999 Mar;81(3):338-44
references.pmid: 10102456
references.citation: Nat Genet. 2006 Oct;38(10):1173-7
references.pmid: 16998489
references.citation: Semin Thromb Hemost. 2006 Mar;32(2):113-20
references.pmid: 16575686
references.citation: Virchows Arch. 2013 Apr;462(4):455-64
references.pmid: 23475501
references.citation: Semin Thromb Hemost. 2010 Sep;36(6):641-52
references.pmid: 20865641
references.citation: Blood. 2008 Feb 1;111(3):1512-4
references.pmid: 18006700
references.citation: BMC Med Genet. 2007 Mar 05;8:9
references.pmid: 17338807
references.citation: Nat Genet. 2013 May;45(5):531-6
references.pmid: 23542698
references.citation: Nature. 2010 Oct 28;467(7319):1061-73
references.pmid: 20981092
references.citation: Blood. 1999 May 15;93(10):3457-66
references.pmid: 10233898
references.citation: Am J Transplant. 2008 Jan;8(1):216-21
references.pmid: 17973958
references.citation: J Am Soc Nephrol. 2006 Jul;17(7):2017-25
references.pmid: 16762990
references.citation: Blood. 2013 Jul 11;122(2):282-92
references.pmid: 23692858
references.citation: J Clin Invest. 2003 Apr;111(8):1181-90
references.pmid: 12697737
references.citation: Blood Coagul Fibrinolysis. 2003 Jun;14(4):411-6
references.pmid: 12945885
references.citation: Nat Rev Genet. 2011 Jun;12(6):443-51
references.pmid: 21587300
references.citation: PLoS Med. 2006 Oct;3(10):e431
references.pmid: 17076561
references.citation: J Exp Med. 2007 Jun 11;204(6):1249-56
references.pmid: 17517971
references.citation: Mol Immunol. 2012 Jan;49(4):640-8
references.pmid: 22153652
references.citation: J Immunol. 2012 Feb 15;188(4):2030-7
references.pmid: 22250080
references.citation: Semin Thromb Hemost. 2001 Jun;27(3):201-5
references.pmid: 11446653
references.citation: Am J Kidney Dis. 2004 Jun;43(6):976-82
references.pmid: 15168377
references.citation: Genome Biol. 2010;11(8):R86
references.pmid: 20738864
references.citation: Thromb Haemost. 1997 Jul;78(1):396-400
references.pmid: 9198186
references.citation: Lancet. 2003 Nov 8;362(9395):1542-7
references.pmid: 14615110
references.citation: Blood. 2006 Nov 1;108(9):3021-6
references.pmid: 16849641
references.citation: Blood. 2008 Jun 1;111(11):5307-15
references.pmid: 18268093
references.citation: Kidney Int. 1998 Apr;53(4):836-44
references.pmid: 9551389
references.citation: BMC Biotechnol. 2012 May 04;12:20
references.pmid: 22559009
references.citation: Kidney Int. 1998 Oct;54(4):1324-30
references.pmid: 9767551
references.citation: Proc Natl Acad Sci U S A. 2003 Oct 28;100(22):12966-71
references.pmid: 14566051
references.citation: Thromb Haemost. 1997 Jul;78(1):392-5
references.pmid: 9198185
references.citation: Semin Nephrol. 2012 Mar;32(2):208-14
references.pmid: 22617770
references.citation: Hum Mol Genet. 1995 Jul;4(7):1235-7
references.pmid: 8528215
references.citation: BMC Bioinformatics. 2008 Jun 04;9:261
references.pmid: 18522760
references.citation: N Engl J Med. 2002 Jan 3;346(1):23-32
references.pmid: 11777999
references.citation: Blood. 2008 Dec 15;112(13):4948-52
references.pmid: 18796626
references.citation: Hum Mutat. 2010 Jun;31(6):E1445-60
references.pmid: 20513133
references.citation: PLoS Genet. 2007 Mar 16;3(3):e41
references.pmid: 17367211
references.citation: Pediatr Nephrol. 2010 Dec;25(12):2431-42
references.pmid: 20526633
references.citation: Blood. 2010 Jan 14;115(2):379-87
references.pmid: 19861685
references.citation: N Engl J Med. 2009 Jul 23;361(4):345-57
references.pmid: 19625716
references.citation: J Immunol. 1997 May 15;158(10):5043-9
references.pmid: 9144525