The clinical significance of small copy number variants in neurodevelopmental disorders

Background: Despite abundant evidence for pathogenicity of large copy number variants (CNVs) in neurodevelopmental disorders (NDDs), the individual significance of genome-wide rare CNVs <500 kb has not been well elucidated in a clinical context. Methods: By high-resolution chromosomal microarray analysis, we investigated the clinical significance of all rare non-polymorphic exonic CNVs sizing 1–500 kb in a cohort of 714 patients with undiagnosed NDDs. Results: We detected 96 rare CNVs <500 kb affecting coding regions, of which 58 (60.4%) were confirmed. 6 of 14 confirmed de novo, one of two homozygous and four heterozygous inherited CNVs affected the known microdeletion regions 17q21.31, 16p11.2 and 2p21 or OMIM morbid genes (CASK, CREBBP, PAFAH1B1, SATB2; AUTS2, NRXN3, GRM8). Two further de novo CNVs affecting single genes (MED13L, CTNND2) were instrumental in delineating novel recurrent conditions. For the first time, we here report exonic deletions of CTNND2 causing low normal IQ with learning difficulties with or without autism spectrum disorder. Additionally, we discovered a homozygous out-of-frame deletion of ACOT7 associated with features comparable to the published mouse model. In total, 24.1% of the confirmed small CNVs were categorised as pathogenic or likely pathogenic (median size 130 kb), 17.2% as likely benign, 3.4% represented incidental findings and 55.2% remained unclear. Conclusions: These results verify the diagnostic relevance of genome-wide rare CNVs <500 kb, which were found pathogenic in ∼2% (14/714) of cases (1.1% de novo, 0.3% homozygous, 0.6% inherited) and highlight their inherent potential for discovery of new conditions

The clinical significance of small copy number variants in neurodevelopmental disorders

BACKGROUND Despite abundant evidence for pathogenicity of large copy number variants (CNVs) in neurodevelopmental disorders (NDDs), the individual significance of genome-wide rare CNVs <500 kb has not been well elucidated in a clinical context. METHODS By high-resolution chromosomal microarray analysis, we investigated the clinical significance of all rare non-polymorphic exonic CNVs sizing 1-500 kb in a cohort of 714 patients with undiagnosed NDDs. RESULTS We detected 96 rare CNVs <500 kb affecting coding regions, of which 58 (60.4%) were confirmed. 6 of 14 confirmed de novo, one of two homozygous and four heterozygous inherited CNVs affected the known microdeletion regions 17q21.31, 16p11.2 and 2p21 or OMIM morbid genes (CASK, CREBBP, PAFAH1B1, SATB2; AUTS2, NRXN3, GRM8). Two further de novo CNVs affecting single genes (MED13L, CTNND2) were instrumental in delineating novel recurrent conditions. For the first time, we here report exonic deletions of CTNND2 causing low normal IQ with learning difficulties with or without autism spectrum disorder. Additionally, we discovered a homozygous out-of-frame deletion of ACOT7 associated with features comparable to the published mouse model. In total, 24.1% of the confirmed small CNVs were categorised as pathogenic or likely pathogenic (median size 130 kb), 17.2% as likely benign, 3.4% represented incidental findings and 55.2% remained unclear. CONCLUSIONS These results verify the diagnostic relevance of genome-wide rare CNVs <500 kb, which were found pathogenic in ∼2% (14/714) of cases (1.1% de novo, 0.3% homozygous, 0.6% inherited) and highlight their inherent potential for discovery of new conditions

Development and Nutrition of Ocotea odorifera (canela sassafrás) Submitted to the Fertilization and Omission of Nutrients Crescimento e Nutrição de Ocotea odorifera (Canela Sassafrás) Submetido à Fertilização e à Omissão de Nutrientes

&lt;p&gt;The present paper has as objective the evaluation of the nutritional aspects, fertilization effect and omission of nutrients in the plants grow of canela sassafras (Ocotea odorifera (Vell.) Rohwer), in a vegetation house for 24 months, consisting of 11 treatments and five repetitions, with seasonal collections, using the springer material. The treatments consisted of control (natural soil), complete fertilization (N, P, K, Ca, Mg, S, Zn and B), fertilization with individual nutrients omission (-N, -P, -K, -Ca, -Mg, -S, -B, -Zn) and organic fertilization (bovine manure). Natural fertility soil and plants of canela sassafras originally from natural  regeneration dispossess in causality statistical  delineation were utilized. The height, diameter length and biomass were evaluated. To the development in height of the canela sassafras, the more limited  nutrient were sulphur and to the diameter  length was the fertilization with macro and micronutrients, but there was no significant difference between the treatments. The roots dry mass reduced when used macro and  micronutrients fertilization, and the dry mass of the  aerial part with the omission of N and P. The organic fertilization demonstrated to be efficient, so much for the increment in height, as for the production of foliar mass.&lt;/p&gt;&lt;p&gt; &lt;/p&gt;&lt;p&gt;doi: 10.4336/2009.pfb.58.17&lt;/p&gt;&lt;p&gt;Avaliaram-se os aspectos nutricionais e o efeito da fertilização e da omissão de nutrientes no desenvolvimento de plântulas de canela sassafrás (Ocotea odorifera (Vell.) Rohwer), conduzido em casa de vegetação durante 24 meses, constando de 11 tratamentos e cinco repetições, com coletas sazonais, sendo utilizado o material obtido na primavera. Os tratamentos consistiram de controle (solo natural), adubação completa (N, P, K, Ca, Mg, S, Zn, B), adubação com omissão individual de nutrientes (-N, -P, -K, -Ca, -Mg, -S, -B, -Zn) e tratamento com adubação orgânica (esterco bovino curtido). Foram utilizados vasos com solo de baixa fertilidade natural e plântulas de canela sassafrás oriundas de regeneração natural dispostos em delineamento estatístico inteiramente casualizado. Foram avaliados desenvolvimento em altura, diâmetro do colo e biomassa. Para o crescimento em altura da canela sassafrás, o nutriente mais limitante foi o enxofre, e para o diâmetro do colo foi a fertilização com macro e micronutrientes, embora não tenha havido diferença significativa entre os tratamentos. A massa seca radicular foi reduzida quando da fertilização com macro e micronutrientes e a massa seca aérea quando se omitiu N e P. A adubação orgânica demonstrou ser eficiente, tanto para o incremento em altura, quanto para a produção de massa foliar.&lt;/p&gt;&lt;p&gt; &lt;/p&gt;&lt;p&gt;&lt;span class="t"&gt;doi:&lt;/span&gt;&lt;span class="m"&gt; &lt;/span&gt;&lt;span class="tx"&gt;10.4336/2009.pfb.58.17&lt;/span&gt;&lt;/p&gt

The genetic relationship between handedness and neurodevelopmental disorders

Handedness and brain asymmetry have been linked to neurodevelopmental disorders such as dyslexia and schizophrenia. The genetic nature of this correlation is not understood. Recent discoveries have shown handedness is determined in part by the biological pathways that establish left/right (LR) body asymmetry during development. Cilia play a key role in this process, and candidate genes for dyslexia have also been recently shown to be involved in cilia formation. Defective cilia result not only in LR body asymmetry phenotypes but also brain midline phenotypes such as an absent corpus callosum. These findings suggest that the mechanisms for establishing LR asymmetry in the body are reused for brain midline development, which in turn influences traits such as handedness and reading ability.Publisher PDFPeer reviewe

The heavy subunit of ferritin stimulates NLRP3 inflammasomes in hepatic stellate cells through ICAM-1 to drive hepatic inflammation

Serum ferritin concentrations increase during hepatic inflammation and correlate with the severity of chronic liver disease. Here, we report a molecular mechanism whereby the heavy subunit of ferritin (FTH) contributes to hepatic inflammation. We found that FTH induced activation of the NLRP3 inflammasome and secretion of the proinflammatory cytokine interleukin-1β (IL-1β) in primary rat hepatic stellate cells (HSCs) through intercellular adhesion molecule-1 (ICAM-1). FTH-ICAM-1 stimulated the expression of , NLRP3 inflammasome activation, and the processing and secretion of IL-1β in a manner that depended on plasma membrane remodeling, clathrin-mediated endocytosis, and lysosomal destabilization. FTH-ICAM-1 signaling at early endosomes stimulated expression, implying that this endosomal signaling primed inflammasome activation in HSCs. In contrast, lysosomal destabilization was required for FTH-induced IL-1β secretion, suggesting that lysosomal damage activated inflammasomes. FTH induced IL-1β production in liver slices from wild-type mice but not in those from or mice. Thus, FTH signals through its receptor ICAM-1 on HSCs to activate the NLRP3 inflammasome. We speculate that this pathway contributes to hepatic inflammation, a key process that stimulates hepatic fibrogenesis associated with chronic liver disease

RV SONNE Fahrtbericht / Cruise Report SO277 OMAX: Offshore Malta Aquifer Exploration, Emden (Germany) – Emden (Germany), 14.08. – 03.10.2020

SO277 OMAX served two scientific projects. The objectives of the first project, SMART, were to develop multi-disciplinary methodologies to detect, quantify, and model offshore groundwater reservoirs in regions dominated by carbonate geology such as the Mediterranean Sea. To this end we acquired controlled-source electromagnetic, seismic, hydroacoustic, geochemical, seafloor imagery data off Malta. Preliminary evaluation of the geophysical data show that there are resisitivity anomalies that may represent offshore freshwater aquifers. The absence of evidence for offshore springs means that these aquifers would be confined and that it will be difficult to use them in a sustainable manner. The objective of the second project, MAPACT-ETNA, is to monitor the flank of Etna volcano on Sicily which is slowly deforming seaward. Here, we deployed six seafloor geodesy stations and six ocean bottom seismometers for long-term observation (1-3 years). In addition, we mapped the seafloor off Mt. Etna and off the island of Stromboli to constrain the geological processes that control volcanic flank stability