title: Definition of mutations in polyautoimmunity.
abstract: Familial autoimmunity and polyautoimmunity represent extreme phenotypes ideal for identifying major genomic variants contributing to autoimmunity. Whole exome sequencing (WES) and linkage analysis are well suited for this purpose due to its strong resolution upon familial segregation patterns of functional protein coding and splice variants. The primary objective of this study was to identify potentially autoimmune causative variants using WES data from extreme pedigrees segregating polyautoimmunity phenotypes.
  
  
  
  DNA of 47 individuals across 10 extreme pedigrees, ascertained from probands affected with polyautoimmunity and familial autoimmunity, were selected for WES. Variant calls were obtained through Genome Analysis Toolkit. Filtration and prioritization framework to identify mutation(s) were applied, and later implemented for genetic linkage analysis. Sanger sequencing corroborated variants with significant linkage.
  
  
  
  Novel and mostly rare variants harbored in SRA1, MLL4, ABCB8, DHX34 and PLAUR showed significant linkage (LOD scores are >3.0). The strongest signal was in SRA1, with a LOD score of 5.48. Network analyses indicated that SRA1, PLAUR and ABCB8 contribute to regulation of apoptotic processes.
  
  
  
  Novel and rare variants in genetic linkage with polyautoimmunity were identified throughout WES. Genes harboring these variants might be major players of autoimmunity.
authors.affiliation: Genomics and Predictive Medicine, Genome Biology Department, John Curtin School of Medical Research, ANU College of Medicine, Biology & Environment, The Australian National University, Canberra, ACT, Australia.
authors.forename: Angad
authors.initials: A
authors.lastname: Johar
authors.affiliation: Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad del Rosario, Bogota, Colombia.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Sarmiento-Monroy
authors.affiliation: Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad del Rosario, Bogota, Colombia.
authors.forename: Adriana
authors.initials: A
authors.lastname: Rojas-Villarraga
authors.affiliation: Genomics and Predictive Medicine, Genome Biology Department, John Curtin School of Medical Research, ANU College of Medicine, Biology & Environment, The Australian National University, Canberra, ACT, Australia.
authors.forename: Maria F
authors.initials: MF
authors.lastname: Silva-Lara
authors.affiliation: Genome Discovery Unit, Genome Biology Department, John Curtin School of Medical Research, ANU College of Medicine, Biology & Environment, The Australian National University, Canberra, ACT, Australia.
authors.forename: Hardip R
authors.initials: HR
authors.lastname: Patel
authors.affiliation: Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad del Rosario, Bogota, Colombia.
authors.forename: Ruben D
authors.initials: RD
authors.lastname: Mantilla
authors.affiliation: Genomics and Predictive Medicine, Genome Biology Department, John Curtin School of Medical Research, ANU College of Medicine, Biology & Environment, The Australian National University, Canberra, ACT, Australia.
authors.forename: Jorge I
authors.initials: JI
authors.lastname: Velez
authors.affiliation: Department of Immunology, John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.
authors.forename: Klaus-Martin
authors.initials: KM
authors.lastname: Schulte
authors.affiliation: Genomics and Predictive Medicine, Genome Biology Department, John Curtin School of Medical Research, ANU College of Medicine, Biology & Environment, The Australian National University, Canberra, ACT, Australia.
authors.forename: Claudio
authors.initials: C
authors.lastname: Mastronardi
authors.affiliation: Genomics and Predictive Medicine, Genome Biology Department, John Curtin School of Medical Research, ANU College of Medicine, Biology & Environment, The Australian National University, Canberra, ACT, Australia; Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad del Rosario, Bogota, Colombia. Electronic address: Mauricio.Arcos-Burgos@anu.edu.au.
authors.forename: Mauricio
authors.initials: M
authors.lastname: Arcos-Burgos
authors.affiliation: Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad del Rosario, Bogota, Colombia. Electronic address: anayajm@gmail.com.
authors.forename: Juan-Manuel
authors.initials: JM
authors.lastname: Anaya
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D015551:Autoimmunity / Q000235:genetics*; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D059472:Exome / Q000235:genetics; D005192:Family Health; D005260:Female; D053263:Gene Regulatory Networks; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D023281:Genomics / Q000379:methods*; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D008126:Lod Score; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D020365:RNA Helicases / Q000235:genetics; D055293:Receptors, Urokinase Plasminogen Activator / Q000235:genetics; D017422:Sequence Analysis, DNA
chemical_list: D018528:ATP-Binding Cassette Transporters; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C524898:PLAUR protein, human; D055293:Receptors, Urokinase Plasminogen Activator; C548898:steroid receptor RNA activator, human; D011495:Histone-Lysine N-Methyltransferase; C530816:MLL4 protein, human; C559844:DHX34 protein, human; D020365:RNA Helicases
keywords: Extreme phenotype; Familial autoimmunity; Genetics; Linkage; Network analysis; Polyautoimmunity