Arthritis & Rheumatism, Volume 63,
November 2011 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Chicago, Illinois November 4-9, 2011.

An Insertion Mutation in the MDFIC (MyoD Family Inhibitor Domain Containing) Gene Defines a Novel Autoinflammatory Syndrome Associated with Lymphedema.

Gul1,  Ahmet, Ustek2,  Duran, Hatemi3,  Gulen, Azakli2,  Hulya, Emrence2,  Zeliha, Cosan2,  Fulya, Cakiris2,  Aris

Istanbul University, Istanbul Faculty of Medicine, Istanbul, Turkey
Istanbul University, Istanbul, Turkey
Rheumatology, Istanbul, Turkey


Autoinflammatory syndromes encompass an expanding spectrum of disorders characterized by seemingly unprovoked inflammatory attacks resulting from inborn errors of the innate immune system. 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. 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. Because of autosomal recessive inheritance pattern and availability of 3-generation family members, we aimed to identify the responsible gene using a homozygosity mapping approach.


Genomic DNA was isolated from 18 family members including two index patients; and all were genotyped using the human 370CNV SNP chip of Illumina. Homozygosity mapping was carried out to identify the candidate genomic regions using the SNP Variation Suite v7 of the Golden Helix. A targeted 385K Capture Array was prepared using the genomic DNA of four family members by NimbleGen for the mapped region; and all coding regions 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 by using the classical DNA sequencing method.


All individuals were successfully genotyped using the Illumina 370CNV chips. The homozygosity mapping revealed a 7.8Mb-long region in the long arm of chromosome 7 that was homozygous only in 2 patients and heterozygous in their parents; 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 24 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 changes at position 131 and 132 (p.131 M>N, p.132 H>A) and a frameshift at position 133, which inhibits the translation of its functional cysteine-rich C-terminal domain. This variation was confirmed by sequencing of genomic DNA of all the available family members. None of the screened 200 regionally matched healthy individuals was carrying this variation.


MDFIC gene was identified as the gene responsible for the manifestations of these two patients, who show features of autoinflammatory disorders and a later onset lymphedema. The gene is reported to be expressed in immune cells without a known function, and recent studies have 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 affecting the wnt/beta-catenin pathway, which may also be responsible for the development of lymphedema.

To cite this abstract, please use the following information:
Gul, Ahmet, Ustek, Duran, Hatemi, Gulen, Azakli, Hulya, Emrence, Zeliha, Cosan, Fulya, et al; An Insertion Mutation in the MDFIC (MyoD Family Inhibitor Domain Containing) Gene Defines a Novel Autoinflammatory Syndrome Associated with Lymphedema. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :166

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