Pediatric Granulomatous Arthritis via the NOD2 Gene

Pediatric Granulomatous Arthritis (PGA) is an autoinflammatory syndrome due to pathogenic variants in the NOD2 gene and is hallmarked by granulomatous inflammation of eyes, joints, and skin. Chronic arthritis occurs within the first decade of life. Joint inflammation occurs in all cases of PGA and starts with minimal swelling in wrists, knees, and elbows but progresses to flexion contractures in fingers. Uveitis occurs in about 80% of cases with patients developing bilateral panuveitis. Progressive inflammation can also results in cataract, glaucoma, and synechiae. In some cases, fever, central neuropathy, arteritis, and granulomatous involvement of visceral organs has been reported. There are two different forms of PGA with identical phenotypes, Blau Syndrome and Early Onset Sarcoidosis, which represent familial and sporadic forms respectively (Rosé et. al. 2009; Ikeda et al. 2014; Sanchez et al. 2013).

Pathogenic variants in the NOD2 gene have also been reported in patients with increased risk for Crohn’s disease. In a study of 612 patients with Crohn’s disease, 50% of patients carried at least one pathogenic variant in the NOD2 gene. Patients with two pathogenic variants in the NOD2 gene had earlier onset of disease (16 years vs. 19 years of age). However, NOD2 variants are not the sole cause of this complex disease with both environmental and other genetic factors playing roles in onset (Lesage et al. 2002). Testing for the NOD2 pathogenic variants for Crohn’s disease is not recommended at this time.

PGA is inherited in an autosomal dominant manner through pathogenic variants in the NOD2 gene. Missense gain of function variants, primarily in exon 4 of the NOD2 gene, have been reported in all PGA cases to date with the p.Arg334Gln and p.Arg334Trp variants being found in greater than half of cases (Rosé et. al. 2009; Miceli-Richard et al. 2001; Ikeda et al. 2014). The NOD2 protein is involved in innate immune responses to bacterial infections and initiates pro-inflammatory responses. In patients with PGA, heightened NOD2 pro-inflammatory responses result in disease (Kanazawa et al. 2005).

Several polymorphisms in the NOD2 gene have been associated with susceptibility to Crohn’s disease. In particular the p.Arg702Trp, p.Gly908Arg, and c.3019dupC variants have been found more frequently in patients with Crohn’s disease (Lesage et al. 2002). However, these variants are also commonly found with minor allele frequencies as high as of 4.5%, 1.5% and 2% in certain populations (exac.broadinstitute.org). This indicates that these variants have low penetrance for disease. To date, pathogenic variants in the NOD2 gene are non-overlapping between individuals with PGA and susceptibility to Crohn’s.

In an international registry for pediatric granulomatous diseases, 75 individuals were assessed for pathogenic variants in the NOD2 gene. In this cohort, 45 symptomatic patients had a pathogenic variant in the NOD2 gene. Of these 45 individuals, 22 were familial (Blau syndrome) and 23 were sporadic (Early Onset Sarcoidosis) (Rosé et. al. 2009). Analytical sensitivity should >99% as all reported variants in the NOD2 gene are detectable by sequencing.

This test provides full coverage of all coding exons of the NOD2 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).