Background The Synovitis, Acne, Pustulosis, Hyperostosis and Osteitis (SAPHO) syndrome is a rare autoinflammatory disorder of skin and bone that can be classified with the inflammatory spondyloarthropathies (1). Genetic predisposing factors for SAPHO syndrome have been long suspected because of (i) reported familial clustering of the syndrome - although most cases are sporadic - (2), and (ii) the existence of two mouse models of the syndrome (the cmo and Lupo strains), each with a different spontaneous recessive mutation in the Pstpip2 gene (3,4). Previous studies excluded a role for the genes PSTPIP2, LPIN, NOD2, IL1RL2, IL1RN, IL36RN and SIGLEC15 in the pathogenesis of the syndrome (5,6).
Objectives Identify and validate candidate genes involved in the pathogenesis of familial SAPHO syndrome by performing whole-exome sequencing (WES) of affected subjects and unaffected relatives.
Methods We investigated a cohort of 44 SAPHO subjects that includes 5 families segregating the syndrome. After obtaining written informed consent, we extracted DNA from peripheral blood samples by using automated magnetic-bead technology (Chemagen). Exomes captured with Agilent SureSelect V5+UTR kit were subjected to paired-end sequencing on an Illumina HiSeq200 sequencer (Sistemas Genόmicos). Candidate genes and putatively pathogenic variants were identified by using Variant Analysis software (Ingenuity). Validation was undertaken by Sanger sequencing, segregation analysis and functional assays when appropriate.
Results We identified several potentially pathogenic variants in our cohort in genes whose products are potentially involved in the pathogenesis of SAPHO syndrome. In affected subjects we also found variants known to predispose to autoinflammatory/autoimmune disease in genes such as NOD2/CARD15.
Conclusions WES is a very powerful tool to investigate the genetic factors underlying rare inherited autoinflammatory disorders that cannot be analyzed by classical genetic methods such as positional cloning.
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Disclosure of Interest : None declared
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