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1.
J Allergy Clin Immunol ; 145(1): 368-378.e13, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31194989

RESUMO

BACKGROUND: Cryopyrin-associated periodic syndromes (CAPS) are a group of autoinflammatory diseases linked to gain-of-function mutations in the NOD-like receptor family, pyrin domain containing 3 (NLRP3) gene, which cause uncontrolled IL-1ß secretion. Proton pump inhibitors (PPIs), which are commonly used as inhibitors of gastric acid production, also have anti-inflammatory properties, protect mice from sepsis, and prevent IL-1ß secretion by monocytes from patients with CAPS. OBJECTIVE: We sought to develop a novel Nlrp3 knock-in (KI) mouse model of CAPS to study amyloidosis, a severe CAPS complication, and test novel therapeutic approaches. METHODS: We generated KI mice by engineering the N475K mutation, which is associated with the CAPS phenotype, into the mouse Nlrp3 gene. KI and wild-type mice received PPIs or PBS intraperitoneally and were analyzed for survival, inflammation, cytokine secretion, and amyloidosis development. RESULTS: Mutant Nlrp3 KI mice displayed features that recapitulate the immunologic and clinical phenotype of CAPS. They showed systemic inflammation with high levels of serum proinflammatory cytokines, inflammatory infiltrates in various organs, and amyloid deposits in the spleen, liver, and kidneys. Toll-like receptor stimulated macrophages from KI mice secreted high levels of IL-1ß, IL-18, and IL-1α but low amounts of IL-1 receptor antagonist. Treatment of KI mice with PPIs had a clear clinical effect, showing a reduction in inflammatory manifestations, regression of amyloid deposits, and normalization of proinflammatory and anti-inflammatory cytokine production by macrophages. CONCLUSION: Nlrp3 KI mice displayed a CAPS phenotype with many characteristics of autoinflammation, including amyloidosis. The therapeutic effectiveness of PPIs associated with a lack of toxicity indicates that these drugs could represent relevant adjuvants to the anti-IL-1 drugs in patients with CAPS and other IL-1-driven diseases.

3.
Rheumatology (Oxford) ; 59(2): 344-360, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31325311

RESUMO

OBJECTIVES: The number of innate immune system disorders classified as systemic autoinflammatory diseases (SAID) has increased in recent years. More than 70% of patients with clinical manifestations of SAID did not receive a molecular diagnosis, thus being classed as so-called undifferentiated or undefined SAID (uSAID). The aim of the present study was to evaluate a next-generation sequencing (NGS)-based clinically oriented protocol in patients with uSAID. METHODS: We designed a NGS panel that included 41 genes clustered in seven subpanels. Patients with uSAID were classified into different groups according to their clinical features and sequenced for the coding portions of the 41 genes. RESULTS: Fifty patients were enrolled in the study. Thirty-four patients (72%) displayed recurrent fevers not consistent with a PFAPA phenotype. Sixteen patients displayed a chronic inflammatory disease course. A total of 100 gene variants were found (mean 2 per patient; range 0-6), a quarter of which affected suspected genes. Mutations with a definitive diagnostic impact were detected in two patients. Patients with genetically negative recurrent fevers displayed a prevalent gastrointestinal, skin and articular involvement. Patients responded to steroids on demands (94%) and colchicine, with a response rate of 78%. CONCLUSION: Even with a low molecular diagnostic rate, a NGS-based approach is able to provide a final diagnosis in a proportion of uSAID patients with evident cost-effectiveness. It also allows the identification of a subgroup of genetically negative patients with recurrent fever responding to steroid on demand and colchicine.

4.
Clin Genet ; 97(1): 103-113, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31444792

RESUMO

Paired Like homeobox 2B (PHOX2B) is a gene crucial for the differentiation of the neural lineages of the autonomic nervous system (ANS), whose coding mutations cause congenital central hypoventilation syndrome (CCHS). The vast majority of PHOX2B mutations in CCHS is represented by expansions of a polyalanine region in exon 3, collectively defined PARMs (PolyAlanine Repeat Mutations), the minority being frameshift, missense and nonsense mutations, defined as NPARMs (Non-PARMs). While PARMs are nearly exclusively associated with isolated CCHS, most of NPARMs is detected in syndromic CCHS, presenting with neuroblastoma and/or Hirschsprung disease. More recently, evidence of a complex role of PHOX2B in the pathogenesis of a wider spectrum of ANS disorders has emerged. Indeed, common and hypomorphic PHOX2B variants, including synonymous, polyalanine-contractions, gene deletions may influence the occurrence of either apparent life-threatening event (ALTE), Sudden Infant Death Syndrome (SIDS), neuroblastoma, or isolated HSCR, likely through small effects on PHOX2B expression levels. After an introduction to the role of PHOX2B in the ANS development, causative mutations, common variants, and gene expression deregulation of the PHOX2B gene are discussed, though the involvement of synonymous variants and contractions requires further confirmations with respect to ANS disorders and molecular mechanisms underlying the PHOX2B phenotypic heterogeneity.

5.
Artigo em Inglês | MEDLINE | ID: mdl-31876783

RESUMO

In recent years, monogenic causes of immune dysregulation syndromes, with variable phenotypes, have been documented. Mutations in the lipopolysaccharide-responsive beige-like anchor (LRBA) protein are associated with common variable immunodeficiency, autoimmunity, chronic enteropathy, and immune dysregulation disorders. The LRBA protein prevents degradation of cytotoxic T-lymphocyte antigen 4 (CTLA4) protein, thus inhibiting immune responses. Both LRBA and CTLA4 deficiencies usually present with immune dysregulation, mostly characterized by autoimmunity and lymphoproliferation. In this report, we describe a patient with an atypical clinical onset of LRBA deficiency and the patient's response to abatacept, a fusion protein-drug that mimics the action of CTLA4.

6.
Front Neurol ; 10: 1124, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31781017

RESUMO

Alexander disease (AxD) is a rare, autosomal dominant neurological disorder. Three clinical subtypes are distinguished based on age at onset: infantile (0-2 years), juvenile (2-13 years), and adult (>13 years). The three forms differ in symptoms and prognosis. Rapid neurological decline with a fatal course characterizes the early-onset forms, while symptoms are milder and survival is longer in the adult forms. Currently, the sole known cause of AxD is mutations in the GFAP gene, which encodes a type III intermediate filament protein that is predominantly expressed in astrocytes. A wide spectrum of GFAP mutations comprising point mutations, small insertions, and deletions is associated with the disease. The genotype-phenotype correlation remains unclear. The considerable heterogeneity in severity of disease among individuals carrying identical mutations suggests that other genetic or environmental factors probably modify age at onset or progression of AxD. Describing new cases is therefore important for establishing reliable genotype-phenotype correlations and revealing environmental factors able to modify age at onset or progression of AxD. We report the case of a 54-year-old Caucasian woman, previously diagnosed with ovarian cancer and treated with surgery and chemotherapy, who developed dysarthria, ataxia, and spastic tetraparesis involving mainly the left side. Cerebral and spinal magnetic resonance imaging (MRI) revealed a peculiar tadpole-like atrophy of the brainstem. Genetic analysis of the GFAP gene detected a heterozygous mutation in exon 1 (c.219G>C), resulting in an amino acid exchange from methionine to isoleucine at codon 73 (p.M73I). The expression of this mutant in vitro affected the formation of the intermediate filament network. Thus, we have identified a new GFAP mutation in a patient with an adult form of AxD.

7.
Orphanet J Rare Dis ; 14(1): 270, 2019 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-31767031

RESUMO

BACKGROUND: Hirschsprung Disease (HSCR) is a congenital defect of the intestinal innervations characterized by complex inheritance. Many susceptibility genes including RET, the major HSCR gene, and several linked regions and associated loci have been shown to contribute to disease pathogenesis. Nonetheless, a proportion of patients still remains unexplained. Copy Number Variations (CNVs) have already been involved in HSCR, and for this reason we performed Comparative Genomic Hybridization (CGH), using a custom array with high density probes. RESULTS: A total of 20 HSCR candidate regions/genes was tested in 55 sporadic patients and four patients with already known chromosomal aberrations. Among 83 calls, 12 variants were experimentally validated, three of which involving the HSCR crucial genes SEMA3A/3D, NRG1, and PHOX2B. Conversely RET involvement in HSCR does not seem to rely on the presence of CNVs while, interestingly, several gains and losses did co-occur with another RET defect, thus confirming that more than one predisposing event is necessary for HSCR to develop. New loci were also shown to be involved, such as ALDH1A2, already found to play a major role in the enteric nervous system. Finally, all the inherited CNVs were of maternal origin. CONCLUSIONS: Our results confirm a wide genetic heterogeneity in HSCR occurrence and support a role of candidate genes in expression regulation and cell signaling, thus contributing to depict further the molecular complexity of the genomic regions involved in the Enteric Nervous System development. The observed maternal transmission bias for HSCR associated CNVs supports the hypothesis that in females these variants might be more tolerated, requiring additional alterations to develop HSCR disease.

8.
Front Pediatr ; 7: 326, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31448249

RESUMO

Objectives: Since 2010, several researches demonstrated that microbiota dynamics correlate and can even predispose to Hirschsprung (HSCR) associated enterocolitis (HAEC). This study aims at assessing the structure of the microbiota of HSCR patients in relation to extent of aganglionosis and HAEC status. Methods: All consecutive HSCR patients admitted to Gaslini Institute (Genova, Italy) between May 2012 and November 2014 were enrolled. Institutional review board (IRB) approval was obtained. Stools were sampled and 16S rDNA V3-V4 regions were sequenced using the Illumina-MiSeq. Taxonomy assignments were performed using QIIME RDP. Alpha diversity indexes were analyzed by Shannon and Simpson Indexes, and Phylogenetic Diversity. Results: We enrolled 20 patients. Male to female ratio was 4:1. Six patients suffered from Total Colonic Aganglionosis (TCSA). Considering sample site (i.e., extent of aganglionosis), we confirmed the known relationship between sample site and both biodiversity and composition of intestinal microbiota. Patients with TCSA showed lower biodiversity and increased Proteobacteria/Bacteroidetes relative abundance ratio. When addressing biodiversity, composition and dynamics of TCSA patients we could not find any significant relationship with regard to HAEC occurrences. Conclusions: The composition of HAEC predisposing microbiota is specific to each patient. We could confirm that total colon resections can change the composition of intestinal microbiota and to dramatically reduce microbial diversity. The subsequent reduction of system robustness could expose TCSA patients to environmental microbes that might not be part of the normal microbiota. Future long-term studies should investigate both patients and their family environment, as well as their disease history.

9.
Ital J Pediatr ; 45(1): 111, 2019 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-31443670

RESUMO

BACKGROUND: Familial Mediterranean Fever is a monogenic autoinflammatory disease, typically characterized by recurrent attacks of fever, serositis, aphthous of oral mucosa, erythema. "Pyogenic arthritis, pyoderma gangrenosum and acne syndrome" is a rare autoinflammatory disease with variable expression and typically involving joints and skin. Both the diseases are linked by the overproduction of IL-1. CASE PRESENTATION: We report on the case of two siblings affected by recurrent attacks of fever, oral aphthous stomatitis, abdominal pain, arthritis, undefined dermatitis at the hands, associated with increased AST, ALT, C-reactive protein, erythrocyte sedimentation rate, serum amyloid A, leucocytosis with neutrophilia. Infectious diseases were excluded. The genetic study for Familial Mediterranean Fever, tumor necrosis factor receptor-associated periodic syndrome, Mevalonate kinase deficiency, showed the homozygous mutation p.M680I of exon 10 in MEFV. Their parents were heterozygous for the same mutation p.M680I, however, the mother showed severe symptoms of FMF (recurrent attacks of fever, arthralgia and arthritis, abdominal pain, thoracic pain), the father showed recurrent pustulosis prevalent on the hands and limbs, with arthralgia and abdominal pain. Both the patients started colchicine, with an improvement in clinical manifestations and a reduction of serum amyloid A. For the atypical dermatologic signs present in the two siblings and in the father, the study of other autoinflammatory syndromes was performed with next generation sequencing and showed the heterozygous rare missense mutation of unknown significance: p.(Val408Ile) of PSTPIP1 gene in the two siblings and in the mother, the father was negative. Canakinumab treatment was started in the younger patient, with the resolution of the clinical symptoms and the normalization of serum amyloid A. CONCLUSIONS: Further studies are needed to better describe the correlation between genotype and phenotype in patients with PAPA syndrome and with PAPA syndrome associated with FMF, considering that the presence of mutations in both genes may amplify clinical presentation and evolution of both diseases.

10.
Br J Haematol ; 187(4): 502-508, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31309545

RESUMO

Autoimmune lymphoproliferative syndrome (ALPS) is a congenital disorder that results in an apoptosis impairment of lymphocytes, leading to chronic lymphoproliferation and autoimmunity, mainly autoimmune cytopenias. FAS gene defects are often responsible for the disease, the phenotype of which can vary from asymptomatic/mild forms to severe disease. More rarely, defects are associated to  other genes involved in apoptosis pathway, such as CASP10. Few data are available on CASP10-mutated patients. To date, two CASP10 mutations have been recognized as pathogenic (I406L and L258F) and others have been reported with controversial result on their pathogenicity (V410l, Y446C) or are known to be polymorphic variants (L522l). In this study, we evaluated apoptosis function in patients with an ALPS/ALPS-like phenotype carrying CASP10 variants. Molecular findings were obtained by next generation sequencing analysis of genes involved in immune dysregulation syndromes. Functional studies were performed after inducing apoptosis by FAS-ligand/TRIAL stimulation and analysing cell death and the function of CASP10, CASP8 and PARP proteins. We identified 6 patients with an ALPS (n = 2) or ALPS-like (n = 4) phenotype, carrying I406L (n = 1),V410l (n = 2),Y446C (n = 1) heterozygous CASP10 variants or the L522l polymorphisms (n = 2) associated with another polymorphic homozygote variant on CASP8 or a compound heterozygous mutation on TNFRSF13C. Apoptosis was impaired in all patients showing that such variants may play a role in the development of clinical phenotype.

11.
Eur J Hum Genet ; 27(10): 1502-1508, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31186541

RESUMO

Monogenic autoinflammatory disorders (AIDs) are rare diseases caused by variants in genes regulating the innate immune system. The identification of the first four genes responsible for the prototype group of hereditary recurrent fevers prompted the development of genetic diagnosis, followed by external quality assessment and guidelines for the interpretation of sequence variants in these diseases. Recent changes in the diagnosis of genetic diseases, namely the implementation of next-generation sequencing (NGS), lead to discovery of the new genes associated with at least 40 novel AIDs, which revolutionized patient care and prognosis. However, these rapid advances resulted in nonstandardized molecular strategies that can influence genetic diagnosis and reporting of results. In order to assess factors, which may have an impact on performance and quality of results in the NGS era, we carried out an online survey among member laboratories of the European Molecular Genetics Quality Network, which highlighted different strategies being used and identified pitfalls that deserve discussion and improvement.

12.
Rheumatol Int ; 2019 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-31062074

RESUMO

Blau syndrome is a rare autosomal dominant monogenic auto-inflammatory disorder characterized by triad of granulomatous polyarthritis, dermatitis, and uveitis. However, it may be difficult to recognize this syndrome in the absence of all three characteristic clinical manifestations. A 3-year-old girl presented with early onset symmetric polyarthritis and developed granulomatous uveitis at 13 years of age. However, Blau syndrome was suspected at 21 years of age when she was diagnosed to have disseminated granulomas in liver and kidneys. Diagnosis of Blau syndrome was confirmed by finding a mutation in NOD2 gene (p.Arg334Gln; FP2678). She was initiated on adalimumab therapy and she showed good response to this treatment. We did a literature search to find out all reported cases of Blau syndrome with disseminated granulomatous inflammation and all cases of Blau syndrome that were treated with adalimumab therapy. Seventeen patients with Blau syndrome have been reported to have granulomas at unusual locations (liver; kidneys; lungs; salivary glands; intestine; and lymph nodes). Adalimumab has been reported to be used in 33 patients with Blau syndrome. The indication to initiate adalimumab in large majority of these patients was persistence of uveitis. A possibility of Blau syndrome should be considered in all children presenting with early onset arthritis (especially with the presence of boggy swelling) and granulomatous uveitis. Granulomas in the liver and kidney are uncommon disease manifestations. Adalimumab may be an effective treatment for patients with Blau syndrome who are resistant to other forms of therapy.

13.
Clin Immunol ; 205: 25-28, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31096039

RESUMO

Systemic inflammation in neonates is attributable to an infection in almost all cases. When inflammation persists, an autoinflammatory disease should be promptly suspected. We report here a case of mevalonate kinase deficiency (MKD) that presented at birth with mild symptoms and signs suggestive for a perinatal infection, together with the uncommon finding of interstitial lung disease. An extensive diagnostic work-up, performed after ineffective antibiotic treatment, demonstrated high levels of mevalonic acid in urine (7024 mM/M of creatinine, normal value <0.1). Next-generation sequencing showed a rare c.709A > T (p.T237S) homozygous mutation in the MVK gene, consistent with MKD. Treatment with anakinra led to a prompt resolution of symptoms and a sharp drop in serum inflammatory markers. The patient is now six months-old, currently undergoing evaluation for hematopoietic stem-cell transplantation. To our knowledge, this is the first case of MKD presenting within the first week of life with interstitial lung disease.

14.
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.

16.
Exp Cell Res ; 370(2): 671-679, 2018 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-30036539

RESUMO

The paired-like homeobox 2B gene (PHOX2B) encodes a key transcription factor that plays a role in the development of the autonomic nervous system and the neural structures involved in controlling breathing. In humans, PHOX2B over-expression plays a role in the pathogenesis of tumours arising from the sympathetic nervous system such as neuroblastomas, and heterozygous PHOX2B mutations cause Congenital Central Hypoventilation Syndrome (CCHS), a life-threatening neurocristopathy characterised by the defective autonomic control of breathing and involving altered CO2/H+ chemosensitivity. The recovery of CO2/H+ chemosensitivity and increased ventilation have been observed in two CCHS patients using the potent contraceptive progestin desogestrel. Given the central role of PHOX2B in the pathogenesis of CCHS, and the progesterone-mediated effects observed in the disease, we generated progesterone-responsive neuroblastoma cells, and evaluated the effects of 3-Ketodesogestrel (3-KDG), the biologically active metabolite of desogestrel, on the expression of PHOX2B and its target genes. Our findings demonstrate that, through progesterone nuclear receptor PR-B, 3-KDG down-regulates PHOX2B gene expression, by a post-transcriptional mechanism, and its target genes and open up the possibility that this mechanism may contribute to the positive effects observed in some CCHS patients.


Assuntos
Desogestrel/farmacologia , Proteínas de Homeodomínio/efeitos dos fármacos , Células-Tronco Neurais/efeitos dos fármacos , Progesterona/genética , Fatores de Transcrição/efeitos dos fármacos , Núcleo Celular/metabolismo , Regulação para Baixo/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Hipoventilação/congênito , Hipoventilação/genética , Células-Tronco Neurais/metabolismo , Neuroblastoma/tratamento farmacológico , Neuroblastoma/genética , Apneia do Sono Tipo Central/genética , Fatores de Transcrição/metabolismo
17.
Eur J Paediatr Neurol ; 22(4): 725-728, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29709427

RESUMO

Pseudoxanthoma elasticum (PXE) is a rare genetic disorder characterized by fragmented and mineralized elastic fibers in the mid-dermis of the skin, eye, digestive tract and cardiovascular system. Clinical presentation includes typical skin lesions, ocular angioid streaks, and multisystem vasculopathy. The age of onset varies considerably from infancy to old age, but the diagnosis is usually made in young adults due to frequent absence of pathognomonic skin and ocular manifestations in early childhood. We report two children with PXE presenting with isolated multisystem vasculopathy and early-onset stroke. In the first patient, diagnosis was delayed until typical dermatologic alterations appeared; in the second patient, next-generation sequencing (NGS) study led to early diagnosis and specific follow-up, underlying the crucial role in idiopathic pediatric stroke of early genetic testing using NGS-based panels.


Assuntos
Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Pseudoxantoma Elástico/complicações , Pseudoxantoma Elástico/diagnóstico , Pseudoxantoma Elástico/genética , Acidente Vascular Cerebral/genética , Adolescente , Pré-Escolar , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Mutação
18.
J Forensic Leg Med ; 58: 1-5, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29679838

RESUMO

The heterozygous PHOX2B gene mutation is related to congenital central hypoventilation syndrome (CCHS). It is characterized by defective autonomous nervous system development leading to inadequate breathing response to hypoxia and hypercapnia, leading to hypoventilation especially during non-REM sleep, but also during waking in the more severe cases. Herein we report a case of sudden death in a 28-day-old child. The mother reported the infant was found lying on her own bed in the prone position. The infant was wearing a romper and lying in her crib without any blanket or other objects. At autopsy no significant pathological findings were detected. Histologically, sparse aspirated milk residues were present in some lung fields. Toxicological and microbiological examinations were within the norm. The initial postmortem investigation ruled out any readily identifiable cause of death. However, genetic analysis revealed a rare heterozygous 21bp in-frame deletion of the polyalanine coding sequences of the PHOX2B gene. In-frame contractions of the poly-Ala tract of the PHOX2B gene have already been reported in patients with symptoms suggestive of sporadic hypoventilation, apparent life-threatening events or neonatal respiratory distress.


Assuntos
Proteínas de Homeodomínio/genética , Hipoventilação/congênito , Apneia do Sono Tipo Central/genética , Morte Súbita do Lactente/etiologia , Fatores de Transcrição/genética , Feminino , Heterozigoto , Humanos , Hipoventilação/genética , Recém-Nascido , Deleção de Sequência
19.
J Med Genet ; 55(8): 530-537, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29599418

RESUMO

BACKGROUND: Hereditary recurrent fevers (HRFs) are rare inflammatory diseases sharing similar clinical symptoms and effectively treated with anti-inflammatory biological drugs. Accurate diagnosis of HRF relies heavily on genetic testing. OBJECTIVES: This study aimed to obtain an experts' consensus on the clinical significance of gene variants in four well-known HRF genes: MEFV, TNFRSF1A, NLRP3 and MVK. METHODS: We configured a MOLGENIS web platform to share and analyse pathogenicity classifications of the variants and to manage a consensus-based classification process. Four experts in HRF genetics submitted independent classifications of 858 variants. Classifications were driven to consensus by recruiting four more expert opinions and by targeting discordant classifications in five iterative rounds. RESULTS: Consensus classification was reached for 804/858 variants (94%). None of the unsolved variants (6%) remained with opposite classifications (eg, pathogenic vs benign). New mutational hotspots were found in all genes. We noted a lower pathogenic variant load and a higher fraction of variants with unknown or unsolved clinical significance in the MEFV gene. CONCLUSION: Applying a consensus-driven process on the pathogenicity assessment of experts yielded rapid classification of almost all variants of four HRF genes. The high-throughput database will profoundly assist clinicians and geneticists in the diagnosis of HRFs. The configured MOLGENIS platform and consensus evolution protocol are usable for assembly of other variant pathogenicity databases. The MOLGENIS software is available for reuse at http://github.com/molgenis/molgenis; the specific HRF configuration is available at http://molgenis.org/said/. The HRF pathogenicity classifications will be published on the INFEVERS database at https://fmf.igh.cnrs.fr/ISSAID/infevers/.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Variação Genética , Doenças Hereditárias Autoinflamatórias/diagnóstico , Doenças Hereditárias Autoinflamatórias/genética , Fluxo de Trabalho , Alelos , Biologia Computacional/métodos , Consenso , Bases de Dados Genéticas , Gerenciamento Clínico , Estudos de Associação Genética/métodos , Testes Genéticos , Humanos , Fenótipo , Guias de Prática Clínica como Assunto , Navegador
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