Skip to main content
  • Poster presentation
  • Open access
  • Published:

NOD2 mosaicism in Blau syndrome


Gene mosaicism describes an individual who has developed from a single zygote and has two or more cell types with distinct genotypes. Three major types of mosaicism have been described and are referred as gonadal, somatic and gonosomic mosaicism. They mainly differ on the body distribution of the somatic mutation and in their clinical consequences. The recent use of next-generation sequencing technologies is revealing the relevant role of gene mosaicism in various diseases other than cancer, including monogenic autoinflammatory diseases such as cryopyrinopathies and STING-associated vasculopathy with onset in infancy [13].


To describe the first known cases of somatic and gonosomic NOD2 mosaicism in Blau syndrome (BS).

Patients and methods

Genomic DNA was extracted from hematopoietic and non-hematopoietic cell types. NOD2 analyses were performed by both Sanger sequencing and targeted deep sequencing (TDS).


The first patient is a 17-year-old Moroccan girl who presented with bilateral red eye at the age of 3 years. Severe panuveitis, erythematous rash and oligoarthritis were observed during the following years. Sanger sequencing did not clearly detect any disease-causing NOD2 mutation. However, a careful analysis of Sanger chromatograms revealed a potential c.1001G>A transition that might cause the appearance of the well-known p.Arg334Gln NOD2 mutation. TDS confirmed the presence of somatic NOD2 mosaicism by means of the detection of the somatic p.Arg334Gln mutation in hematopoietic and non-hematopoietic tissues with variable frequencies (4.9-11.0%).

The second patient is a 37-year-old Malaysian male suffering from skin rash and bilateral uveitis since the age of 22 years. He has two affected daughters, aged 4- and 2-year-old, with the classical BS triad (skin rash, polyarthritis and uveitis). Sanger NOD2 sequencing revealed the germline p.Arg334Gln mutation in both daughters, and unexpectedly its absence in the father. Further analysis of father's Sanger chromatograms suggested the presence of the p.Arg334Gln mutation as a potential somatic mutation. TDS confirmed the presence of gonosomic NOD2 mosaicism in the father by means of the detection of the somatic p.Arg334Gln mutation in different tissues with different allele frequencies (0.9-12.9%).


We describe for the first time the involvement of NOD2 mosaicism in BS pathogenesis by using the novel TDS technology. Our findings clearly support that gene mosaicism might have a relevant role in either “mutation-negative” BS patients or in parents of an affected child with an apparent de novo germline mutation.

Consent to publish

Written informed consent for publication of their clinical details was obtained from the patient/parent/guardian/relative of the patient.


  1. Arthritis Rheum. 2011, 63: 3625-3632. 10.1002/art.30512.

  2. Ann Rheum Dis. 2015, 74: 603-10.

  3. N Engl J Med. 2014, 371: 507-518. 10.1056/NEJMoa1312625.

Download references

Author information

Authors and Affiliations


Rights and permissions

Open Access  This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made.

The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

To view a copy of this licence, visit

The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mensa-Vilaro, A., De Inocencio, J., Cham, W.T. et al. NOD2 mosaicism in Blau syndrome. Pediatr Rheumatol 13 (Suppl 1), P59 (2015).

Download citation

  • Published:

  • DOI: