Submission Details

The NOD2 gene is located on chromosome 16 at 16q12.1 and encodes the nucleotide-binding oligomerization domain-containing protein 2, a member of the NOD-like receptor family. NOD2 is a cytoplasmic pattern recognition receptor and plays an important role in regulating the innate immune response. The NOD2 gene was first reported in relation to autosomal dominant Blau syndrome in 2001 (11528384: Miceli-Richard et al. 2001). At least 20 unique missense variants have been reported in clinical cases, with up to 80% of Blau syndrome associated with two recurrent NOD2 variants; p.Arg334Trp and p.Arg334Gln (25182201: Caso et al. 2014). Evidence supporting this gene-disease relationship includes case-level data, segregation data and experimental data. Variants in this gene have been reported in at least nineteen probands in twelve publications (11528384; 15459013; 19116920; 19479837; 28721627; 28721627; 12428248; 17916199; 20084402; 31543536; 31803699; 17207093). Wang et al. (12428248: Wang et al. 2002) performed linkage analysis on ten families with Blau syndrome and reported a combined LOD score of 5.67. De novo variants have also been reported. The mechanism of disease is unknown, in vitro experiments suggest variants lead to a gain of function and ligand independent activation of NOD2 (25093298), however patient cell and mouse model data suggest a downregulation of NOD2 signalling pathways. This gene-disease relationship is supported by data from patient cells which point to a disruption of NOD2 signalling pathways (21296813; 20052476; 20052476; 20052476; 28587749). Mouse models also showed partial recapitulation of aspects of disease (25429073; 21296813). In summary, NOD2 is definitively associated with autosomal dominant Blau syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

PubMed IDs:

31543536 31803699 11528384 15459013 19116920 19479837 28721627 28587749 25429073 21296813

Assertion Criteria:

Click here to view assertion criteria

https://www.clinicalgenome.org/site/assets/files/3975/gene-disease_validity_standard_operating_procedures_version_7-1.pdf

Submitter Submitted Date:

10/15/2020

The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).

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