Erratum: The genomic architecture of NLRP7 is Alu rich and predisposes to disease-associated large deletions

NLRP7 is a major gene responsible for recurrent hydatidiform moles. Here, we report 11 novel NLRP7 protein truncating variants, of which five deletions of more than 1-kb. We analyzed the transcriptional consequences of four variants. We demonstrate that one large homozygous deletion removes NLRP7 transcription start site and results in the complete absence of its transcripts in a patient in good health besides her reproductive problem. This observation strengthens existing data on the requirement of NLRP7 only for female reproduction. We show that two other variants affecting the splice acceptor of exon 6 lead to its in-frame skipping while another variant affecting the splice donor site of exon 9 leads to an in-frame insertion of 54 amino acids. Our characterization of the deletion breakpoints demonstrated that most of the breakpoints occurred within Alu repeats and the deletions were most likely mediated by microhomology events. Our data define a hotspot of Alu instability and deletions in intron 5 with six different breakpoints and rearrangements. Analysis of NLRP7 genomic sequences for repetitive elements demonstrated that Alu repeats represent 48% of its intronic sequences and these repeats seem to have been inserted into the common NLRP2/7 primate ancestor before its duplication into two genes

Le déficit en mévalonate kinase en 2016

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Is gene panel sequencing more efficient than clinical-based gene sequencing to diagnose autoinflammatory diseases? A randomized study

International audienceThe aim of this study was to compare the effectiveness of the gene-panel next-generation sequencing (NGS) strategy versus the clinical-based gene Sanger sequencing for the genetic diagnosis of autoinflammatory diseases (AIDs). Secondary goals were to describe the gene and mutation distribution in AID patients and to evaluate the impact of the genetic report on the patient's medical care and treatment. Patients with AID symptoms were enrolled prospectively and randomized to two arms, NGS (n = 99) (32–55 genes) and Sanger sequencing (n = 197) (one to four genes). Genotypes were classified as ‘consistent/confirmatory’, ‘uncertain significance’ or ‘non-contributory’. The proportion of patients with pathogenic genotypes concordant with the AID phenotype (consistent/confirmatory) was significantly higher with NGS than Sanger sequencing [10 of 99 (10·1%) versus eight of 197 (4·1%)]. MEFV, ADA2 and MVK were the most represented genes with a consistent/confirmed genotype, whereas MEFV, NLRP3, NOD2 and TNFRSF1A were found in the ‘uncertain significance’ genotypes. Six months after the genetic report was sent, 54 of 128 (42·2%) patients had received effective treatment for their symptoms; 13 of 128 (10·2%) had started treatment after the genetic study. For 59 of 128 (46%) patients, the results had an impact on their overall care, independent of sequencing group and diagnostic conclusion. Targeted NGS improved the diagnosis and global care of patients with AIDs

Mefv/Mir-326 Axis Involvement In Human Macrophage Polarization

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La fièvre récurrente liée au récepteur 1 du TNF ( TNF receptor associated periodic syndrome – TRAPS)

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NLRC4~associated autoinflammatory diseases: A systematic review of the current literature

International audienceThe auto-inflammatory diseases linked to NLRC4~mutations are recently described entities. Transmission is autosomal dominant in 80~% of cases; cases of somatic mutation have already been reported. The disease may display two very different clinical phenotypes: the phenotype 1 (30~%), severe, is dominated by a multisystemic inflammation starting in the first year of life with symptoms of chronic inflammatory bowel disease (IBD), macrophagic actication syndrome (MAS), or even a presentation suggesting a cryopyrinopathy in its CINCA form; the mortality of this phenotype is high (25~%). The phenotype 2 (70~%), mild, usually starts after the age of 3~and is characterized by cold urticaria, arthralgia, ocular features and fever in 50~% of cases without visceral failure. Anti-interleukin-1~inhibitors are effective in most cases (83~%). Interleukin-18 (IL-18) levels are very high in both clinical forms. Interleukin-18~inhibitors and anti-interferon-gamma inhibitors were remarkably effective in two very severe phenotype 1~patients. Thus, NLRC4~mutations can induce various clinical manifestations with two distinct phenotypes. Although still rare, because very recently described, this group of diseases could be evoked by an internist in front of cold familial urticarial; probably more and more cases will be diagnosed thanks to the major progresses of genetic diagnostic tools such as next generation sequencing

Les multiples facettes du déficit en ADA2, vascularite, maladie auto-inflammatoire et immunodéficit : mise au point à partir des 135 cas de la littérature

International audienceDeficiency of adenosine deaminase 2 (DADA2) is a recently described auto-inflammatory disorder. It is an autosomal recessive inherited disease, caused by mutations in the ADA2 gene (formerly known as CECR1) encoding ADA2 enzyme. Besides its role in the purine metabolism, it has been postulated that ADA2 may act as a growth factor for endothelial cells and in the differenciation of monocytes. Thus, deficiency of ADA2 would lead to endothelial damage and a skewing of monocytes into M1 pro-inflammatory macrophage, causing DADA2 manifestations. Three core clinical features have been described: inflammatory-vascular signs, hematologic abnormalities and immunodeficiency. Clinically, patients display intermittent fever, cutaneous vascular manifestations, such as livedo, ischemic strokes, arthralgia and abdominal pain crisis. Corticosteroids and immunosuppressive agents (i.e. cyclophosphamide, azathioprine, ciclosporin, methotrexate) appear to be poorly effective. Although the mechanism has not been elucidated, anti-TNF agents have been proven efficient in DADA2 and should therefore be used as first line therapy for vasculitis. Role of anti-platelet and anticoagulant therapies in stroke-prophylaxis remains to be discussed, as those patients display a high risk of intracranial bleeding.Le déficit en adénosine déaminase 2 (DADA2) est une maladie auto-inflammatoire rare de description récente. Elle est de transmission génétique autosomique récessive, liée des mutations du gène ADA2 (ou CECR1) codant pour l’enzyme ADA2. Outre son rôle dans le métabolisme des purines, ADA2 agirait comme facteur de croissance pour les cellules endothéliales et dans la différenciation des monocytes ; ainsi ce serait la déviation en macrophages M1 pro-inflammatoire et la survenue de lésions endothéliales secondaires à l’absence d’ADA2 qui seraient à l’origine des manifestations du DADA2. Ses manifestations se regroupent en trois grands types : vasculaire inflammatoire, hématologique et immunologique pouvant remplir les critères diagnostiques d’une périartérite noueuse, d’une aplasie médullaire ou d’un déficit immunitaire commun, variable respectivement. Cliniquement, il existe des manifestations vasculaires cutanées, telles qu’un livedo, et une atteinte du système nerveux central à type d’accidents vasculaires cérébraux ischémiques et hémorragiques, ainsi que des arthralgies et des atteintes digestives. Les corticoïdes et les immunosuppresseurs sont peu efficaces et le traitement repose sur les anti-TNF pour les formes inflammatoires, sans que le mécanisme expliquant leur efficacité ne soit parfaitement élucidé. Ces derniers doivent être introduits en première intention. La place des antithrombotiques est débattue en raison du sur-risque d’hémorragie cérébrale