Specifications of the ACMG/AMP variant curation guidelines for hereditary hemorrhagic telangiectasia genes - ENG and ACVRL1

13 p.-1 fig.-3 tab.The 2015 ACMG/AMP standards and guidelines for interpretation of sequence variants are widely used by laboratories, including for variant curation of the hereditary hemorrhagic telangiectasia (HHT) genes. However, the need for gene- and disease-specific modifications and specifications of these general guidelines to optimize and standardize variant classification was recognized at the time of publication. With this goal, the ClinGen HHT variant curation expert panel was formed. Here, we describe our recommended HHT-specific variant classification criteria and the outcomes from pilot testing of 30 variants of the ENG and ACVRL1 genes. Eight of the original ACMG/AMP rules were determined to not be applicable for ENG- or ACVRL1-related HHT or were previously recommended by ClinGen for removal, two rules were unmodified, and the remaining 18 rules were modified according to HHT specifications or previous ClinGen general recommendations. This study demonstrates the importance of HHT-specific criteria in the optimization and standardization of HHT variant classification and conflicting classification resolution. © 2024 Desiree DeMille et al.The authors would like to acknowledge the support of the ClinGen Sequence Variant Interpretation Working Group and the Hemostasis/Thrombosis Clinical Domain Working Group, especially Kristy Lee. The authors would also like to acknowledge the participation of previous ClinGen HHT VCEP members: Pernille Tørring, Hans Kristian Ploos van Amstel, and Helen Arthur. CLS acknowledges support from the NIHR Imperial Biomedical Research Centre. LJ acknowledges support from Knut and Alice Wallenberg Foundation grant (2018.0042) and Swedish Research Council grant (2020-04936). CB was supported by Consejo Superior de Investigaciones Cientificas (CSIC) of Spain. CC, CO,and AS are funded by the Italian Ministry of University and Research, “Fondo Beneficenza Intesa Sanpaolo,” and Banca d’Italia. ClinGen is primarily funded by the National Human Genome Research Institute (NHGRI) with cofunding from the National Cancer Institute (NCI), through the following grants: Baylor/Stanford (U24HG009649), Broad/Geisinger(U24HG006834), and UNC/Kaiser (U24HG009650).Peer reviewe

Essential metal contents in indigenous gammarids related to exposure levels at the river basin scale: Metal-dependent models of bioaccumulation and geochemical correlations

Biomonitoring, assumed to be an integrative measurement of the chemical exposure of aquatic organisms, is not straightforward for essential metals because they can be actively regulated by animals. Although increasing bioaccumulation with exposure levels is a crucial endpoint for the development of biomonitors, it is rarely verified in real environments, where the metal concentrations are rather low and vary little. This study was designed at the scale of a river basin to assess the ability of Gammarus pulex indigenous populations to accumulate Cu, Zn and Mn in realistic exposure conditions. During two annual campaigns, water and gammarids were collected at various sites contrasted in terms of physicochemistry and contamination. The results show significant relationships between metal concentrations in animals and in freshwaters established by conceptual models of bioaccumulation, but with patterns specific to each metal (base level, internal regulation and maximal accumulation). In particular, a saturation process of Cu accumulation occurs at environmental exposure levels, unlike Mn and Zn. Statistical analyses performed from field data show that Cu and Zn bioaccumulations may be influenced by a complex combination of geochemical variables, unlike Mn. We conclude that G. pulex is a useful candidate to monitor metal bioavailability in freshwaters due to its responsiveness to low exposures of surrounding environments. Nevertheless, a reliable quantification of bioavailability of essential metals requires characterizing some geochemical effects on metal bioaccumulation

Biodisponibilité des métaux particulaires chez la dreissène

Après avoir étudié les facteurs de contrôles de la bioaccumulation des métaux par voie dissoute chez la dreissène en 2008 [2], nous avons cherché au cours de l'année 2009 à quantifier les apports par voie trophique

Les métaux échantillonnés par la DGT sont-ils représentatifs de la fraction biodisponible ?

International audienceBioavailability of trace metals for aquatic organisms in the dissolved compartment of water is usually interpreted with the Free Ion Activity Model (FIAM) and its extension, the Biotic Ligand Model (BLM). Under fame generally hypothesis, the FIAM states that the biological response to a metal exposure is proportional to the activity of the free-ion {Mz+} in solution. The BLM generalizes this concept and includes competition between metal and major cations (Ca2+, Mg2+, Na+, K+ and H+) on specific binding sites at the surface of the biological membrane. As a speciation device, DGT samples labile metal concentration: free ion plus a fraction of organic metal complexes. It is claimed to estimate bioavailable fractions of metals. The aim of this communication is to synthesize the results of some recent work comparing biological response and labile fraction sampled by DGT in order to evaluate the ability of DGT to assess bioavailability. We investigated two types of biological responses: acute toxicity and bioaccumulation. In the first part, DGT were used to measure metals inducing lethality on daphnia magna during acute toxicity tests. Various media were studied: synthetic organic ligands, humic acids, and natural organic matter (algae and river extracts, wastewater), with two types of gels (classical open pores and restrictive pores). Copper and cadmium were studied. Measurements by DGT equipped with restricted gels appear to be in good agreement with inorganic fraction of metal, even if labile fraction could overestimate bioavailable fraction. In the second part, the accumulation of copper by aquatic mosses at environmentally relevant concentrations (1-5 µg.L-1) and with various organic ligands is compared to DGT-labile restricted gels measurements. In this case, DGT tends to underestimate the bioavailable fraction. This suggests that not only inorganic copper but also some weak organic complexes are available for aquatic mosses at realistic metal concentrations. Finally, we discuss the role of major cations in the bioavailability of copper, in the cases of acute toxicity and bioaccumulation at realistic environmental concentrations. Ca2+ and Mg2+ compete indeed with copper and play a protective role, which would not be highlighted by the sampling with DGT

Les métaux échantillonnés par la DGT sont-ils représentatifs de la fraction biodisponible ?

[Notes_IRSTEA]Présentation PowerPoint de 14 diapositives [Departement_IRSTEA]Eaux [TR1_IRSTEA]BELCAInternational audienceBioavailability of trace metals for aquatic organisms in the dissolved compartment of water is usually interpreted with the Free Ion Activity Model (FIAM) and its extension, the Biotic Ligand Model (BLM). Under fame generally hypothesis, the FIAM states that the biological response to a metal exposure is proportional to the activity of the free-ion {Mz+} in solution. The BLM generalizes this concept and includes competition between metal and major cations (Ca2+, Mg2+, Na+, K+ and H+) on specific binding sites at the surface of the biological membrane. As a speciation device, DGT samples labile metal concentration: free ion plus a fraction of organic metal complexes. It is claimed to estimate bioavailable fractions of metals. The aim of this communication is to synthesize the results of some recent work comparing biological response and labile fraction sampled by DGT in order to evaluate the ability of DGT to assess bioavailability. We investigated two types of biological responses: acute toxicity and bioaccumulation. In the first part, DGT were used to measure metals inducing lethality on daphnia magna during acute toxicity tests. Various media were studied: synthetic organic ligands, humic acids, and natural organic matter (algae and river extracts, wastewater), with two types of gels (classical open pores and restrictive pores). Copper and cadmium were studied. Measurements by DGT equipped with restricted gels appear to be in good agreement with inorganic fraction of metal, even if labile fraction could overestimate bioavailable fraction. In the second part, the accumulation of copper by aquatic mosses at environmentally relevant concentrations (1-5 µg.L-1) and with various organic ligands is compared to DGT-labile restricted gels measurements. In this case, DGT tends to underestimate the bioavailable fraction. This suggests that not only inorganic copper but also some weak organic complexes are available for aquatic mosses at realistic metal concentrations. Finally, we discuss the role of major cations in the bioavailability of copper, in the cases of acute toxicity and bioaccumulation at realistic environmental concentrations. Ca2+ and Mg2+ compete indeed with copper and play a protective role, which would not be highlighted by the sampling with DGT

Waterborne nickel bioaccumulation in Gammarus pulex: Comparison of mechanistic models and influence of water cationic composition

The biodynamic and saturation models offer promising lines of enquiry to predict the bioaccumulation of metals by aquatic organisms. However, in order to construct these models, the accumulation strategies have to be defined for each metal/organism couple in controlled conditions. This study aims at modelling the waterborne bioaccumulation of Ni and the influence of the water's geochemical properties on this process in a crustacean that is widely distributed in Europe, Gammarus pulex. In the laboratory, G. pulex was exposed to several Ni concentrations (from 0.001 to 100 mg L(-1)) in aquatic microcosms. Our results show that G. pulex is very tolerant to Ni (LC50(48 h) = 477 mg L(-1) Ni). Time course experiments enabled the construction of a biodynamic model by determining the uptake (k(u)) and elimination (k(e)) rate constants. When the exposure concentration exceeded 1 mg L(-1) Ni, the metal uptake reached a maximum due to a limited number of binding sites for Ni. Therefore, the organism's maximal capacity to accumulate the metal (B(max)) and the half-saturation constant (K) were determined to establish the saturation model. We showed that the two models are comparable for the lowest exposure concentrations (<1 mg L(-1) Ni), with k(u)/k(e) = B(max)/K. Then, the bioaccumulation of Ni was recorded in waters exhibiting various concentrations of three major ions (Na(+), Mg(2+) and Ca(2+)). Only Ca had an inhibitory effect on the Ni uptake. This study reports for the first time the bioaccumulation of Ni in G. pulex. Because of its high tolerance to Ni and its high capacity to accumulate this metal, this crustacean could be used as an indicator of Ni bioavailability in freshwaters. (C) 2011 Elsevier B.V. All rights reserved