Genetically transitional disease: conceptual understanding and applicability to rheumatic disease

Nature Reviews Rheumatology, Год журнала: 2024, Номер 20(5), С. 301 - 310

Опубликована: Фев. 28, 2024

Язык: Английский

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The same genotype gives rise to a spectrum of disorders

The Lancet Rheumatology, Год журнала: 2025, Номер unknown

Опубликована: Фев. 1, 2025

Язык: Английский

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

Frontiers in Immunology, Год журнала: 2024, Номер 15

Опубликована: Янв. 29, 2024

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

Язык: Английский

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Implications of combined NOD2 and other gene mutations in autoinflammatory diseases

Frontiers in Immunology, Год журнала: 2023, Номер 14

Опубликована: Окт. 19, 2023

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

Язык: Английский

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Genetically Transitional Disease and the Road to Personalized Medicine

Genes, Год журнала: 2025, Номер 16(4), С. 401 - 401

Опубликована: Март 30, 2025

Genetically transitional disease (GTD) is emerging as a new concept in genomic medicine to straddle between the traditional binary classification of monogenic and polygenic disease. Genetic testing result reports molecular laboratories have been predicated on model, which focuses pathogenic likely variants. While variants uncertain significance (VUS) are reported by laboratories, there challenges with regard their clinical application so that these often dismissed ordering physicians. Unlike Mendelian disorders, where genetic high penetrance highly probabilistic, GTD employed highlight impact low-to-moderate effect gene whose influence modified background. The may explain health conditions associated necessary but not sufficient for pathogenesis, lying mid gray zone diseases. Although VUSs reach level pathogenicity based American College Medical Genetics Genomics guidelines, they could be provisionally classified GTD-associated annotate interpret relationship VUS human appropriate implementation patient care research focusing attention individual variability responses various

Язык: Английский

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

Journal of the American Academy of Dermatology, Год журнала: 2023, Номер 89(1), С. 166 - 168

Опубликована: Фев. 28, 2023

Язык: Английский

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Genetic variations in NLRP3 and NLRP12 genes in adult-onset patients with autoinflammatory diseases: a comparative study

Frontiers in Immunology, Год журнала: 2024, Номер 14

Опубликована: Янв. 26, 2024

Objectives Cryopyrin-associated periodic syndrome or NLRP3-associated autoinflammatory disease (NLRP3-AID) and NLRP12-AID are both Mendelian disorders with autosomal dominant inheritance. Both diseases rare, primarily reported in the pediatric population, thought to be phenotypically indistinguishable. We provide largest cohort of adult-onset patients compared these gene variant frequency population controls. Methods A adult AIDs were retrospectively studied. All underwent molecular testing for fever panels after extensive negative workups systemic autoimmune other related diseases. Patients divided into Group 1- NLRP3-AID NLRP3 variants (N=15), 2- NLRP12 (N=14) 3- (N=9) variants. Exome sequence data two large control populations including ARIC study used compare distribution frequency. Results 38 Caucasian women accounting 82%. Median age at diagnosis was 41 ± 23 years duration 14 13 years. identified statistically significant differences between groups, notably that gastrointestinal symptoms as well evaluations same significantly more frequent variants, headaches/dizziness less common among patients. Livedo reticularis noted four patients, exclusively carriers. Over 50% Groups 1 2 carry low-frequency disease-associated while remaining rare unprecedently digenic i.e., coexistence NLRP12, which either low frequency/rare. Allele frequencies all our absent lower populations, further strengthening evidence susceptibility SAID phenotypes. Conclusion Our comparative shows share similar clinical phenotypes, yet there them regard neurological symptoms. spectrum high genetic variations genes can contribute individually combination.

Язык: Английский

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Identifying functional dysregulation of NOD2 variant Q902K in patients with Yao syndrome

Arthritis Research & Therapy, Год журнала: 2024, Номер 26(1)

Опубликована: Фев. 23, 2024

Abstract Background and objectives The study investigated the pathogenesis of Yao syndrome (YAOS), a rare systemic autoinflammatory disease associated with nucleotide-binding oligomerization domain containing 2 ( NOD2 ) gene variants. Methods RNA sequencing analyses were used to detect transcriptomic profile changes. Immunoblot immunohistochemistry examine NOD2-mediated inflammatory signaling pathways ELISA was cytokines. Results Transcriptome analysis YAOS revealed NOD-like receptor pathway enrichment. Compared HCs, P-RIP2, p-p65, p-p38, p-ERK, p-JNK notably increased in PBMCs patient YAOS. p-p38 elevated small intestinal mucosa tissues. P-p65 synovial tissues from higher than those patients rheumatoid arthritis (RA) osteoarthritis (OA). Serum interleukin (IL)-6 level along tumor necrosis factor (TNF)-α IL-6 secreted markedly comparison healthy controls (HCs). supernatants cells showed substantially IL-1β levels RA OA. Canakinumab therapy Q902K heterozygous resulted notable clinical improvement. Conclusion Overproduction pro-inflammatory cytokines hyperactivation found variant NOD2-RIP2-MAPK might play pivotal role These results provide new perspectives for targeted therapies

Язык: Английский

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2024 VCP International Conference: Exploring multi-disciplinary approaches from basic science of valosin containing protein, an AAA+ ATPase protein, to the therapeutic advancement for VCP-associated multisystem proteinopathy

Neurobiology of Disease, Год журнала: 2025, Номер unknown, С. 106861 - 106861

Опубликована: Март 1, 2025

Valosin-containing protein (VCP/p97) is a ubiquitously expressed AAA+ ATPase associated with numerous protein-protein interactions and critical cellular functions including degradation clearance, mitochondrial homeostasis, DNA repair replication, cell cycle regulation, endoplasmic reticulum-associated degradation, lysosomal autophagy apoptosis. Autosomal-dominant missense mutations in the VCP gene may result VCP-associated multisystem proteinopathy (VCP-MSP), rare degenerative disorder linked to heterogeneous phenotypes inclusion body myopathy (IBM) Paget's disease of bone (PDB) frontotemporal dementia (FTD) or IBMPFD, amyotrophic lateral sclerosis (ALS), Alzheimer's (AD), parkinsonism, Charcot-Marie Tooth (CMT), spastic paraplegia. The complexity VCP-MSP makes collaboration among stakeholders essential necessitates multi-disciplinary approach. 2024 International Conference was hosted at Caltech between February 22 25. Co-organized by Cure Disease Dr. Tsui-Fen Chou, meeting aimed center patient as research partner, harmonize diverse stakeholder engagement, bridge gap basic clinical neuroscience it relates VCP-MSP. Over 100 experts attended, ranging from scientists clinicians advocates. Attendees discussed genetics presentation, molecular mechanisms underlying disease, therapeutic approaches, strategies for future research. conference included three roundtable discussions, 29 scientific presentations, 32 posters, nine caregiver closing discussion forum. following proceedings summarize these sessions, highlighting both identified gaps knowledge significant strides made towards understanding treating diseases.

Язык: Английский

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DAG1 haploinsufficiency is associated with sporadic and familial isolated or pauci-symptomatic hyperCKemia

European Journal of Human Genetics, Год журнала: 2024, Номер unknown

Опубликована: Янв. 4, 2024

Язык: Английский

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