AN INSERTION MUTATION IN THE MDFIC (MYOD FAMILY INHIBITOR DOMAIN CONTAINING) GENE DEFINES A NOVEL AUTOINFLAMMATORY SYNDROME ASSOCIATED WITH LYMPHEDEMA

Background: We previously described two patients, who were second degree cousins with shared features of recurrent inflammatory attacks lasting 3-10 days since the first year of life, quite similar to other inherited autoinflammatory disorders. These attacks are characterized by fever, erythematous/urticarial rash with hyperesthesia, serositis and edema on the face and extremities. The latter feature did not resolve completely between the attacks later in the course of the disease, and both patients eventually developed a lymphedema symmetrically affecting lower extremities and genitalia. Objectives: We aimed to identify the responsible gene using a homozygosity mapping because of autosomal recessive inheritance pattern and availability of 3-generation family members. Methods: Genomic DNA was isolated from 18 family members including two index patients, their parents, siblings, and grandparents; and all were genotyped using the human 370CNV SNP chip of Illumina. Homozygosity mapping was carried out to identify the candidate genomic regions using SNP Variation Suite version 7 of the Golden Helix software. A targeted 385K Capture Array was prepared using genomic DNA of 4 family members by NimbleGen for mapped region, and all exons of the known genes were then deep sequenced using the GS-FLX 454 Titanium system (Roche Diagnostics). Confirmation of the identified variation and screening of healthy controls were done with classical DNA sequencing. Results: All individuals were successfully genotyped, and the homozygosity mapping revealed a 7.8Mb-long region in the long arm of chromosome 7 that was homozygous only in 2 patients; and a smaller homozygous segment was also identified in chromosome 14. We searched the mapped Chr7q31.1 region by exon sequencing of the all known 23 genes using the GS-FLX 454 system in the two index patients, one parent and one sibling. A homozygous insertion mutation in the exon 3 of the MyoD family inhibitor domain containing gene (MDFIC) was identified only in two index patients. MDFIC is a 247 amino acid long protein, and this insertion causes an amino acid change at position 131 (p.131 M>N) and a frameshift at position 132, which inhibits the translation of its functional cysteine-rich C-terminal domain. This variation was confirmed with DNA sequencing in all of the family members. None of the screened 100 regionally matched healthy individuals was carrying this variation. Conclusions: MDFIC gene was identified as the gene responsible for the manifestations of the two patients showing features of autoinflammatory disorders and a later onset lymphedema. The gene has been known to be expressed in immune cells without a clear function, and recent studies indicated a role in the regulation of wnt/beta-catenin pathway. We suggest that this is a novel type of autoinflammatory disorder, and a loss-of-function mutation in the MDFIC gene may be associated with a dysregulated inflammatory response and a tendency for fibrosis during repair, which may be responsible for the development of lymphedema. Disclosure of Interest: None DeclaredCitation: Annals of the Rheumatic Diseases, volume 70, supplement 3, year 2011, page 147Session: Abstract Session: Genomics, genetics and epigenetics of rheumatic diseases (Oral Presentations )