Time is -ending: Sublexical information activates the horizontal mental time line in word processing.

The mental time line (MTL) is a spatial continuum on which earlier events are generally associated with the left space and later events with the right space. Accordingly, past- and future-related words receive faster responses with, respectively, the left and the right hand. Yet, it is currently unclear whether the MTL is activated by the whole word or whether it can be triggered by more subtle sublexical cues, such as verb-endings, and whether the activation of this spatial continuum is an automatic phenomenon. The aim of this study is to test whether verb-endings do bring conceptual information that is in turn capable to activate the MTL and whether this activation holds also when the temporal information is not explicitly processed. We designed three experiments. In Experiment 1, consisting of a temporal categorization task, and in Experiment 2, consisting of a lexical decision task, we tested Italian tensed verbs (trov-avo "I found," trov-erò "I will find") and pseudo-verbs (trop-avo, trop-erò). Results of Experiment 1 showed that both tensed verbs and pseudo-verbs were spatially coded on the MTL. Results from Experiment 2 showed that the MTL is activated by the verb-endings also when temporal information was task-irrelevant (i.e., lexical decision task). Experiment 3 further clarified that the spatial-temporal congruency effect does not emerge during the evaluation of an inhomogeneous set of stimuli (i.e., when adding to the stimuli time-unrelated fillers). Overall, the present findings indicate that sublexical strings carry specific semantic information that comes into play in the generation of spatial-temporal associations. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Cloze probability, predictability ratings, and computational estimates for 205 English sentences, aligned with existing EEG and reading time data.

We release a database of cloze probability values, predictability ratings, and computational estimates for a sample of 205 English sentences (1726 words), aligned with previously released word-by-word reading time data (both self-paced reading and eye-movement records; Frank et al., Behavior Research Methods, 45(4), 1182-1190. 2013) and EEG responses (Frank et al., Brain and Language, 140, 1-11. 2015). Our analyses show that predictability ratings are the best predictors of the EEG signal (N400, P600, LAN) self-paced reading times, and eye movement patterns, when spillover effects are taken into account. The computational estimates are particularly effective at explaining variance in the eye-tracking data without spillover. Cloze probability estimates have decent overall psychometric accuracy and are the best predictors of early fixation patterns (first fixation duration). Our results indicate that the choice of the best measurement of word predictability in context critically depends on the processing index being considered.

Form to meaning mapping and the impact of explicit morpheme combination in novel word processing.

In the present study, we leveraged computational methods to explore the extent to which, relative to direct access to semantics from orthographic cues, the additional appreciation of morphological cues is advantageous while inducing the meaning of affixed pseudo-words. We re-analyzed data from a study on a lexical decision task for affixed pseudo-words. We considered a parsimonious model only including semantic variables (namely, semantic neighborhood density, entropy, magnitude, stem proximity) derived through a word-form-to-meaning approach (ngram-based). We then explored the extent to which the addition of equivalent semantic variables derived by combining semantic information from morphemes (combination-based) improved the fit of the statistical model explaining human data. Results suggest that semantic information can be extracted from arbitrary clusters of letters, yet a computational model of semantic access also including a combination-based strategy based on explicit morphological information better captures the cognitive mechanisms underlying human performance. This is particularly evident when participants recognize affixed pseudo-words as meaningful stimuli.

CHAMP1-related disorders: pathomechanisms triggered by different genomic alterations define distinct nosological categories.

Loss-of-function variants in CHAMP1 were recently described as cause of a neurodevelopmental disorder characterized by intellectual disability (ID), autism, and distinctive facial characteristics. By exome sequencing (ES), we identified a truncating variant in CHAMP1, c.1858A > T (p.Lys620*), in a patient who exhibited a similar phenotype of severe ID and dysmorphisms. Whether haploinsufficiency or a dominant negative effect is the underlying pathomechanism in these cases is a question that still needs to be addressed. By array-CGH, we detected a 194 kb deletion in 13q34 encompassing CHAMP1, CDC16 and UPF3, in another patient who presented with borderline neurodevelopmental impairment and with no dysmorphisms. In a further patient suffering from early onset refractory seizures, we detected by ES a missense variant in CHAMP1, c.67 G > A (p.Gly23Ser). Genomic abnormalities were all de novo in our patients. We reviewed the clinical and the genetic data of patients reported in the literature with: loss-of-function variants in CHAMP1 (total 40); chromosome 13q34 deletions ranging from 1.1 to 4 Mb (total 7) and of the unique patient with a missense variant. We could infer that loss-of-function variants in CHAMP1 cause a homogeneous phenotype with severe ID, autism spectrum disorders (ASD) and highly distinctive facial characteristics through a dominant negative effect. CHAMP1 haploinsufficiency results in borderline ID with negligible consequences on the quality of life. Missense variants give rise to a severe epileptic encephalopathy through gain-of-function mechanism, most likely. We tentatively define for the first time distinct categories among the CHAMP1-related disorder on the basis of pathomechanisms.

Prediction at the intersection of sentence context and word form: Evidence from eye-movements and self-paced reading.

A key issue in language processing is how we recognize and understand words in sentences. Research on sentence reading indicates that the time we need to read a word depends on how (un)expected it is. Research on single word recognition shows that each word also has its own recognition dynamics based on the relation between its orthographic form and its meaning. It is not clear, however, how these sentence-level and word-level dynamics interact. In the present study, we examine the joint impact of these sources of information during sentence reading. We analyze existing eye-tracking and self-paced reading data (Frank et al., 2013, Behavior Research Methods, 45[4], 1182-1190) to investigate the interplay of sentence-level prediction (operationalized as Surprisal) and word Orthography-Semantics Consistency in activating word meaning in sentence processing. Results indicate that both Surprisal and Orthography-Semantics Consistency exert an influence on several reading measures. The shape of the observed interaction differs, but the results give compelling indication for a general trade-off between expectations based on sentence context and cues to meaning from word orthography.

Very early and late form-to-meaning computations during visual word recognition as revealed by electrophysiology.

We used a large-scale data-driven approach to investigate the role of word form in accessing semantics. By using distributional semantic methods and taking advantage of an ERP lexical decision mega-study, we investigated the exact time dynamic of semantic access from printed words as driven by orthography-semantics consistency (OSC) and phonology-semantics consistency (PSC). Generalized Additive Models revealed very early and late OSC-by-PSC interactions, visible at 100 and 400 msec, respectively. This pattern suggests that, during visual word recognition: a) meaning is accessed by means of two distinct and interactive paths - the orthography-to-meaning and the orthography-to-phonology-to-meaning path -, which mutually contribute to recognition since early stages; b) the system may exploit a dual mechanism for semantic access, with early and late effects associated to a fast-coarse and a slow-fine grained semantic analysis, respectively. The results also highlight the high sensitivity of the visual word recognition system to arbitrary form-meaning relations.

Mother and Daughter Carrying of the Same Pathogenic Variant in FGFR2 with Discordant Phenotype.

Craniosynostosis are a heterogeneous group of genetic conditions characterized by the premature fusion of the skull bones. The most common forms of craniosynostosis are Crouzon, Apert and Pfeiffer syndromes. They differ from each other in various additional clinical manifestations, e.g., syndactyly is typical of Apert and rare in Pfeiffer syndrome. Their inheritance is autosomal dominant with incomplete penetrance and one of the main genes responsible for these syndromes is FGFR2, mapped on chromosome 10, encoding fibroblast growth factor receptor 2. We report an FGFR2 gene variant in a mother and daughter who present with different clinical features of Crouzon syndrome. The daughter is more severely affected than her mother, as also verified by a careful study of the face and oral cavity. The c.1032G>A transition in exon 8, already reported as a synonymous p.Ala344 = variant in Crouzon patients, also activates a new donor splice site leading to the loss of 51 nucleotides and the in-frame removal of 17 amino acids. We observed lower FGFR2 transcriptional and translational levels in the daughter compared to the mother and healthy controls. A preliminary functional assay and a molecular modeling added further details to explain the discordant phenotype of the two patients.

Expanding horizons of cross-linguistic research on reading: The Multilingual Eye-movement Corpus (MECO).

Scientific studies of language behavior need to grapple with a large diversity of languages in the world and, for reading, a further variability in writing systems. Yet, the ability to form meaningful theories of reading is contingent on the availability of cross-linguistic behavioral data. This paper offers new insights into aspects of reading behavior that are shared and those that vary systematically across languages through an investigation of eye-tracking data from 13 languages recorded during text reading. We begin with reporting a bibliometric analysis of eye-tracking studies showing that the current empirical base is insufficient for cross-linguistic comparisons. We respond to this empirical lacuna by presenting the Multilingual Eye-Movement Corpus (MECO), the product of an international multi-lab collaboration. We examine which behavioral indices differentiate between reading in written languages, and which measures are stable across languages. One of the findings is that readers of different languages vary considerably in their skipping rate (i.e., the likelihood of not fixating on a word even once) and that this variability is explained by cross-linguistic differences in word length distributions. In contrast, if readers do not skip a word, they tend to spend a similar average time viewing it. We outline the implications of these findings for theories of reading. We also describe prospective uses of the publicly available MECO data, and its further development plans.

Evaluation of gene validity for CPVT and short QT syndrome in sudden arrhythmic death.

AIMS: Catecholaminergic polymorphic ventricular tachycardia (CPVT) and short QT syndrome (SQTS) are inherited arrhythmogenic disorders that can cause sudden death. Numerous genes have been reported to cause these conditions, but evidence supporting these gene-disease relationships varies considerably. To ensure appropriate utilization of genetic information for CPVT and SQTS patients, we applied an evidence-based reappraisal of previously reported genes. METHODS AND RESULTS: Three teams independently curated all published evidence for 11 CPVT and 9 SQTS implicated genes using the ClinGen gene curation framework. The results were reviewed by a Channelopathy Expert Panel who provided the final classifications. Seven genes had definitive to moderate evidence for disease causation in CPVT, with either autosomal dominant (RYR2, CALM1, CALM2, CALM3) or autosomal recessive (CASQ2, TRDN, TECRL) inheritance. Three of the four disputed genes for CPVT (KCNJ2, PKP2, SCN5A) were deemed by the Expert Panel to be reported for phenotypes that were not representative of CPVT, while reported variants in a fourth gene (ANK2) were too common in the population to be disease-causing. For SQTS, only one gene (KCNH2) was classified as definitive, with three others (KCNQ1, KCNJ2, SLC4A3) having strong to moderate evidence. The majority of genetic evidence for SQTS genes was derived from very few variants (five in KCNJ2, two in KCNH2, one in KCNQ1/SLC4A3). CONCLUSIONS: Seven CPVT and four SQTS genes have valid evidence for disease causation and should be included in genetic testing panels. Additional genes associated with conditions that may mimic clinical features of CPVT/SQTS have potential utility for differential diagnosis.

Adult phenotype in Koolen-de Vries/KANSL1 haploinsufficiency syndrome.

BACKGROUND: Koolen-de Vries syndrome (KdVS) is a multisystem neurodevelopmental disorder caused by 17q21.31 deletions or mutations in KANSL1. It was mainly described in children. METHODS: A retrospective study on 9 subjects aged 19-45 years and revision of 18 literature patients, with the purpose to get insights into the phenotypic evolution with time, and into the clinical manifestations in adulthood. RESULTS: Seven patients had a 17q21.31 deletion and two a point mutation in KANSL1. All had intellectual disability, which was mild in five (56%) and moderate in four (44%). Epilepsy was diagnosed in four subjects (44%), with onset from 1 to 7 years and full remission before 9 years in 3/4 patients. Scoliosis affected seven individuals (77.7%) and it was substantially stable with age in 5/7 patients, allowing for simple daily activities. Two subjects had severely progressive scoliosis, which was surgically corrected. Overweight or true obesity did occur after puberty in six patients (67%). Behaviour abnormalities were recorded in six patients (67%). The facial phenotype slightly evolved with time to include thick eyebrows, elongated nose and pronounced pointed chin. Despite behaviour abnormalities, happy disposition and sociable attitudes were common. Half of patients had fluent language and were good at writing and reading. Rich language, although limited to single words or short sentences, and very limited or absent skills in writing and reading were observed in the remaining patients. Autonomy in daily activities and personal care was usually limited. CONCLUSIONS: Distinctive features in adult KdVS subjects include intellectual disability, overweight/obesity, behaviour abnormalities with preserved social interest, ability in language, slight worsening of the facial phenotype and no seizures.

Variants of uncertain significance (VUS) in cancer predisposing genes: What are we learning from multigene panels?

One of the main factors influencing the clinical utility of genetic tests for cancer predisposition is the ability to provide actionable classifications (ie pathogenic or benign). However, a large fraction of the variants identified in cancer predisposing genes (CPGs) are of uncertain significance (VUS), and cannot be used for clinical purposes either to identify individuals at risk or to drive treatment. Here we analyze the current status of VUS identification in a subset of 24 CPGs included by the American College of Medical Genetics/Association for Molecular Pathology in the list of genes that should be considered for the return of incidental findings. To this purpose we retrieved published literature using different search strings according to the frequency of the condition and we extracted corresponding data from ClinVar. The total number of VUS has not decreased with time, due to widespread multigene panel testing, and the relative yield of VUS compared to pathogenic variants is higher in more recent studies, which tend to involve series not selected for the presence of specific high risk criteria. In addition, only few studies adopt gene specific interpretation criteria when these are available. Despite the large yield of VUS associated with multigene testing, the data obtained from such studies can be very useful for variant classification, especially for those variants that are more likely to be benign, since these are expected to be detected more frequently in a population that does not show gene specific manifestations. In addition, wider use of gene specific interpretation criteria should be promoted in order to optimize the interpretation process.

Consistency measures individuate dissociating semantic modulations in priming paradigms: A new look on semantics in the processing of (complex) words.

In human language the mapping between form and meaning is arbitrary, as there is no direct connection between words and the objects that they represent. However, within a given language, it is possible to recognise systematic associations that support productivity and comprehension. In this work, we focus on the consistency between orthographic forms and meaning, and we investigate how the cognitive system may exploit it to process words. We take morphology as our case study, since it arguably represents one of the most notable examples of systematicity in form-meaning mapping. In a series of three experiments, we investigate the impact of form-meaning mapping in word processing by testing new consistency metrics as predictors of priming magnitude in primed lexical decision. In Experiment 1, we re-analyse data from five masked morphological priming studies and show that orthography-semantics-consistency explains independent variance in priming magnitude, suggesting that word semantics is accessed already at early stages of word processing and that crucially semantic access is constrained by word orthography. In Experiments 2 and 3, we investigate whether this pattern is replicated when looking at semantic priming. In Experiment 2, we show that orthography-semantics-consistency is not a viable predictor of priming magnitude with longer stimulus onset asynchrony (SOA). However, in Experiment 3, we develop a new semantic consistency measure based on the semantic density of target neighbourhoods. This measure is shown to significantly predict independent variance in semantic priming effect. Overall, our results indicate that consistency measures provide crucial information for the understanding of word processing. Specifically, the dissociation between measures and priming paradigms shows that different priming conditions are associated with the activation of different semantic cohorts.

An International, Multicentered, Evidence-Based Reappraisal of Genes Reported to Cause Congenital Long QT Syndrome.

BACKGROUND: Long QT syndrome (LQTS) is the first described and most common inherited arrhythmia. Over the last 25 years, multiple genes have been reported to cause this condition and are routinely tested in patients. Because of dramatic changes in our understanding of human genetic variation, reappraisal of reported genetic causes for LQTS is required. METHODS: Utilizing an evidence-based framework, 3 gene curation teams blinded to each other's work scored the level of evidence for 17 genes reported to cause LQTS. A Clinical Domain Channelopathy Working Group provided a final classification of these genes for causation of LQTS after assessment of the evidence scored by the independent curation teams. RESULTS: Of 17 genes reported as being causative for LQTS, 9 (AKAP9, ANK2, CAV3, KCNE1, KCNE2, KCNJ2, KCNJ5, SCN4B, SNTA1) were classified as having limited or disputed evidence as LQTS-causative genes. Only 3 genes (KCNQ1, KCNH2, SCN5A) were curated as definitive genes for typical LQTS. Another 4 genes (CALM1, CALM2, CALM3, TRDN) were found to have strong or definitive evidence for causality in LQTS with atypical features, including neonatal atrioventricular block. The remaining gene (CACNA1C) had moderate level evidence for causing LQTS. CONCLUSIONS: More than half of the genes reported as causing LQTS have limited or disputed evidence to support their disease causation. Genetic variants in these genes should not be used for clinical decision-making, unless accompanied by new and sufficient genetic evidence. The findings of insufficient evidence to support gene-disease associations may extend to other disciplines of medicine and warrants a contemporary evidence-based evaluation for previously reported disease-causing genes to ensure their appropriate use in precision medicine.

A database of orthography-semantics consistency (OSC) estimates for 15,017 English words.

Orthography-semantics consistency (OSC) is a measure that quantifies the degree of semantic relatedness between a word and its orthographic relatives. OSC is computed as the frequency-weighted average semantic similarity between the meaning of a given word and the meanings of all the words containing that very same orthographic string, as captured by distributional semantic models. We present a resource including optimized estimates of OSC for 15,017 English words. In a series of analyses, we provide a progressive optimization of the OSC variable. We show that computing OSC from word-embeddings models (in place of traditional count models), limiting preprocessing of the corpus used for inducing semantic vectors (in particular, avoiding part-of-speech tagging and lemmatization), and relying on a wider pool of orthographic relatives provide better performance for the measure in a lexical-processing task. We further show that OSC is an important and significant predictor of reaction times in visual word recognition and word naming, one that correlates only weakly with other psycholinguistic variables (e.g., family size, word frequency), indicating that it captures a novel source of variance in lexical access. Finally, some theoretical and methodological implications are discussed of adopting OSC as one of the predictors of reaction times in studies of visual word recognition.

From sound to meaning: Phonology-to-Semantics mapping in visual word recognition.

In the present study, the role of phonological information in visual word recognition is investigated by adopting a large-scale data-driven approach that exploits a new consistency measure based on distributional semantics methods. A recent study by Marelli, Amenta, and Crepaldi (2015) showed that the consistency between an orthographic string and the meanings to which it is associated in a large corpus is a relevant predictor in lexical decision experiments. Exploiting irregular mappings between orthography and phonology in English, we were able to compute a phonology-to-semantics consistency measure that dissociates from its orthographic counterpart and tested both measures on lexical decision data taken from the British Lexicon Project (Keuleers et al., 2012). Results showed that both orthography and phonology are activated during visual word recognition. However, their contribution is crucially determined by the extent to which they are informative of the word semantics, and phonology plays a crucial role in accessing word meaning.

The fruitless effort of growing a fruitless tree: Early morpho-orthographic and morpho-semantic effects in sentence reading.

In this eye-tracking study, we investigated how semantics inform morphological analysis at the early stages of visual word identification in sentence reading. We exploited a feature of several derived Italian words, that is, that they can be read in a "morphologically transparent" way or in a "morphologically opaque" way according to the sentence context to which they belong. This way, each target word was embedded in a sentence eliciting either its transparent or opaque interpretation. We analyzed whether the effect of stem frequency changes according to whether the (very same) word is read as a genuine derivation (transparent context) versus as a pseudoderived word (opaque context). Analysis of the first fixation durations revealed a stem-word frequency effect in both opaque and transparent contexts, thus showing that stems were accessed whether or not they contributed to word meaning, that is, word decomposition is indeed blind to semantics. However, while the stem-word frequency effect was facilitatory in the transparent context, it was inhibitory in the opaque context, thus showing an early involvement of semantic representations. This pattern of data is revealed by words with short suffixes. These results indicate that derived and pseudoderived words are segmented into their constituent morphemes also in natural reading; however, this blind-to-semantics process activates morpheme representations that are semantically connoted.

Semantic transparency in free stems: The effect of Orthography-Semantics Consistency on word recognition.

A largely overlooked side effect in most studies of morphological priming is a consistent main effect of semantic transparency across priming conditions. That is, participants are faster at recognizing stems from transparent sets (e.g., farm) in comparison to stems from opaque sets (e.g., fruit), regardless of the preceding primes. This suggests that semantic transparency may also be consistently associated with some property of the stem word. We propose that this property might be traced back to the consistency, throughout the lexicon, between the orthographic form of a word and its meaning, here named Orthography-Semantics Consistency (OSC), and that an imbalance in OSC scores might explain the "stem transparency" effect. We exploited distributional semantic models to quantitatively characterize OSC, and tested its effect on visual word identification relying on large-scale data taken from the British Lexicon Project (BLP). Results indicated that (a) the "stem transparency" effect is solid and reliable, insofar as it holds in BLP lexical decision times (Experiment 1); (b) an imbalance in terms of OSC can account for it (Experiment 2); and