title: Novel and rare functional genomic variants in multiple autoimmune syndrome and Sjögren's syndrome.
abstract: BACKGROUND
  Multiple autoimmune syndrome (MAS), an extreme phenotype of autoimmune disorders, is a very well suited trait to tackle genomic variants of these conditions. Whole exome sequencing (WES) is a widely used strategy for detection of protein coding and splicing variants associated with inherited diseases.
  
  
  METHODS
  The DNA of eight patients affected by MAS [all of whom presenting with Sjögren's syndrome (SS)], four patients affected by SS alone and 38 unaffected individuals, were subject to WES. Filters to identify novel and rare functional (pathogenic-deleterious) homozygous and/or compound heterozygous variants in these patients and controls were applied. Bioinformatics tools such as the Human gene connectome as well as pathway and network analysis were applied to test overrepresentation of genes harbouring these variants in critical pathways and networks involved in autoimmunity.
  
  
  RESULTS
  Eleven novel and rare functional variants were identified in cases but not in controls, harboured in: MACF1, KIAA0754, DUSP12, ICA1, CELA1, LRP1/STAT6, GRIN3B, ANKLE1, TMEM161A, and FKRP. These were subsequently subject to network analysis and their functional relatedness to genes already associated with autoimmunity was evaluated. Notably, the LRP1/STAT6 novel mutation was homozygous in one MAS affected patient and heterozygous in another. LRP1/STAT6 disclosed the strongest plausibility for autoimmunity. LRP1/STAT6 are involved in extracellular and intracellular anti-inflammatory pathways that play key roles in maintaining the homeostasis of the immune system. Further; networks, pathways, and interaction analyses showed that LRP1 is functionally related to the HLA-B and IL10 genes and it has a substantial impact within immunological pathways and/or reaction to bacterial and other foreign proteins (phagocytosis, regulation of phospholipase A2 activity, negative regulation of apoptosis and response to lipopolysaccharides). Further, ICA1 and STAT6 were also closely related to AIRE and IRF5, two very well known autoimmunity genes.
  
  
  CONCLUSIONS
  Novel and rare exonic mutations that may account for autoimmunity were identified. Among those, the LRP1/STAT6 novel mutation has the strongest case for being categorised as potentially causative of MAS given the presence of intriguing patterns of functional interaction with other major genes shaping autoimmunity.
authors.affiliation: Genomics and Predictive Medicine, Genome Biology Department, John Curtin School of Medical Research, ANU College of Medicine, Biology and Environment, The Australian National University, Canberra, ACT, Australia. u4842377@anu.edu.au.
authors.forename: Angad S
authors.initials: AS
authors.lastname: Johar
authors.affiliation: Genomics and Predictive Medicine, Genome Biology Department, John Curtin School of Medical Research, ANU College of Medicine, Biology and Environment, The Australian National University, Canberra, ACT, Australia. claudio.mastronardi@anu.edu.au.
authors.forename: Claudio
authors.initials: C
authors.lastname: Mastronardi
authors.affiliation: Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad del Rosario, Bogota, Colombia. adrirojas@gmail.com.
authors.forename: Adriana
authors.initials: A
authors.lastname: Rojas-Villarraga
authors.affiliation: Genome Discovery Unit, Genome Biology Department, John Curtin School of Medical Research, ANU College of Medicine, Biology and Environment, The Australian National University, Canberra, ACT, Australia. Hardip.Patel@anu.edu.au.
authors.forename: Hardip R
authors.initials: HR
authors.lastname: Patel
authors.affiliation: Genome Discovery Unit, Genome Biology Department, John Curtin School of Medical Research, ANU College of Medicine, Biology and Environment, The Australian National University, Canberra, ACT, Australia. Aaron.Chuah@anu.edu.au.
authors.forename: Aaron
authors.initials: A
authors.lastname: Chuah
authors.affiliation: Biomolecular Resource Facility, John Curtin School of Medical Research, ANU College of Medicine, Biology and Environment, The Australian National University, Canberra, ACT, Australia. kaiman.peng@anu.edu.au.
authors.forename: Kaiman
authors.initials: K
authors.lastname: Peng
authors.affiliation: Biomolecular Resource Facility, John Curtin School of Medical Research, ANU College of Medicine, Biology and Environment, The Australian National University, Canberra, ACT, Australia. angela.higgins@anu.edu.au.
authors.forename: Angela
authors.initials: A
authors.lastname: Higgins
authors.affiliation: Biomolecular Resource Facility, John Curtin School of Medical Research, ANU College of Medicine, Biology and Environment, The Australian National University, Canberra, ACT, Australia. peter.milburn@anu.edu.au.
authors.forename: Peter
authors.initials: P
authors.lastname: Milburn
authors.affiliation: Biomolecular Resource Facility, John Curtin School of Medical Research, ANU College of Medicine, Biology and Environment, The Australian National University, Canberra, ACT, Australia. stephanie.palmer@anu.edu.au.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Palmer
authors.affiliation: Genomics and Predictive Medicine, Genome Biology Department, John Curtin School of Medical Research, ANU College of Medicine, Biology and Environment, The Australian National University, Canberra, ACT, Australia. maria.silva@anu.edu.au.
authors.forename: Maria Fernanda
authors.initials: MF
authors.lastname: Silva-Lara
authors.affiliation: Genomics and Predictive Medicine, Genome Biology Department, John Curtin School of Medical Research, ANU College of Medicine, Biology and Environment, The Australian National University, Canberra, ACT, Australia. jorge.velez@anu.edu.au.
authors.forename: Jorge I
authors.initials: JI
authors.lastname: Velez
authors.affiliation: Immunogenomics and Bioinformatics Group, Immunology Department, John Curtin School of Medical Research, ANU College of Medicine, Biology and Environment, The Australian National University, Canberra, ACT, Australia. dan.andrews@anu.edu.au.
authors.forename: Dan
authors.initials: D
authors.lastname: Andrews
authors.affiliation: Immunogenomics and Bioinformatics Group, Immunology Department, John Curtin School of Medical Research, ANU College of Medicine, Biology and Environment, The Australian National University, Canberra, ACT, Australia. matthew.field@anu.edu.au.
authors.forename: Matthew
authors.initials: M
authors.lastname: Field
authors.affiliation: Biomolecular Resource Facility, John Curtin School of Medical Research, ANU College of Medicine, Biology and Environment, The Australian National University, Canberra, ACT, Australia. gavin.huttley@anu.edu.au.
authors.forename: Gavin
authors.initials: G
authors.lastname: Huttley
authors.affiliation: Immunogenomics and Bioinformatics Group, Immunology Department, John Curtin School of Medical Research, ANU College of Medicine, Biology and Environment, The Australian National University, Canberra, ACT, Australia. chris.goodnow@anu.edu.au.
authors.forename: Chris
authors.initials: C
authors.lastname: Goodnow
authors.affiliation: Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad del Rosario, Bogota, Colombia. anayajm@gmail.com.
authors.forename: Juan-Manuel
authors.initials: JM
authors.lastname: Anaya
authors.affiliation: Genomics and Predictive Medicine, Genome Biology Department, John Curtin School of Medical Research, ANU College of Medicine, Biology and Environment, The Australian National University, Canberra, ACT, Australia. mauricio.arcos-burgos@anu.edu.au.
authors.forename: Mauricio
authors.initials: M
authors.lastname: Arcos-Burgos
mesh_terms: D000328:Adult; D000368:Aged; D015551:Autoimmunity / Q000235:genetics; D001483:Base Sequence; D016022:Case-Control Studies; D063132:Connectome; D005260:Female; D053263:Gene Regulatory Networks; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D006801:Humans; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D012859:Sjogren's Syndrome / Q000235:genetics*