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1.
Life Sci Alliance ; 3(2)2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31882397

RESUMO

We identified a consanguineous kindred, of three affected children with severe autoinflammation, resulting in the death of one sibling and allogeneic stem cell transplantation in the other two. All three were homozygous for MEFV p.S208C mutation; however, their phenotype was more severe than previously reported, prompting consideration of an oligogenic autoinflammation model. Further genetic studies revealed homozygous mutations in TRAP1, encoding the mitochondrial/ER resident chaperone protein tumour necrosis factor receptor associated protein 1 (TRAP1). Identification of a fourth, unrelated patient with autoinflammation and compound heterozygous mutation of TRAP1 alone facilitated further functional studies, confirming the importance of this protein as a chaperone of misfolded proteins with loss of function, which may contribute to autoinflammation. Impaired TRAP1 function leads to cellular stress and elevated levels of serum IL-18. This study emphasizes the importance of considering digenic or oligogenic models of disease in particularly severe phenotypes and suggests that autoinflammatory disease might be enhanced by bi-allelic mutations in TRAP1.

2.
Ann Rheum Dis ; 78(10): 1405-1411, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31278138

RESUMO

OBJECTIVES: To describe the clinical characteristics, treatment response and genetic findings in a large cohort of patients with undefined systemic autoinflammatory diseases (SAIDs). METHODS: Clinical and genetic data from patients with undefined SAIDs were extracted from the Eurofever registry, an international web-based registry that retrospectively collects clinical information on patients with autoinflammatory diseases. RESULTS: This study included 187 patients. Seven patients had a chronic disease course, 180 patients had a recurrent disease course. The median age at disease onset was 4.3 years. Patients had a median of 12 episodes per year, with a median duration of 4 days. Most commonly reported symptoms were arthralgia (n=113), myalgia (n=86), abdominal pain (n=89), fatigue (n=111), malaise (n=104) and mucocutaneous manifestations (n=128). In 24 patients, relatives were affected as well. In 15 patients, genetic variants were found in autoinflammatory genes. Patients with genetic variants more often had affected relatives compared with patients without genetic variants (p=0.005). Most patients responded well to non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, colchicine and anakinra. Complete remission was rarely achieved with NSAIDs alone. Notable patterns were found in patients with distinctive symptoms. Patients with pericarditis (n=11) were older at disease onset (33.8 years) and had fewer episodes per year (3.0/year) compared with other patients. Patients with an intellectual impairment (n=8) were younger at disease onset (2.2 years) and often had relatives affected (28.6%). CONCLUSION: This study describes the clinical characteristics of a large cohort of patients with undefined SAIDs. Among these, patients with pericarditis and intellectual impairment appear to comprise distinct subsets.

3.
Pediatr Rheumatol Online J ; 17(1): 39, 2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31291964

RESUMO

BACKGROUND: Deficiency of adenosine deaminase 2 (DADA2) is a rare autosomal recessive autoinflammatory condition. Recognised features include vasculitis predominantly affecting medium sized vessels, livedoid skin rash, central and peripheral nervous system involvement, variable degrees of immunodeficiency, and marrow failure, amongst other clinical presentations. We present the case of a six year old male with DADA2 who presented with acute testicular ischaemia secondary to vasculitis, the first such description in DADA2. CASE PRESENTATION: A six year old male presented acute right-sided testicular pain. His history included transient infantile neutropenia, resolved hepatosplenomegaly, and longstanding livedo racemosa, leading to screening and confirmation of DADA2 caused by homozygous c.139G > C (p.G47R) mutation of ADA2. As his only clinical feature was that of mild livedo racemosa with normal laboratory parameters at diagnosis, he was being actively monitored prior to starting any treatment. At a routine clinic follow-up a 24 h history of testicular pain was noted on systems review. He was afebrile, and his only physical signs were that of moderate livedo racemosa, and tenderness of the right testicle. Laboratory parameters revealed C-reactive protein (CRP) 8 mg/L (reference range [RR] < 20 mg/L); erythrocyte sedimentation rate (ESR) 28 mm/hr. (RR < 10); and serum amyloid A (SAA)5 mg/L (RR < 10). Ultrasound-scan of the scrotum revealed significantly reduced perfusion of the right testes, without torsion. Surgical scrotal exploration confirmed testicular ischaemia without torsion. Histology demonstrated ischaemic seminiferous tubules with intervening haemorrhage and acute inflammatory cells, consistent with vasculitis of the testis as the cause. He was treated with high dose intravenous methyl-prednisolone followed by a weaning course of oral prednisolone, and subcutaneous adalimumab (anti-tumour necrosis factor alpha, anti-TNFα). Repeat ultrasound-scan 3 weeks later revealed good testicular perfusion, with a small area of focal infarction. At last follow-up (11 months post-event) he remained asymptomatic, on treatment with adalimumab. CONCLUSION: The phenotype of DADA2 continues to expand, and we add testicular infarction to the features of DADA2. CRP and SAA cannot be relied on as reliable biomarkers to predict tissue ischaemia and hence who to target for anti-TNFα therapy in DADA2, since these remained steadfastly normal before, during, and after testicular infarction in this case.


Assuntos
Adenosina Desaminase/deficiência , Infarto/patologia , Peptídeos e Proteínas de Sinalização Intercelular/deficiência , Doenças Testiculares/patologia , Vasculite/patologia , Adenosina Desaminase/genética , Criança , Doenças Hereditárias Autoinflamatórias/complicações , Doenças Hereditárias Autoinflamatórias/genética , Humanos , Infarto/diagnóstico por imagem , Infarto/etiologia , Peptídeos e Proteínas de Sinalização Intercelular/genética , Isquemia/diagnóstico por imagem , Isquemia/etiologia , Isquemia/patologia , Masculino , Doenças Testiculares/diagnóstico por imagem , Doenças Testiculares/etiologia , Testículo/irrigação sanguínea , Testículo/diagnóstico por imagem , Testículo/patologia , Vasculite/diagnóstico por imagem , Vasculite/etiologia
4.
Arthritis Rheumatol ; 71(11): 1955-1963, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31161734

RESUMO

OBJECTIVE: To assess long-term efficacy and safety of canakinumab and the response to vaccination in children ages ≤5 years with cryopyrin-associated periodic syndrome (CAPS). METHODS: CAPS patients (ages ≤5 years) received 2 mg/kg canakinumab subcutaneously every 8 weeks; patients with neonatal-onset multisystem inflammatory disease (NOMID) received a starting dose of 4 mg/kg in this open-label trial. Efficacy was evaluated using physician global assessment of disease activity and serum levels of C-reactive protein (CRP) and amyloid A (SAA). Adverse events (AEs) were recorded. Vaccination response was evaluated using postvaccination antibody titers at 4 and 8 weeks after immunization. RESULTS: Of the 17 patients enrolled, 12 (71%) had Muckle-Wells syndrome, 4 (24%) had NOMID, and 1 (6%) had familial cold autoinflammatory syndrome. All 17 patients had a complete response to canakinumab. Disease activity improved according to the physician global assessment, and for 65% of the patients autoinflammatory disease was characterized as "absent" at the end of the study. Median CRP levels decreased over time. No such change was evident in SAA levels. During the extension study, postvaccination antibody titers increased above protective levels in 16 (94%) of 17 assessable vaccinations. Ten of the patients (59%) had AEs suspected to be related to canakinumab; 8 (47%) experienced at least 1 serious AE (SAE). None of the AEs or SAEs required interruption of canakinumab therapy. CONCLUSION: Our findings indicate that canakinumab effectively maintains efficacy through 152 weeks and appears to have no effect on the ability to produce antibodies against standard childhood non-live vaccines. The safety profile of canakinumab was consistent with previous studies, supporting long-term use of canakinumab for CAPS in children ≤5 years of age.

6.
Br J Clin Pharmacol ; 85(8): 1790-1797, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31026092

RESUMO

AIMS: Rituximab is a chimeric IgG-1 monoclonal antibody that depletes B cells, aiding in the treatment of several conditions including autoimmune diseases. It is not licensed for use in children. This study aimed to quantify the B cell-related pharmacodynamics of rituximab in children with autoimmune disease. METHODS: Routine electronic health record data were collected at a large paediatric tertiary hospital in London, UK. Dosing protocols were either 2 × 750 mg/m2 intravenous infusions of rituximab on days 1 and 15, or 4 × 375 mg/m2 infusions on days 1, 8, 15 and 22. Rituximab pharmacokinetics (PK) were not measured but CD19+ lymphocyte counts were taken before and after rituximab treatment. A dose-response model was constructed describing the life cycle of CD19+ lymphocytes, with rituximab assumed to increase the death rate. Rituximab effect was assumed to decay by first-order kinetics. RESULTS: In total, 258 measurements of CD19+ lymphocyte counts were collected from 39 children with 8 autoimmune diseases. The elimination rate constant (% relative standard error) of rituximab effect decay was 0.036 (22.7%) days-1 and CD19+ turnover was 0.02 (41%) days-1 corresponding to half-lives of 19 and 35 days respectively. Rituximab increased CD19+ death rate 35-fold, with methotrexate and cyclophosphamide associated with further increases. Simulations suggested that a single infusion of 750 mg/m2 provides similar 6-month suppression of CD19+ lymphocytes to current dosing. CONCLUSIONS: Rituximab pharmacodynamics (PD) in paediatric autoimmune diseases has been described. Compared with rituximab alone, the additional effect of methotrexate or cyclophosphamide was statistically significant but small.

7.
Ann Rheum Dis ; 78(8): 1025-1032, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31018962

RESUMO

BACKGROUND: Different diagnostic and classification criteria are available for hereditary recurrent fevers (HRF)-familial Mediterranean fever (FMF), tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS), mevalonate kinase deficiency (MKD) and cryopyrin-associated periodic syndromes (CAPS)-and for the non-hereditary, periodic fever, aphthosis, pharyngitis and adenitis (PFAPA). We aimed to develop and validate new evidence-based classification criteria for HRF/PFAPA. METHODS: Step 1: selection of clinical, laboratory and genetic candidate variables; step 2: classification of 360 random patients from the Eurofever Registry by a panel of 25 clinicians and 8 geneticists blinded to patients' diagnosis (consensus ≥80%); step 3: statistical analysis for the selection of the best candidate classification criteria; step 4: nominal group technique consensus conference with 33 panellists for the discussion and selection of the final classification criteria; step 5: cross-sectional validation of the novel criteria. RESULTS: The panellists achieved consensus to classify 281 of 360 (78%) patients (32 CAPS, 36 FMF, 56 MKD, 37 PFAPA, 39 TRAPS, 81 undefined recurrent fever). Consensus was reached for two sets of criteria for each HRF, one including genetic and clinical variables, the other with clinical variables only, plus new criteria for PFAPA. The four HRF criteria demonstrated sensitivity of 0.94-1 and specificity of 0.95-1; for PFAPA, criteria sensitivity and specificity were 0.97 and 0.93, respectively. Validation of these criteria in an independent data set of 1018 patients shows a high accuracy (from 0.81 to 0.98). CONCLUSION: Eurofever proposes a novel set of validated classification criteria for HRF and PFAPA with high sensitivity and specificity.

9.
Rheumatology (Oxford) ; 58(7): 1188-1195, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30668879

RESUMO

OBJECTIVES: To provide an overview of the paediatric rheumatology (PR) services in Europe, describe current delivery of care and training, set standards for care, identify unmet needs and inform future specialist service provision. METHODS: An online survey was developed and presented to national coordinating centres of the Paediatric Rheumatology International Trials Organisation (PRINTO) (country survey) and to individual PR centres (centre and disease surveys) as a part of the European Union (EU) Single Hub and Access point for paediatric Rheumatology in Europe project. The survey contained components covering the organization of PR care, composition of teams, education, health care and research facilities and assessment of needs. RESULTS: Response rates were 29/35 (83%) for country surveys and 164/288 (57%) for centre surveys. Across the EU, approximately one paediatric rheumatologist is available per million population. In all EU member states there is good access to specialist care and medications, although biologic drug availability is worse in Eastern European countries. PR education is widely available for physicians but is insufficient for allied health professionals. The ability to participate in clinical trials is generally high. Important gaps were identified, including lack of standardized clinical guidelines/recommendations and insufficient adolescent transition management planning. CONCLUSION: This study provides a comprehensive description of current specialist PR service provision across Europe and did not reveal any major differences between EU member states. Rarity, chronicity and complexity of diseases are major challenges to PR care. Future work should facilitate the development, dissemination and implementation of standards of care, treatment and service recommendations to further improve patient-centred health care across Europe.

11.
Arch Dis Child ; 104(7): 640-646, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30104394

RESUMO

OBJECTIVE: Kawasaki disease (KD) is an increasingly common vasculitis with risk of coronary artery aneurysms (CAAs). The last UK survey was in 1990, whereas current epidemiology, treatment patterns and complication rates are unknown. The aim of this study was to address this knowledge gap. METHODS: A British Paediatric Surveillance Unit survey in the UK and Ireland from 1 January 2013 to 28 February 2015 ascertained demographics, ethnicity, seasonal incidence, treatment and complication rates. RESULTS: 553 cases were notified: 389 had complete KD, 46 had atypical KD and 116 had incomplete KD; 2 were diagnosed at postmortem with an incidence of 4.55/100 000 children under 5 years, with a male to female ratio of 1.5:1 and a median age of 2.7 years (2.5 months-15 years). Presentation was highest in January and in rural areas. Most were white (64%), and Chinese and Japanese Asians were over-represented as were black African or African mixed-race children. 94% received intravenous immunoglobulin (IVIG). The overall CAA rate was 19%, and all-cardiac complications affected 28%. Those with CAA received IVIG later than in those without (median 10 days vs 7 days). Those under 1 year had fewer symptoms, but the highest CAA rate (39%). Overall 8 of 512 cases (1.6%) had giant CAA, and 4 of 86 cases (5%) under 1 year of age developed giant CAA. Mortality from KD was 0.36%. CONCLUSIONS: The UK and Ireland incidence of KD has increased and is more frequently seen in winter and rural areas. Delayed IVIG treatment is associated with CAA, suggesting earlier and adjunctive primary treatment might reduce complications to prevent CAA, particularly in the very young.

12.
Front Immunol ; 9: 2524, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30443255

RESUMO

It is now increasingly recognized that some monogenic autoinflammatory diseases and immunodeficiencies cause vasculitis, although genetic causes of vasculitis are extremely rare. We describe a child of non-consanguineous parents who presented with cutaneous vasculitis, digital ischaemia and hypocomplementaemia. A heterozygous p.R1042G gain-of-function mutation (GOF) in the complement component C3 gene was identified as the cause, resulting in secondary C3 consumption and complete absence of alternative complement pathway activity, decreased classical complement activity, and low levels of serum C3 with normal C4 levels. The same heterozygous mutation and immunological defects were also identified in another symptomatic sibling and his father. C3 deficiency due GOF C3 mutations is thus now added to the growing list of monogenic causes of vasculitis and should always be considered in vasculitis patients found to have persistently low levels of C3 with normal C4.


Assuntos
Complemento C3/genética , Mutação com Ganho de Função/genética , Isquemia/genética , Dermatopatias/genética , Vasculite/genética , Criança , Complemento C4/genética , Feminino , Heterozigoto , Humanos , Masculino
13.
Case Rep Pediatr ; 2018: 3514645, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30225156

RESUMO

Mevalonate kinase deficiency (MKD) is a severe autoinflammatory disease caused by recessive mutations in MVK resulting in reduced function of the enzyme mevalonate kinase, involved in the cholesterol/isoprenoid pathway. MKD presents with periodic episodes of severe systemic inflammation, poor quality of life, and life-threatening sequelae if inadequately treated. We report the case of a 12-year-old girl with MKD and severe autoinflammation that was resistant to IL-1 and TNF-α blockade. In view of this, she commenced intravenous tocilizumab (8 mg/kg every 2 weeks), a humanised monoclonal antibody targeting the IL-6 receptor (IL-6R) that binds to membrane and soluble IL-6R, inhibiting IL-6-mediated signaling. She reported immediate cessation of fever and marked improvement in her energy levels following the first infusion; after the fifth dose, she was in complete clinical and serological remission, now sustained for 24 months. This is one of the first reported cases of a child with MKD treated successfully with tocilizumab and adds to the very limited experience of this treatment for MKD. IL-6 blockade could therefore be an important addition to the armamentarium for the treatment of this rare monogenic autoinflammatory disease.

14.
Ann Rheum Dis ; 77(11): 1599-1605, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30077992

RESUMO

INTRODUCTION: Autoinflammatory diseases can cause irreversible tissue damage due to systemic inflammation. Recently, the Autoinflammatory Disease Damage Index (ADDI) was developed. The ADDI is the first instrument to quantify damage in familial Mediterranean fever, cryopyrin-associated periodic syndromes, mevalonate kinase deficiency and tumour necrosis factor receptor-associated periodic syndrome. The aim of this study was to validate this tool for its intended use in a clinical/research setting. METHODS: The ADDI was scored on paper clinical cases by at least three physicians per case, independently of each other. Face and content validity were assessed by requesting comments on the ADDI. Reliability was tested by calculating the intraclass correlation coefficient (ICC) using an 'observer-nested-within-subject' design. Construct validity was determined by correlating the ADDI score to the Physician Global Assessment (PGA) of damage and disease activity. Redundancy of individual items was determined with Cronbach's alpha. RESULTS: The ADDI was validated on a total of 110 paper clinical cases by 37 experts in autoinflammatory diseases. This yielded an ICC of 0.84 (95% CI 0.78 to 0.89). The ADDI score correlated strongly with PGA-damage (r=0.92, 95% CI 0.88 to 0.95) and was not strongly influenced by disease activity (r=0.395, 95% CI 0.21 to 0.55). After comments from disease experts, some item definitions were refined. The interitem correlation in all different categories was lower than 0.7, indicating that there was no redundancy between individual damage items. CONCLUSION: The ADDI is a reliable and valid instrument to quantify damage in individual patients and can be used to compare disease outcomes in clinical studies.


Assuntos
Doenças Hereditárias Autoinflamatórias/diagnóstico , Índice de Gravidade de Doença , Adolescente , Adulto , Criança , Simulação por Computador , Síndromes Periódicas Associadas à Criopirina/complicações , Síndromes Periódicas Associadas à Criopirina/diagnóstico , Febre Familiar do Mediterrâneo/complicações , Febre Familiar do Mediterrâneo/diagnóstico , Doenças Hereditárias Autoinflamatórias/complicações , Humanos , Deficiência de Mevalonato Quinase/complicações , Deficiência de Mevalonato Quinase/diagnóstico , Variações Dependentes do Observador , Sistema de Registros , Reprodutibilidade dos Testes , Adulto Jovem
15.
Front Immunol ; 9: 735, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29696024

RESUMO

Cutaneous leukocytoclastic vasculitis arises from immune complex deposition and dysregulated complement activation in small blood vessels. There are many causes, including dysregulated host response to infection, drug reactions, and various autoimmune conditions. It is increasingly recognised that some monogenic autoinflammatory diseases cause vasculitis, although genetic causes of vasculitis are extremely rare. We describe a child of consanguineous parents who presented with chronic cutaneous leukocytoclastic vasculitis, recurrent upper respiratory tract infection, and hypocomplementaemia. A homozygous p.His380Arg mutation in the complement factor I (CFI) gene CFI was identified as the cause, resulting in complete absence of alternative complement pathway activity, decreased classical complement activity, and low levels of serum factor I, C3, and factor H. C4 and C2 levels were normal. The same homozygous mutation and immunological defects were also identified in an asymptomatic sibling. CFI deficiency is thus now added to the growing list of monogenic causes of vasculitis and should always be considered in vasculitis patients found to have persistently low levels of C3 with normal C4.


Assuntos
Complemento C3/deficiência , Fator I do Complemento/genética , Doenças Genéticas Inatas/genética , Vasculite Leucocitoclástica Cutânea/genética , Criança , Complemento C3/genética , Feminino , Humanos , Recidiva
17.
J Pediatr Endocrinol Metab ; 31(1): 101-105, 2018 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-29252198

RESUMO

BACKGROUND: Polyglandular autoimmune syndrome (PGA) and eosinophilic granulomatosis with polyangiitis (EGPA) do not seem to represent a coincidental association. CASE PRESENTATION: A case of a 15-year-old boy is reported who presented with severe systemic inflammation, perimyocarditis and cardiogenic shock, in whom EGPA was initially suspected and later diagnosed with autoimmune adrenalitis with PGA. CONCLUSIONS: The severity of the systemic inflammation and perimyocarditis suggests a more widespread autoimmune-mediated process. Autoimmune adrenal insufficiency should be considered in all cases of pericarditis and perimyocarditis, especially when the severity of clinical manifestations exceeds the expected for the severity of the cardiac findings, as timely identification and prompt treatment may be life-saving.


Assuntos
Doença de Addison/diagnóstico , Miocardite/diagnóstico , Pericardite/diagnóstico , Pericárdio/patologia , Doença de Addison/complicações , Adolescente , Humanos , Masculino , Miocardite/etiologia , Pericardite/etiologia , Prognóstico
19.
Pediatrics ; 140(5)2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29079714

RESUMO

Pigmentary hypertrichosis and non-autoimmune insulin-dependent diabetes mellitus (PHID) is associated with recessive mutations in SLC29A3, encoding the equilibrative nucleoside transporter hENT3 expressed in mitochondria, causing PHID and H syndromes, familial Rosai-Dorfman disease, and histiocytosis-lymphadenopathy-plus syndrome. Autoinflammation is increasingly recognized in these syndromes. We previously reported a 16-year-old girl with PHID syndrome associated with severe autoinflammation that was recalcitrant to interleukin-1 and tumor necrosis factor-α blockade. Tocilizumab is a humanized, monoclonal, anti-human interleukin-6 receptor antibody routinely used to treat arthritis in children and adults. Herein we report the first case of successful treatment of PHID syndrome using tocilizumab. Before commencing tocilizumab, there was evidence of significant systemic inflammation, and progressive sclerodermatous changes (physician global assessment [PGA] 7/10). Twelve weeks after starting tocilizumab (8 mg/kg every 2 weeks, intravenously) systemic inflammatory symptoms improved, and acute phase response markers normalized; serum amyloid A reduced from 178 to 8.4 mg/L. After a dose increase to 12 mg/kg every 2 weeks her energy levels, appetite, fevers, and night sweats further improved. Less skin tightness (PGA 5/10) was documented 12 months later. This excellent clinical and serological response was sustained over 48 months, and cutaneous sclerosis had improved further (PGA 3/10). Her height remained well below the 0.4th centile, and tocilizumab also had no impact on her diabetes or exocrine pancreatic insufficiency. Although the mechanism of autoinflammation of PHID remains uncertain, we suggest that tocilizumab should be the first choice when considering treatment of the autoinflammatory or cutaneous manifestations of this genetic disease.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Contratura/tratamento farmacológico , Contratura/genética , Perda Auditiva Neurossensorial/tratamento farmacológico , Perda Auditiva Neurossensorial/genética , Histiocitose/tratamento farmacológico , Histiocitose/genética , Mutação/genética , Proteínas de Transporte de Nucleosídeos/genética , Adolescente , Contratura/diagnóstico , Feminino , Perda Auditiva Neurossensorial/diagnóstico , Histiocitose/diagnóstico , Humanos , Síndrome , Resultado do Tratamento
20.
PLoS One ; 12(7): e0181874, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28750028

RESUMO

BACKGROUND: Monogenic autoinflammatory diseases (AID) are a rapidly expanding group of genetically diverse but phenotypically overlapping systemic inflammatory disorders associated with dysregulated innate immunity. They cause significant morbidity, mortality and economic burden. Here, we aimed to develop and evaluate the clinical impact of a NGS targeted gene panel, the "Vasculitis and Inflammation Panel" (VIP) for AID and vasculitis. METHODS: The Agilent SureDesign tool was used to design 2 versions of VIP; VIP1 targeting 113 genes, and a later version, VIP2, targeting 166 genes. Captured and indexed libraries (QXT Target Enrichment System) prepared for 72 patients were sequenced as a multiplex of 16 samples on an Illumina MiSeq sequencer in 150bp paired-end mode. The cohort comprised 22 positive control DNA samples from patients with previously validated mutations in a variety of the genes; and 50 prospective samples from patients with suspected AID in whom previous Sanger based genetic screening had been non-diagnostic. RESULTS: VIP was sensitive and specific at detecting all the different types of known mutations in 22 positive controls, including gene deletion, small INDELS, and somatic mosaicism with allele fraction as low as 3%. Six/50 patients (12%) with unclassified AID had at least one class 5 (clearly pathogenic) variant; and 11/50 (22%) had at least one likely pathogenic variant (class 4). Overall, testing with VIP resulted in a firm or strongly suspected molecular diagnosis in 16/50 patients (32%). CONCLUSIONS: The high diagnostic yield and accuracy of this comprehensive targeted gene panel validate the use of broad NGS-based testing for patients with suspected AID.


Assuntos
Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Inflamação/genética , Vasculite/genética , Idoso , Criança , Pré-Escolar , DNA/genética , Feminino , Heterozigoto , Humanos , Masculino , Mutação/genética , Reprodutibilidade dos Testes
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