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Pseudodominance of autoinflammatory disease in a single Turkish family explained by co-inheritance of haploinsufficiency of A20 and familial Mediterranean fever

1, 2, 3, 4, 5

  1. Inflammatory Disease Section, National Human Genome Research Institute, US National Institutes of Health, Bethesda, MD, USA.
  2. Department of Internal Medicine, Division of Rheumatology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.
  3. Inflammatory Disease Section, National Human Genome Research Institute, US National Institutes of Health, Bethesda, MD, USA.
  4. Inflammatory Disease Section, National Human Genome Research Institute, US National Institutes of Health, Bethesda, MD, USA.
  5. Inflammatory Disease Section, National Human Genome Research Institute, US National Institutes of Health, Bethesda, MD, USA. elaine.remmers@nih.gov

CER12301 Submission on line
Full Papers

Rheumatology Article

 

Abstract

OBJECTIVES:
We investigated a Turkish family with multiple patients presenting with familial Mediterranean fever (FMF) and Behçet’s disease (BD)-like manifestations. The index case and the two daughters with Behçet-like disease, were previously found to have a TNFAIP3 frameshift mutation. The high number of affected cases in this expanded family could be consistent with a dominantly inherited inflammatory disease, although some individuals had clinical features more consistent with recessively inherited FMF. We sequenced DNA from members of this family to determine whether the TNFAIP3 frameshift mutation and/or MEFV variants could explain this autoinflammatory disease pedigree.
METHODS:
Patients were clinically diagnosed to have FMF or BD. Sanger sequence targeting TNFAIP3 exon 5 and MEFV exon 10 was carried out.
RESULTS:
The symptomatic mother of the index case and her affected maternal uncle had compound heterozygous FMF-associated MEFV mutations, p.Met680Ile and p.Arg761His. Two affected daughters of the maternal uncle also had compound heterozygous FMF-associated mutations, p.Met680Ile and p.Val726Ala. The index case and her two affected daughters had a TNFAIP3 frameshift mutation (c.799delG; p.Pro268Leufs*19), which is consistent with their HA20 diagnosis, and also carried a heterozygous MEFV p.Arg761His mutation.
CONCLUSIONS:
Autoinflammatory disease manifestations in a Turkish family with multiple affected cases could be explained by co-inheritance of pathogenic MEFV variants and a heterozygous HA20-associated mutation. FMF-associated p.Arg761His allele carried with the loss of function TNFAIP3 mutation by all three HA20 patients may contribute to their autoinflammatory phenotype and could also be responsible for their favourable response to colchicine.

PMID: 31376265 [PubMed]

Received: 05/04/2019 - Accepted : 18/06/2019 - In Press: 15/07/2019