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Purpose: This study aims to comprehensively delineate the phenotypic spectrum of ACTL6B-related disorders, previously associated with both autosomal recessive and autosomal dominant neurodevelopmental disorders. Molecularly, the role of the nucleolar protein ACTL6B in contributing to the disease has remained unclear., Methods: We identified 105 affected individuals, including 39 previously reported cases, and systematically analysed detailed clinical and genetic data for all individuals. Additionally, we conducted knockdown experiments in neuronal cells to investigate the role of ACTL6B in ribosome biogenesis., Results: Biallelic variants in ACTL6B are associated with severe-to-profound global developmental delay/intellectual disability (GDD/ID), infantile intractable seizures, absent speech, autistic features, dystonia, and increased lethality. De novo monoallelic variants result in moderate-to-severe GDD/ID, absent speech, and autistic features, while seizures and dystonia were less frequently observed. Dysmorphic facial features and brain abnormalities, including hypoplastic corpus callosum, parenchymal volume loss/atrophy, are common findings in both groups. We reveal that in the nucleolus, ACTL6B plays a crucial role in ribosome biogenesis, in particular in pre-rRNA processing., Conclusion: This study provides a comprehensive characterization of the clinical spectrum of both autosomal recessive and dominant forms of ACTL6B-associated disorders. It offers a comparative analysis of their respective phenotypes provides a plausible molecular explanation and suggests their inclusion within the expanding category of 'ribosomopathies'., (Copyright © 2024. Published by Elsevier Inc.)

Background: Genetic variants that cause rare disorders may remain elusive even after expansive testing, such as exome sequencing. The diagnostic yield of genome sequencing, particularly after a negative evaluation, remains poorly defined., Methods: We sequenced and analyzed the genomes of families with diverse phenotypes who were suspected to have a rare monogenic disease and for whom genetic testing had not revealed a diagnosis, as well as the genomes of a replication cohort at an independent clinical center., Results: We sequenced the genomes of 822 families (744 in the initial cohort and 78 in the replication cohort) and made a molecular diagnosis in 218 of 744 families (29.3%). Of the 218 families, 61 (28.0%) - 8.2% of families in the initial cohort - had variants that required genome sequencing for identification, including coding variants, intronic variants, small structural variants, copy-neutral inversions, complex rearrangements, and tandem repeat expansions. Most families in which a molecular diagnosis was made after previous nondiagnostic exome sequencing (63.5%) had variants that could be detected by reanalysis of the exome-sequence data (53.4%) or by additional analytic methods, such as copy-number variant calling, to exome-sequence data (10.8%). We obtained similar results in the replication cohort: in 33% of the families in which a molecular diagnosis was made, or 8% of the cohort, genome sequencing was required, which showed the applicability of these findings to both research and clinical environments., Conclusions: The diagnostic yield of genome sequencing in a large, diverse research cohort and in a small clinical cohort of persons who had previously undergone genetic testing was approximately 8% and included several types of pathogenic variation that had not previously been detected by means of exome sequencing or other techniques. (Funded by the National Human Genome Research Institute and others.)., (Copyright © 2024 Massachusetts Medical Society.)

Microbial-based biostimulants are emerging as effective strategies to improve agricultural productivity; however, the modes of action of such formulations are still largely unknown. Thus, herein we report elucidated metabolic reconfigurations in maize (Zea mays) leaves associated with growth promotion and drought stress tolerance induced by a microbial-based biostimulant, a Bacillus consortium. Morphophysiological measurements revealed that the biostimulant induced a significant increase in biomass and enzymatic regulators of oxidative stress. Furthermore, the targeted metabolomics approach revealed differential quantitative profiles in amino acid-, phytohormone-, flavonoid- and phenolic acid levels in plants treated with the biostimulant under well-watered, mild, and severe drought stress conditions. These metabolic alterations were complemented with gene expression and global DNA methylation profiles. Thus, the postulated framework, describing biostimulant-induced metabolic events in maize plants, provides actionable knowledge necessary for industries and farmers to confidently and innovatively explore, design and fully implement microbial-based formulations and strategies into agronomic practices for sustainable agriculture and food production., (© 2022. The Author(s).)

Humic substance (HS)-based biostimulants show potentials as sustainable strategies for improved crop development and stress resilience. However, cellular and molecular mechanisms governing the agronomically observed effects of HS on plants remain enigmatic. Here, we report a global metabolic reprogramming of maize leaves induced by a humic biostimulant under normal and nutrient starvation conditions. This reconfiguration of the maize metabolism spanned chemical constellations, as revealed by molecular networking approaches. Plant growth and development under normal conditions were characterized by key differential metabolic changes such as increased levels of amino acids, oxylipins and the tricarboxylic acid (TCA) intermediate, isocitric acid. Furthermore, under starvation, the humic biostimulant significantly impacted pathways that are involved in stress-alleviating mechanisms such as redox homeostasis, strengthening of the plant cell wall, osmoregulation, energy production and membrane remodelling. Thus, this study reveals that the humic biostimulant induces a remodelling of inter-compartmental metabolic networks in maize, subsequently readjusting the plant physiology towards growth promotion and stress alleviation. Such insights contribute to ongoing efforts in elucidating modes of action of biostimulants, generating fundamental scientific knowledge that is necessary for development of the biostimulant industry, for sustainable food security.