Background/Purpose

Fibroblastic Rheumatism is a rare disease, first described in 1980 with almost 30 cases reported thus far. One-third of the patients are children. The disease is characterized by sudden and rapidly progressive symmetric arthritis in large and small joints with cutaneous nodules over hands and para-articular sites. Sclerodactyly with thickened palmar fascia and Raynaud’s phenomenon can also be seen. Laboratory tests are usually normal and the diagnosis is based on the histology of the nodules. The etiology of the disease is unknown and no genetic testing has been published on patients with fibroblastic rheumatism to date.

The objective of this study was to identify possible causative candidate genes for this disease using whole exome sequencing.

Methods

We performed exome sequencing analysis on the DNA of a 14 year old patient with biopsy-proven fibroblastic rheumatism and her unaffected brother. It was performed at Perkin Elmer DNA Sequencing and Analysis Branford, CT. Target enrichment was performed using Illumina TruSeq Exome capture.  Sequencing was performed on an Illumina HiSeq 2000. Alignment and variant calls were made using the Broad Institute’s Genome Analysis Toolkit (GATK). Variant calls were analyzed using Golden Helix SNP and Variation Suite ver 7.7.5.

We focused on candidate variations that altered the amino-acid sequence of a protein and followed either a recessive homozygous, compound heterozygous or dominant model. Genotypes common with the unaffected sibling were removed as candidates.

Results

After quality control filtering and requiring a minor allele frequency of  ≤1% in the general population, we identified 191 different candidate variations. Of those, 156 mutations fit a dominant model in which the patient was heterozygous for the polymorphism; 6 were recessive homozygous and 29 were compound heterozygous variants in 14 genes.

Several interesting candidate genes causing variants in the dominant model were identified (Table).

Conclusion

Although we did not identify one strong candidate gene, these results will form a basis for comparison to variants identified in other patients. If this is, indeed, a disorder with genetic etiology, we believe the identification of one responsible gene can assist in future genetic research of other arthritic syndromes.Table

Mutation	Gene name	Amino acid	Protein function	Related to disease
1:151804213 Stopgain	RORC [RAR related orphan receptor C]	Arg10	DNA-binding transcription factor and member of the NR1 subfamily of nuclear hormone receptors. In mice this gene inhibits the expression of FAS ligand and IL2	Dermatitis; one suspect gene for Systemic lupus Erythematosus (SLE).
4:99027142 Stopgain	C4orf37/ STPG2 [Sperm-Tail PG-Rich Repeat-Containing 2]	Arg192	No known function	Rheumatoid arthritis and response to anti TNF alpha medication
1:201182308 Stopgain	IGFN1 [immunoglobulin-like and fibronectin type III domain containing 1]	Gln2763	protein-coding gene	Muscular dystrophy; bone repair.
5:70860710 Stoploss	BDP1/ PTPN18 [Protein Tyrosine Phosphatase, Non-Receptor Type 18]	Glu12	The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. The encoded protein localizes to aggregates in the nucleus, and is required for transcription from all three types of polymerase III promoters	Rheumatoid arthritis and response to anti TNF alpha medication; Pyoderma gangrenosum

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/whole-exome-sequencing-analysis-performed-on-a-patient-with-fibroblastic-rheumatism/