Introduction
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Autoinflammatory disorders are disorders of the innate immune system. Standard genetic testing provided no correct diagnosis in a female patient from a non-consanguineous family of British descent with a colchicine-responsive autosomal dominant periodic fever syndrome.

Objectives
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We aimed to unravel the genetic cause of the symptoms in this family.

Methods
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Whole exome sequencing was used to screen for novel sequence variants, which were validated by direct Sanger sequencing. Ex-vivo stimulations with peripheral blood mononuclear cells were done to study the functional consequences of the mutation. mRNA and cytokine levels were measured by q-PCR and ELISA, respectively.

Results
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Whole exome sequencing revealed a novel missense sequence variant, not seen in around 6800 controls, mapping to exon 8 of the *MEFV* gene (c.1730C\>A; p.T577N), co-segregating perfectly with disease in this family. Other mutations at the same amino acid (c.1730C\>G; p.T577S; c.1729A\>T; p.T577S) were found in a family of Turkish descent, with autosomal dominant inheritance of FMF-like phenotype, and a Dutch patient, respectively. Moreover, a mutation (c.1729A\>G; p.T577A) was detected in 2 Dutch siblings, suffering from episodes of inflammation of varying severity not resembling FMF. PBMCs from one patient of the index family revealed increased basal IL-1β mRNA levels and cytokine responses after LPS stimulation. Responses normalized under colchicine treatment.

Conclusion
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Heterozygous mutations at amino acid position 577 of pyrin can induce an autosomal dominant autoinflammatory syndrome. This suggests that T577, located in front of the C-terminal B30.2/SPRY domain, is crucial for pyrin function.

Disclosure of interest
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M. Stoffels: None declared, A. Szperl: None declared, A. Simon Consultant for: Novartis and Swedish Orphan Biovitrum, M. Netea: None declared, T. Plantinga: None declared, M. van Deuren: None declared, S. Kamphuis: None declared, H. Lachmann: None declared, E. Cuppen: None declared, W. Kloosterman: None declared, J. Frenkel Consultant for: Novartis and Swedish Orphan Biovitrum, C. van Diemen: None declared, C. Wijmenga: None declared, M. van Gijn: None declared, J. van der Meer Consultant for: Novartis and Swedish Orphan Biovitrum
