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

To the Editor: Yao syndrome (YAOS, Online Mendelian Inheritance in Man [OMIM] 617321) is formerly termed nucleotide-binding oligomerization domain 2(NOD2)-associated autoinflammatory disease. It is characterized by periodic fever, dermatitis, arthritis, swelling of the distal extremities, gastrointestinal and sicca-like symptoms, and eyelid swelling. Specific NOD2 variants increase susceptibility to the disease.1Yao Q. Shen B. A systematic analysis of treatment and outcomes of NOD2-associated autoinflammatory disease.Am J Med. 2017; 130: 365.e13-365.e18https://doi.org/10.1016/j.amjmed.2016.09.028Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar, 2Yao Q. Su L.C. Tomecki K.J. Zhou L. Jayakar B. Shen B. Dermatitis as a characteristic phenotype of a new autoinflammatory disease associated with NOD2 mutations.J Am Acad Dermatol. 2013; 68: 624-631https://doi.org/10.1016/j.jaad.2012.09.025Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar, 3Yao Q. Kontzias A. Expansion of phenotypic and genotypic spectrum in Yao syndrome: a case series.J Clin Rheumatol. 2022; 28: e156-e160Crossref PubMed Scopus (4) Google Scholar Herein, we report a new genetic marker for YAOS. We conducted a retrospective study of a single site cohort of 43 adult patients with autoinflammatory disease. All patients underwent testing for periodic fever syndrome 6-gene panel including NOD2 whole gene sequencing. YAOS was daignosed based on characteristic phenotype and geneotype with exclusion of other relevant diseases.1Yao Q. Shen B. A systematic analysis of treatment and outcomes of NOD2-associated autoinflammatory disease.Am J Med. 2017; 130: 365.e13-365.e18https://doi.org/10.1016/j.amjmed.2016.09.028Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar Twenty-seven patients carried a variant of uncertain significance, NOD2 V955I. These patients included 16 patients with NOD2 V955I only in group 1 and 11 patients with YAOS with compound NOD2 V955I/previously known variants in group 2. They were compared with 16 typical patients with YAOS with only previously known NOD2 variants in group 3. Patients in group 1 had characteristic clinical findings for YAOS. There was no statistically significant difference in demographic and clinical manifestations between the 3 groups except headaches (Table I). Cutaneous presentations of a representative patient with NOD2 V955I are presented (Fig 1). Patients presented with patchy erythema in the majority and urticaria, livedo reticularis, and red external ears in the minority. Lymphadenopathy and splenomegaly occurred in 16% patients. Some patients had chronic sinusitis, asthma-like symptoms, or mast cell activation syndrome. Tachycardia, ventricular hypertrophy and pulmonary hypertension could occur. Distal leg swelling could resemble lymphedema. In all groups, 44% (19/43) of patients were treated with interleukin 1 inhibitors with good response in the majority.Table IComparison of patients with nucleotide-binding oligomerization domain 2 V955I ± previously known nucleotide-binding oligomerization domain 2 variants with patients with Yao syndrome onlyVariableTotal (N = 43)NOD2 V955I (N = 16)NOD2 V955I/known variants (N = 11)Known NOD2 variants only (N = 16)P value∗For continuous variables, P values were based on t tests; for categorical variables, P values were based on on χ2 test with exact P value from Monte Carlo simulation.Age at diagnosis (year)40.81 ± 15.0638.69 ± 16.6241.91 ± 14.5542.19 ± 14.50.8010Disease duration at diagnosis (year)12.08 ± 12.8611.31 ± 8.5818.82 ± 20.178.22 ± 8.26.2356Female39 (91%)13 (81%)11 (100%)15 (94%).3175Caucasian43 (100%)16 (100%)11 (100%)16 (100%).Fatigue42 (98%)16 (100%)11 (100%)15 (94%)1.0000Night sweats11 (26%)6 (38%)4 (36%)1 (6%).0901Headaches28 (65%)14 (88%)8 (73%)6 (38%).0125Fever35 (81%)14 (88%)9 (82%)12 (75%).8861Skin rash39 (91%)14 (88%)11 (100%)14 (88%).5540Arthralgia35 (81%)12 (75%)9 (82%)14 (88%).8849Lower extremity swelling27 (63%)8 (50%)6 (55%)13 (81%).2093Myalgia26 (61%)10 (63%)9 (82%)7 (44%).1560Oral ulcer21 (49%)8 (50%)7 (64%)6 (38%).4728Lymphadenopathy7 (16%)4 (25%)1 (9%)2 (13%).5868Gastrointestinal symptoms39 (91%)13 (81%)11 (100%)15 (94%).3230Pain35 (81%)12 (75%)9 (82%)14 (88%).8820Diarrhea30 (70%)9 (56%)9 (82%)12 (75%).3443Dry eyes and mouth27 (63%)9 (56%)7 (64%)11 (69%).9197Eyelid swelling21 (49%)8 (50%)4 (36%)9 (56%).6864Hearing loss/decrease7 (16%)2 (13%)1 (9%)4 (25%).5868Chest pain18 (42%)7 (44%)5 (46%)6 (38%).9017Pleuritis5 (12%)4 (25%)0 (0%)1 (6%).1586Pericarditis8 (19%)4 (25%)1 (9%)3 (19%).5582Asthma13 (30%)6 (44%)1 (9%)5 (31%).2060Proteinuria/hematuria1 (2%)1 (6%)0 (0%)0 (0%)1.0000Raised ESR/CRP/ferritin27 (63%)12 (75%)7 (64%)8 (50%).3818Mean ± SD were reported for continuous variables; column percentages were reported for categorical variables.NOD2, Nucleotide-binding oligomerization domain 2; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein.∗ For continuous variables, P values were based on t tests; for categorical variables, P values were based on on χ2 test with exact P value from Monte Carlo simulation. Open table in a new tab Mean ± SD were reported for continuous variables; column percentages were reported for categorical variables. NOD2, Nucleotide-binding oligomerization domain 2; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein. Known YAOS-associated NOD2 variants include but are not limited to NOD2 IVS8+158, R702W, and 1007fs,3Yao Q. Kontzias A. Expansion of phenotypic and genotypic spectrum in Yao syndrome: a case series.J Clin Rheumatol. 2022; 28: e156-e160Crossref PubMed Scopus (4) Google Scholar and are mainly located within the NOD2 exons encoding the leucin-rich repeat and adjacent regions. These variants are mostly present in compound heterozygote with 30% having IVS8+158/R702W followed by IVS8+158/1007fs, IVS8+158/G908R, and IVS8+158/N852S. All 27 patients in group 2 and 3 carried heterozygous V955I, with 11 patients having compound NOD2 V955I/previously known variant IVS8+158. Patients in both group 2 and 3 were diagnosed as having YAOS because of carriage of known risk NOD2 variants. The NOD2 V955I is located within the leucin-rich repeat variants, with a minor allele frequency of 3.3% close to the known risk variants. Taken together, these data support disease association of this variant alone or in combination with known risk variants of the same gene. The NOD2 variants that increase susceptibility to YAOS are mostly of low penetrance, and this disease has been recently reclassified as a Genetically Transitional Disease, a new concept in genomic medicine.4Yao Q. Gorevic P. Shen B. Gibson G. Genetically transitional disease: a new concept in genomic medicine.Trends Genet. 2023; 39: 98-108Abstract Full Text Full Text PDF PubMed Google Scholar YAOS may result from a complex interaction among deficient innate defense NOD2 receptors, modification of genetic background, and environmental triggers.5McDonald C. Shen M. Johnson E.E. Kabi A. Yao Q. Alterations in nucleotide-binding oligomerization domain-2 expression, pathway activation, and cytokine production in Yao syndrome.Autoimmunity. 2018; 51: 53-61https://doi.org/10.1080/08916934.2018.1442442Crossref PubMed Scopus (16) Google Scholar NOD2 V955I has been detected in a significant portion of patients with YAOS and will help identify more cases that could be missed previously. This study has expanded the genotypic-phenotypic spectrum of the disease to further raise awareness among clinicians. None disclosed. The authors are thankful to Baozhong Xin, PhD and Heng Wang, MD, PhD at DDC, Middlefield, Ohio for providing the molecular testing. We are also grateful to Mrs. Lyn Hastings, Communication Specialist, the Department of Medicine, Stony Brook University Renaissance School of Medicine for making the figures.