title: Private rare deletions in SEC16A and MAMDC4 may represent novel pathogenic variants in familial axial spondyloarthritis.
abstract: OBJECTIVE
  Axial spondyloarthritis (AxSpA) represents a group of inflammatory axial diseases that share common clinical and histopathological manifestations. Ankylosing spondylitis (AS) is the best characterised subset of AxSpA, and its genetic basis has been extensively investigated. Given that genome-wide association studies account for only 25% of AS heritability, the objective of this study was to discover rare, highly penetrant genetic variants in AxSpA pathogenesis using a well-characterised, multigenerational family.
  
  
  METHODS
  HLA-B*27 genotyping and exome sequencing was performed on DNA collected from available family members. Variant frequency was assessed by mining publically available datasets and using fragment analysis of unrelated AxSpA cases and unaffected controls. Gene expression was performed by qPCR, and protein expression was assessed by western blot analysis and immunofluorescence microscopy using patient-derived B-cell lines. Circular dichroism spectroscopy was performed to assess the impact of discovered variants on secondary structure.
  
  
  RESULTS
  This is the first report identifying two rare private familial variants in a multigenerational AxSpA family, an in-frame SEC16A deletion and an out-of-frame MAMDC4 deletion. Evidence suggests the causative mechanism for SEC16A appears to be a conformational change induced by deletion of three highly conserved amino acids from the intrinsically disordered Sec16A N-terminus and RNA-mediated decay for MAMDC4.
  
  
  CONCLUSIONS
  The results suggest that it is the presence of rare syntenic SEC16A and MAMDC4 deletions that increases susceptibility to AxSpA in family members who carry the HLA-B*27 allele.
authors.affiliation: Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada.
authors.forename: Darren D
authors.initials: DD
authors.lastname: O'Rielly
authors.affiliation: Program in Genetics and Genome Biology, The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Uddin
authors.affiliation: Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada.
authors.forename: Dianne
authors.initials: D
authors.lastname: Codner
authors.affiliation: Biochemistry Department, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Hayley
authors.affiliation: Department of Computer Science, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada.
authors.forename: Jiayi
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Computer Science, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada.
authors.forename: Lourdes
authors.initials: L
authors.lastname: Pena-Castillo
authors.affiliation: Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada.
authors.forename: Ahmed A
authors.initials: AA
authors.lastname: Mostafa
authors.affiliation: Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada.
authors.forename: S M Mahmudul
authors.initials: SM
authors.lastname: Hasan
authors.affiliation: Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada.
authors.forename: William
authors.initials: W
authors.lastname: Liu
authors.affiliation: Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Nigil
authors.initials: N
authors.lastname: Haroon
authors.affiliation: Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Robert
authors.initials: R
authors.lastname: Inman
authors.affiliation: Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada.
authors.forename: Proton
authors.initials: P
authors.lastname: Rahman
mesh_terms: D000293:Adolescent; D000328:Adult; D001402:B-Lymphocytes / Q000378:metabolism*; D015153:Blotting, Western; D002648:Child; D002872:Chromosome Deletion; D002879:Chromosomes, Human, Pair 10; D002942:Circular Dichroism; D005260:Female; D008040:Genetic Linkage; D015796:HLA-B27 Antigen / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D008297:Male; D008856:Microscopy, Fluorescence; D009154:Mutation; D010375:Pedigree; D016133:Polymerase Chain Reaction; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D025242:Spondylarthropathies / Q000235:genetics*; D033921:Vesicular Transport Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D015796:HLA-B27 Antigen; D011506:Proteins; C517555:SEC16A protein, human; D033921:Vesicular Transport Proteins
keywords: Ankylosing Spondylitis; Autoimmune Diseases; Inflammation; Low Back Pain; Spondyloarthritis