Epidémiologie et Epidémiogénétique de l'hémochromatose HFE 1 (stratégies de dépistage, facteurs modificateurs et pénétrance du génotype C282Y homozygote)

Les hémochromatoses génétiques ou surcharges en fer primaires désignent des maladies innées du métabolisme du fer. La forme principale, l'hémochromatose héréditaire de type 1 (HFE 1), est aujourd'hui connue comme étant la maladie héréditaire la plus fréquente chez les descendants des populations du Nord-Ouest de l'Europe (prévalence comprise entre 3 et 8 pour 1000). La majorité des surcharges en fer primaires est associée à la mutation C282Y du gène HFE. Cette pathologie, transmise selon un mode autosomique récessif, est caractérisée par une hyperabsorption intestinale du fer. Sans traitement déplétif, le fer s'accumule dans le parenchyme de nombreux organes à l'origine de complications articulaires, endocriniennes (diabète, hypogonadisme), cardiaques et hépatiques (cirrhose avec risque de carcinome hépatocellulaire). De par ses caractéristiques, l'hémochromatose HFE 1 répond à de nombreux critères permettant d'entreprendre son dépistage précoce. Dans ce travail, nous rapportons, dans un premier temps, les résultats de différentes expériences de dépistage effectué dans 1) une population d'assurés sociaux volontaires pour un bilan de santé, 2) une population de patients hospitalisés dans les services d'endocrinologie, de médecine interne et de rhumatologie du CHU d'Amiens, 3) une population de nouveau-nés. Un des obstacles majeurs à la mise en place d'un dépistage systématique concerne la pénétrance incomplète de l'homozygotie C282Y. Dans le but d'établir une estimation de la pénétrance dans le département de la Somme, nous avons défini, comme critère de pénétrance complète, la soustraction de 5 grammes de fer au moins comme capables de normaliser les paramètres du métabolisme du fer. Cette pénétrance, dite thérapeutique, a ainsi pu être estimée à 26%. La mise en évidence de différences dans l'expressivité de la maladie chez des sujets de même génotype, y compris au sein d'une même famille, a permis de suggérer l'existence de gènes modificateurs modulateurs ou aggravants. Une partie de ce travail a ainsi porté sur l'étude de deux "modificateurs" potentiels à savoir le gène HAMP et le variant mitochondrial T16189C. Les résultats obtenus nous ont permis de suggérer d'une part, l'existence d'un mode de transmission digénique de surcharges en fer primaires associant des mutations dans les gènes HFE et HAMP et, d'autre part, que la gravité de la surcharge en fer des sujets C282Y homozygotes était fortement associée à la présence du variant mitochondrial 16189. Nous rapportons enfin l'identification d'une nouvelle mutation (G490D) dans le gène codant la ferroportine chez 3 individus de la même famille. Depuis la découverte du gène HFE en 1996, de nouvelles notions relatives à l'hémochromatose génétique sont donc apparues, celles de pénétrance incomplète du génotype morbide, de gènes modificateurs identifiés et d'hétérogénéité génétique. Les résultats acquis montrent l'importance de l'épidémiogénétique dans une politique de dépistage de la maladieAMIENS-BU Santé (800212102) / SudocSudocFranceF

PREVENTION DU SYNDROME D'HYPERPHENYLALANINEMIE FOETAL CHEZ UNE PHENYLCETONURIQUE

AMIENS-BU Santé (800212102) / SudocSudocFranceF

JAK2 allele burden is correlated with a risk of venous but not arterial thrombosis

International audienceBackground: Thrombosis is the main complication in myeloproliferative neoplasms (MPN). A JAK2V617F mu-tation has been shown to be a risk factor for thrombosis. The implication of other risk factors alongside a mu-tation allele burden needs to be clarified (Trifa et al., 2018; Borowczyk et al., 2015). Objective: Our aim was to investigate the role of the JAK2 mutation allele burden in the risk of cardiovascular events (CVE) and/or venous thrombosis (VTE) in a cohort of patients with confirmed MPN, as well as in patients without confirmed MPN. Methods: We restrospectively included all consecutive patients who were positive for JAK2V617F seen by our unit between December 2008 and September 2016. Inclusion criteria were a positive test for the JAK2V617F mutation, with at least 1% allele burden, with or without confirmed MPN. Results: We included 239 patients of median age 71 years [60-81], followed-up for a median of 82.8 months [41.08-146.88]. For JAK2V617F positive patients having an allele burden superior to 50% the cumulative incidence of VTE was significantly higher than for those with an allele burden inferior to 50% (HR 3.11 95% CI [1.10-8.76] p = 0.031). The cumulative incidence of VTE was also higher in patients with obesity (HR 4.58 95% CI [1.33-15.8] p = 0.016). There was no significant association between a JAK2V617F allele burden and arterial thrombosis (manifesting as CVE). Previous VTE was also associated with a higher cumulative incidence of recurrence during follow-up HR 3.22 95% CI [1.17-8.81] p = 0.0231. Conclusion: We show that a JAK2V617F allele burden is associated with risk of VTE but not with CVE

A New Intergenic α -Globin Deletion ( α – α Δ125 ) Found in a Kabyle Population

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New intragenic rearrangements in non-Finnish mulibrey nanism

International audiencePrenatal growth is a complex dynamic process controlled by various genetic and environmental factors. Among genetic syndromes characterized by growth restriction, MULIBREY nanism represents a rare autosomal recessive condition presenting with severe pre- and post-natal growth failure, characteristic dysmorphic features but normal neurological development. The phenotype of MULIBREY nanism is variable and overlaps with others such as the Silver-Russell syndrome. We report here three patients in two distinct non-Finnish families from North France who were first suspected to have Silver-Russell syndrome which failed to be confirmed on molecular analyses. Clinical features in the three patients led us to also consider the diagnosis of MULIBREY nanism. Sequencing of the TRIM37 gene showed the three patients shared a novel nonsense mutation (c.181 C>T p.Arg61*) in a heterozygous state. Quantitative fluorescent multiplex PCR identified a new deletion of exons 15 and 16 in TRIM37 in one isolated patient and another deletion of exon 9 in two siblings. Breakpoints of both the deletions were localized in Alu sequences. Given the high number of Alu repeats, which predispose to gene rearrangements, one should always consider such genetic rearrangements in the molecular diagnosis of non-Finnish MULIBREY nanism patients. Early diagnosis of the disease would prompt careful cardiac follow up of such patients as cardiological complication is a characteristic feature of the MULIBREY nanism as described in this report

New intragenic rearrangements in non-Finnish MULIBREY nanism

50th European-Society-of-Human-Genetics (ESHG) Conference, Copenhagen, DENMARK, MAY 27-30, 2017International audienc

Click-Crosslinked Injectable Gelatin Hydrogels

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Comprehensive functional annotation of 18 missense mutations found in suspected hemochromatosis type 4 patients

International audienceHemochromatosis type 4 is a rare form of primary iron overload transmitted as an autosomal dominant trait caused by mutations in the gene encoding the iron transport protein ferroportin 1 (SLC40A1). SLC40A1 mutations fall into two functional categories (loss- versus gain-of-function) underlying two distinct clinical entities (hemochromatosis type4Aversus type 4B). However, the vast majority ofSLC40A1 mutations are rare missense variations, with only a few showing strong evidence of causality. The present study reports the results of an integrated approach collecting genetic and phenotypic data from 44 suspected hemochromatosis type 4 patients, with comprehensive structural and functional annotations. Causality was demonstrated for 10 missense variants, showing a clear dichotomy between the two hemochromatosis type 4 subtypes. Two subgroups of loss-of-function mutations were distinguished: one impairing cell-surface expression and one altering only iron egress. Additionally, a new gain-of-function mutation was identified, and the degradation of ferroportin on hepcidin binding was shown to probably depend on the integrity of a large extracellular loop outside of the hepcidin-binding domain. Eight further missense variations, on the other hand, were shown to have no discernible effects at either protein or RNA level; these were found in apparently isolated patients and were associated with a less severe phenotype. The present findings illustrate the importance ofcombining in silico and biochemical approaches to fully distinguish pathogenic SLC40A1 mutations from benign variants. This has profound implications for patient management