A novel nucleotide-binding oligomerization domain 2 genetic marker for Yao syndrome

Navetta-Modrov, Brianne; Nomani, Hafsa; Yun, Mark; Yang, Jie; Salvemini, Joann; Aroniadis, Olga C.; Clark, Richard E.; Gorevic, Peter D.; Yao, Qingping

doi:10.1016/j.jaad.2023.02.029

Cited by 11 publications

(5 citation statements)

References 5 publications

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“…YAOS was diagnosed according to our published criteria, i.e., characteristic phenotype and specific NOD2 variants with the exclusion of relevant diseases, such as early onset sarcoidosis or Blau syndrome (BS) and IBD ( 7 , 18 , 19 ). YAOS-associated NOD2 variants are often compound heterozygous for IVS8 + 158(rs5743289, Minor Allele Frequency, MAF=0.10 in gnomAD) and another one or more NOD2 variants, such as Arg702Trp (R702W/SNP8; rs2066804; MAF=0.025),1007fs (SNP13; rs2066847; MAF=0.015), Val955Ile (V955I; rs5743291; MAF=0.06) or rare NOD2 variants ( 20 ). A single heterozygous NOD2 variant, such as IVS8 + 158, V955I or rare variants are also seen.…”

Section: Methodsmentioning

confidence: 99%

Implications of combined NOD2 and other gene mutations in autoinflammatory diseases

Nomani,

Deng,

Navetta-Modrov

et al. 2023

Front. Immunol.

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NOD-like receptors (NLRs) are intracellular sensors associated with systemic autoinflammatory diseases (SAIDs). We investigated the largest monocentric cohort of patients with adult-onset SAIDs for coinheritance of low frequency and rare mutations in NOD2 and other autoinflammatory genes. Sixty-three patients underwent molecular testing for SAID gene panels after extensive clinical workups. Whole exome sequencing data from the large Atherosclerosis Risk in Communities (ARIC) study of individuals of European-American ancestry were used as control. Of 63 patients, 44 (69.8%) were found to carry combined gene variants in NOD2 and another gene (Group 1), and 19 (30.2%) were carriers only for NOD2 variants (Group 2). The genetic variant combinations in SAID patients were digenic in 66% (NOD2/MEFV, NOD2/NLRP12, NOD2/NLRP3, and NOD2/TNFRSF1A) and oligogenic in 34% of cases. These variant combinations were either absent or significantly less frequent in the control population. By phenotype-genotype correlation, approximately 40% of patients met diagnostic criteria for a specific SAID, and 60% had mixed diagnoses. There were no statistically significant differences in clinical manifestations between the two patient groups except for chest pain. Due to overlapping phenotypes and mixed genotypes, we have suggested a new term, “Mixed NLR-associated Autoinflammatory Disease “, to describe this disease scenario. Gene variant combinations are significant in patients with SAIDs primarily presenting with mixed clinical phenotypes. Our data support the proposition that immunological disease expression is modified by genetic background and environmental exposure. We provide a preliminary framework in diagnosis, management, and interpretation of the clinical scenario.

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Section: Methodsmentioning

confidence: 99%

Implications of combined NOD2 and other gene mutations in autoinflammatory diseases

Nomani,

Deng,

Navetta-Modrov

et al. 2023

Front. Immunol.

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“…Skin manifestations vary in different SAIDs, including urticarial or maculopapular rashes, neutrophilic dermatosis, erythematous patches, among others ( Table 2 ). [ 15 , 16 , 17 , 18 , 19 , 20 , 21 ] Skin presentations associated with SAIDs can be nonspecific [ 22 ] and mimic those associated with DM/ADM ( Figure 1 ), [ 23 ] some of which could be interpreted as Heliotrope rash, Gottron’s sign, or V sign. The skin has limited responsiveness and therefore diagnosis cannot rely on eruptions only; close correlation between clinical, pathologic and, at times, laboratory studies are required to arrive at a correct diagnosis.…”

Section: Resultsmentioning

confidence: 99%

“…Many variants identified are in the “grey area” between monogenic and polygenic [ 36 ] and in fact, some low frequency variants (minor allele frequency 1% to 5%) are linked to SAIDs, such as CAPS, TRAPS, NLRP12-AID and YAOS. [ 14 , 20 ] To meet the growing need and to supplement the traditional classification, we recently proposed and defined “Genetically Transitional Diseases (GTD) ”, as a new concept in genomic medicine to denote a disease or disease status between monogenic and polygenic diseases. In these diseases a mutation is necessary, but not sufficient to cause disease.…”

Section: Discussionmentioning

confidence: 99%

Amyopathic dermatomyositis may be on the spectrum of autoinflammatory disease: A clinical review

Sharmeen,

Christopher-Stine,

Salvemini

et al. 2024

Rheumatology and Immunology Research

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Systemic autoinflammatory diseases (SAIDs) are distinct from autoimmune diseases. The former primarily results from abnormal innate immune response and genetic testing is crucial for disease diagnosis. Similar cutaneous involvement is a main feature for both SAID and dermatomyositis (DM), so they can be confused with each other. A literature search of PubMed and MEDLINE was conducted for relevant articles. The similarities and differences between these two types of diseases were analyzed. We found phenotypic similarities between these two types of disorders. Accumulating data supports a major role of the innate immune system and a similar cytokine profile. Molecular testing using an autoinflammatory disease gene panel may help identify SAID patients from the DM population and may offer therapeutic benefit using interleukin-1 (IL-1) inhibitors. A subset of DM, notably amyopathic dermatomyositis in the absence of autoantibodies may be on the spectrum of autoinflammatory disease.

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“…Indeed, YAOS was the fourth in order of frequency SAID in our whole cohort following FMF, unclassified disease and Still’s disease, and the most frequent diagnosis among patients with NOD2 variants (52%), as also previously described ( 20 ). According to the largest studies ( 20 , 33 , 41 , 42 ), YAOS is principally sporadic and is predominantly reported in white adults with a female-to-male ratio of 2:1; the disease occurs at any age, however, it is most common between age 20 and 50 ( 6 ), and recurrent episodes last from days to several weeks alternating with asymptomatic periods of weeks, months or years ( 5 ). The inflammatory nature of YAOS is supported by studies showing spontaneous IL-6 production by monocytes derived from the patient peripheral blood, as well as aberrant NOD2 transcriptional levels and its signal NF-κB pathway; nevertheless, plasma levels of pro-inflammatory cytokines such as TNFa, IL-1β, IFNγ, IL-6 and IL-17 are not elevated ( 43 ).…”

Section: Discussionmentioning

confidence: 99%

The expanding clinical spectrum of autoinflammatory diseases with NOD2 variants: a case series and literature review

Karamanakos,

Vougiouka,

Sapountzi

et al. 2024

Front. Immunol.

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ObjectiveTo assess the impact conferred by NOD2 variants on the clinical spectrum of patients with systemic autoinflammatory diseases (SAIDs) in Greece.MethodsConsecutive patients (n=167) with confirmed SAIDs who underwent screening by next generation sequencing (NGS) targeting 26 SAID-associated genes, and carried at least one NOD2 gene variant, were retrospectively studied. The demographic, clinical and laboratory parameters were recorded.ResultsIn total, 24 rare NOD2 variants in 23/167 patients (14%) were detected. Notably, 18 patients had at least one co-existing variant in 13 genes other than NOD2. Nine patients had juvenile- and 14 adult-onset disease. All patients presented with symptoms potentially induced by the NOD2 variants. In particular, the candidate clinical diagnosis was Yao syndrome (YAOS) in 12 patients (7% of the whole SAID cohort). The clinical spectrum of patients with YAOS (mean episode duration 8 days) was fever (n=12/12), articular symptoms (n=8), gastrointestinal symptoms (n=7; abdominal pain/bloating in 7; diarrhea in 4; oral ulcers in 3), serositis (n=7), and rash (n=5), while the inflammatory markers were elevated in all but one patient. Most of these patients showed a poor response to nonsteroidal anti-inflammatory drugs (n=7/9), colchicine (n=6/8) and/or anti-TNF treatment (n=3/4), while a complete response was observed in 6/10 patients receiving steroids and 3/5 on anti-IL1 treatment. Another 8 patients were diagnosed with either FMF (n=6) or PFAPA syndrome (n=2) presenting with prominent diarrhea (n=7), oral ulcers (n=2), periorbital swelling and sicca-like symptoms (n=1), or maculopapular rash (n=1). One patient had a clinically undefined SAID, albeit characterized by oral ulcers and diarrhea. Finally, one patient presented with chronic relapsing urticaria with periorbital edema and inflammatory markers, and another one had a Crohn-like syndrome with good response to anti-IL-1 but refractory to anti-TNF treatment.ConclusionNOD2 variants were detected in 1 out of 7 SAID patients and seem to have an impact on disease phenotype and treatment response. Further studies should validate combined molecular and clinical data to better understand these distinct nosological entities.

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A novel nucleotide-binding oligomerization domain 2 genetic marker for Yao syndrome

Cited by 11 publications

References 5 publications

Implications of combined NOD2 and other gene mutations in autoinflammatory diseases

Implications of combined NOD2 and other gene mutations in autoinflammatory diseases

Amyopathic dermatomyositis may be on the spectrum of autoinflammatory disease: A clinical review

The expanding clinical spectrum of autoinflammatory diseases with NOD2 variants: a case series and literature review

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