Clinical and molecular characterization of patients with YWHAG‐related epilepsy

Objective YWHAG variant alleles have been associated with a rare disease trait whose clinical synopsis includes an early onset epileptic encephalopathy with predominantly myoclonic seizures, developmental delay/intellectual disability, and facial dysmorphisms. Through description of a large cohort, which doubles the number of reported patients, we further delineate the spectrum of YWHAG-related epilepsy. Methods We included in this study 24 patients, 21 new and three previously described, with pathogenic/likely pathogenic variants in YWHAG. We extended the analysis of clinical, electroencephalographic, brain magnetic resonance imaging, and molecular genetic information to 24 previously published patients. Results The phenotypic spectrum of YWHAG-related disorders ranges from mild developmental delay to developmental and epileptic encephalopathy (DEE). Epilepsy onset is in the first 2 years of life. Seizure freedom can be achieved in half of the patients (13/24, 54%). Intellectual disability (23/24, 96%), behavioral disorders (18/24, 75%), neurological signs (13/24, 54%), and dysmorphisms (6/24, 25%) are common. A genotype–phenotype correlation emerged, as DEE is more represented in patients with missense variants located in the ligand-binding domain than in those with truncating or missense variants in other domains (90% vs. 19%, p < .001). Significance This study suggests that pathogenic YWHAG variants cause a wide range of clinical presentations with variable severity, ranging from mild developmental delay to DEE. In this allelic series, a genotype–phenotype correlation begins to emerge, potentially providing prognostic information for clinical management and genetic counseling

Spliceosome malfunction causes neurodevelopmental disorders with overlapping features

Pre-mRNA splicing is a highly coordinated process. While its dysregulation has been linked to neurological deficits, our understanding of the underlying molecular and cellular mechanisms remains limited. We implicated pathogenic variants in U2AF2 and PRPF19, encoding spliceosome subunits in neurodevelopmental disorders (NDDs), by identifying 46 unrelated individuals with 23 de novo U2AF2 missense variants (including 7 recurrent variants in 30 individuals) and 6 individuals with de novo PRPF19 variants. Eight U2AF2 variants dysregulated splicing of a model substrate. Neuritogenesis was reduced in human neurons differentiated from human pluripotent stem cells carrying two U2AF2 hyper-recurrent variants. Neural loss of function (LoF) of the Drosophila orthologs U2af50 and Prp19 led to lethality, abnormal mushroom body (MB) patterning, and social deficits, which were differentially rescued by wild-type and mutant U2AF2 or PRPF19. Transcriptome profiling revealed splicing substrates or effectors (including Rbfox1, a third splicing factor), which rescued MB defects in U2af50deficient flies. Upon reanalysis of negative clinical exomes followed by data sharing, we further identified 6 patients with NDD who carried RBFOX1 missense variants which, by in vitro testing, showed LoF. Our study implicates 3 splicing factors as NDD-causative genes and establishes a genetic network with hierarchy underlying human brain development and function

Style and Literary (Self-)Translation

Il numero monografico Style and Literary (Self-)Translation raccoglie i risultati di una ricerca interdisciplinare sullo stile e la traduzione letteraria interlinguistica del XX e del XXI secolo, proponendo metodi di analisi dello stile di testi tradotti, ritradotti e autotradotti, come anche dello stile di traduttori allografi e di autotraduttori, cioè di autori che hanno tradotto proprie opere. A dare avvio a questa indagine è stato il ciclo di conferenze e workshops intitolato Autotraduzioni e traduzioni allografe del XX e del XXI secolo: una ricerca sullo stile del traduttore e dell’autotraduttore letterario / Self-translations and Translations of the 20th and 21st Century: an investigation on the style of literary translators and self-translators svoltosi online, dal mese di maggio al mese di dicembre del 2021, sulla piattaforma Google Meet dell’Università degli Studi di Cassino e del Lazio Meridionale. L’iniziativa – a carattere internazionale – è nata grazie a una sinergia tra il Laboratorio di Tecnologia, Narrativa e Analisi del Linguaggio (TECNAL) del Dipartimento di Scienze Umane, Sociali e della Salute dell’Università degli Studi di Cassino e del Lazio Meridionale (responsabile scientifico Roberto Baronti Marchiò) e il gruppo di ricerca Mediatori e Traduttori Europei (METE) del Dipartimento di Storia, Patrimonio culturale, Formazione e Società dell’Università di Roma Tor Vergata (coordinatrice Gabriella Catalano). Gli obiettivi di ricerca di questo ciclo sono frutto delle attività di un più piccolo gruppo di lavoro e di ricerca sull’autotraduzione e sulla traduzione letteraria del XX e del XXI secolo, formato da Rainier Grutman (University of Ottawa), Eva Gentes (Düsseldorf), Rossana Sebellin (METE, Università di Roma Tor Vergata), Simona Anselmi (Università Cattolica di Milano e Piacenza) e coordinato da Alessandra D’Atena (METE e TECNAL, Università degli Studi di Cassino e del Lazio Meridionale)

Notulae to the Italian native vascular flora: 13

In this contribution, new data concerning the distribution of native vascular flora in Italy are presented. It includes new records, confirmations, and exclusions to the Italian administrative regions. Nomenclatural and distribution updates, published elsewhere, and corrigenda are provided as Suppl. material 1

Notulae to the Italian native vascular flora: 13

In this contribution, new data concerning the distribution of native vascular flora in Italy are presented. It includes new records, confirmations, and exclusions to the Italian administrative regions. Nomenclatural and distribution updates, published elsewhere, and corrigenda are provided as Suppl. materia

Spliceosome malfunction causes neurodevelopmental disorders with overlapping features

: Pre-mRNA splicing is a highly coordinated process. While its dysregulation has been linked to neurological deficits, our understanding of the underlying molecular and cellular mechanisms remains limited. We implicated pathogenic variants in U2AF2 and PRPF19, encoding spliceosome subunits in neurodevelopmental disorders (NDDs), by identifying 46 unrelated individuals with 23 de novo U2AF2 missense variants (including seven recurrent variants in 30 individuals) and six individuals with de novo PRPF19 variants. Eight U2AF2 variants dysregulated splicing of a model substrate. Neuritogenesis was reduced in human neurons differentiated from human pluripotent stem cells carrying two U2AF2 hyper-recurrent variants. Neural loss of function of the Drosophila orthologs, U2af50 and Prp19, led to lethality, abnormal mushroom body (MB) patterning, and social deficits, differentially rescued by wild-type and mutant U2AF2 or PRPF19. Transcriptome profiling revealed splicing substrates or effectors (including Rbfox1, a third splicing factor), which rescued MB defects in U2af50 deficient flies. Upon re-analysis of negative clinical exomes followed by data sharing, we further identified six NDD patients carrying RBFOX1 missense variants which, by in vitro testing, showed loss of function. Our study implicates three splicing factors as NDD causative genes and establishes a genetic network with hierarchy underlying human brain development and function