Expanding the clinical and genetic spectrum of ALPK3 variants: Phenotypes identified in pediatric cardiomyopathy patients and adults with heterozygous variants

Introduction: Biallelic damaging variants in ALPK3, encoding alpha-protein kinase 3, cause pediatric-onset cardiomyopathy with manifestations that are incompletely defined. Methods and Results: We analyzed clinical manifestations of damaging biallelic ALPK3 variants in 19 pediatric patients, including nine previously published cases. Among these, 11 loss-of-function (LoF) variants, seven compound LoF and deleterious missense variants, and one homozygous deleterious missense variant were identified. Among 18 live-born patients, 8 exhibited neonatal dilated cardiomyopathy (44.4%; 95% CI: 21.5%-69.2%) that subsequently transitioned into ventricular hypertrophy. The majority of patients had extracardiac phenotypes, including contractures, scoliosis, cleft palate, and facial dysmorphisms. We observed no association between variant type or location, disease severity, and/or extracardiac manifestations. Myocardial histopathology showed focal cardiomyocyte hypertrophy, subendocardial fibroelastosis in patients under 4 years of age, and myofibrillar disarray in adults. Rare heterozygous ALPK3 variants were also assessed in adult-onset cardiomyopathy patients. Among 1548 Dutch patients referred for initial genetic analyses, we identified 39 individuals with rare heterozygous ALPK3 variants (2.5%; 95% CI: 1.8%-3.4%), including 26 missense and 10 LoF variants. Among 149 U.S. patients without pathogenic variants in 83 cardiomyopathy-related genes, we identified six missense and nine LoF ALPK3 variants (10.1%; 95% CI: 5.7%-16.1%). LoF ALPK3 variants were increased in comparison to matched controls (Dutch cohort, P = 1.6×10−5; U.S. cohort, P = 2.2×10−13). Conclusion: Biallelic damaging ALPK3 variants cause pediatric cardiomyopathy manifested by DCM transitioning to hypertrophy, often with poor contractile function. Additional extracardiac features occur in most patients, including musculoskeletal abnormalities and cleft palate. Heterozygous LoF ALPK3 variants are enriched in adults with cardiomyopathy and may contribute to their cardiomyopathy. Adults with ALPK3 LoF variants therefore warrant evaluations for cardiomyopathy

A miniature world in decline: European Red List of Mosses, Liverworts and Hornworts

AimThis Red List is a summary of the conservation status of the European species of mosses, liverworts and hornworts, collectively known as bryophytes, evaluated according to IUCN’s Guidelines for Application of IUCN Red List Criteria at Regional Level. It provides the first comprehensive, region-wide assessment of bryophytes and it identifies those species that are threatened with extinction at a European level, so that appropriate policy measures and conservation actions, based on the best available evidence, can be taken to improve their status.ScopeAll bryophytes native to or naturalised in Europe (a total of 1,817 species), have been included in this Red List. In Europe, 1,796 species were assessed, with the remaining 21 species considered Not Applicable (NA). For the EU 28, 1,728 species were assessed, with a remaining 20 species considered NA and 69 species considered Not Evaluated (NE). The geographical scope is continentwide, extending from Iceland in the west to the Urals in the east, and from Franz Josef Land in the north to theCanary Islands in the south. The Caucasus region is not included. Red List assessments were made at two regional levels: for geographical Europe and for the 28 Member States of the European Union.ResultsOverall, 22.5% of European bryophyte species assessed in this study are considered threatened in Europe, with two species classified as Extinct and six assessed as Regionally Extinct (RE). A further 9.6% (173 species) are considered Near Threatened and 63.5% (1,140 species) are assessed as Least Concern. For 93 species (5.3%), there was insufficient information available to be able to evaluate their risk of extinction and thus they were classified as Data Deficient (DD). The main threats identified were natural system modifications (i.e., dam construction, increases in fire frequency/intensity, and water management/use), climate change (mainly increasing frequency of droughts and temperature extremes), agriculture (including pollution from agricultural effluents) and aquaculture.RecommendationsPolicy measures• Use the European Red List as the scientific basis to inform regional/national lists of rare and threatened species and to identify priorities for conservation action in addition to the requirements of the Habitats Directive, thereby highlighting the conservation status of bryophytes at the regional/local level.• Use the European Red List to support the integration of conservation policy with the Common Agricultural Policy (CAP) and other national and international policies. For example, CAP Strategic Plans should include biodiversity recovery commitments that could anticipate, among others, the creation of Important Bryophyte Areas. An increased involvement of national environmental agencies in the preparation of these strategic plans, and more broadly in ongoing discussions on the Future CAP Green Architecture, would likely also ensure the design of conservation measures better tailored to conserve bryophytes in agricultural landscapes.• Update the European Red List every decade to ensure that the data remains current and relevant.• Develop Key Biodiversity Areas for bryophytes in Europe with a view to ensuring adequate site-based protection for bryophytes.Research and monitoring• Use the European Red List as a basis for future targeted fieldwork on possibly extinct and understudied species.• Establish a monitoring programme for targeted species (for example, threatened species and/or arable bryophytes).• Use the European Red List to obtain funding for research into the biology and ecology of key targeted species.Action on the ground• Use the European Red List as evidence to support multi-scale conservation initiatives, including designation of protected areas, reform of agricultural practices and land management, habitat restoration and rewilding, and pollution reduction measures.• Use the European Red List as a tool to target species that would benefit the most from the widespread implementation of the solutions offered by the 1991 Nitrates Directive (Council Directive 91/676/EEC), including the application of correct amounts of nutrients for each crop, only in periods of crop growth under suitable climatic conditions and never during periods of heavy rainfall or on frozen ground, and the creation of buffer zones to protect waters from run-off from the application of fertilizers.Ex situ conservation• Undertake ex situ conservation of species of conservation concern in botanic gardens and spore and gene banks, with a view to reintroduction where appropriate.</p

Azole-resistant Aspergillus fumigatus, Iran

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