TY - JOUR
T1 - Definition of mutations in polyautoimmunity
AU - Johar, Angad
AU - Sarmiento-Monroy, Juan C.
AU - Rojas-Villarraga, Adriana
AU - Silva-Lara, Maria F.
AU - Patel, Hardip R.
AU - Mantilla, Ruben D.
AU - Velez, Jorge I.
AU - Schulte, Klaus Martin
AU - Mastronardi, Claudio
AU - Arcos-Burgos, Mauricio
AU - Anaya, Juan Manuel
N1 - Funding Information:
We thank the patients and their families for their cooperation, and the members of the Center for Autoimmune Diseases Research (CREA) for fruitful discussions. Supported by grants from Colciencias ( 373-2011, 0425-2013 ) and the School of Medicine and Health Sciences , Universidad del Rosario ( ABN011 ), Bogota, Colombia.
Publisher Copyright:
© 2016 Elsevier Ltd
Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 2016/8/1
Y1 - 2016/8/1
N2 - 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.
AB - 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.
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U2 - 10.1016/j.jaut.2016.05.003
DO - 10.1016/j.jaut.2016.05.003
M3 - Research Article
C2 - 27209085
AN - SCOPUS:84975472133
SN - 0896-8411
VL - 72
SP - 65
EP - 72
JO - Journal of Autoimmunity
JF - Journal of Autoimmunity
ER -