Definition of mutations in polyautoimmunity

Angad Johar; Juan C Sarmiento-Monroy; Adriana Rojas-Villarraga; Maria F Silva-Lara; Hardip R Patel; Ruben D Mantilla; Jorge I Velez; Klaus-Martin Schulte; Claudio Mastronardi; Mauricio Arcos-Burgos; Juan-Manuel Anaya

doi:10.1016/j.jaut.2016.05.003

Definition of mutations in polyautoimmunity

J Autoimmun. 2016 Aug:72:65-72. doi: 10.1016/j.jaut.2016.05.003. Epub 2016 May 18.

Affiliations

¹ 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.
² Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad del Rosario, Bogota, Colombia.
³ 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.
⁴ Department of Immunology, John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.
⁵ 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.
⁶ Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad del Rosario, Bogota, Colombia. Electronic address: anayajm@gmail.com.

PMID: 27209085
DOI: 10.1016/j.jaut.2016.05.003

Abstract

Objectives: 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.

Methods: 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.

Results: 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.

Conclusions: Novel and rare variants in genetic linkage with polyautoimmunity were identified throughout WES. Genes harboring these variants might be major players of autoimmunity.

Keywords: Extreme phenotype; Familial autoimmunity; Genetics; Linkage; Network analysis; Polyautoimmunity.

MeSH terms

ATP-Binding Cassette Transporters / genetics
Autoimmunity / genetics*
Base Sequence
Carrier Proteins / genetics
DNA-Binding Proteins / genetics
Exome / genetics
Family Health
Female
Gene Regulatory Networks
Genetic Predisposition to Disease / genetics*
Genomics / methods*
Histone-Lysine N-Methyltransferase
Humans
Lod Score
Male
Mutation*
Pedigree
Phenotype
RNA Helicases / genetics
Receptors, Urokinase Plasminogen Activator / genetics
Sequence Analysis, DNA

Substances

ATP-Binding Cassette Transporters
Carrier Proteins
DNA-Binding Proteins
PLAUR protein, human
Receptors, Urokinase Plasminogen Activator
steroid receptor RNA activator, human
Histone-Lysine N-Methyltransferase
MLL4 protein, human
DHX34 protein, human
RNA Helicases