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Missense variants in the NF2 gene result in variable NF2 disease presentation. Clinical classification of missense variants often represents a challenge, due to lack of evidence for pathogenicity and function. This study provides a summary of NF2 missense variants, with variant classifications based on currently available evidence. NF2 missense variants were collated from pathology-associated databases and existing literature. Association for Clinical Genomic Sciences Best Practice Guidelines (2020) were followed in the application of evidence for variant interpretation and classification. The majority of NF2 missense variants remain classified as variants of uncertain significance. However, NF2 missense variants identified in gnomAD occurred at a consistent rate across the gene, while variants compiled from pathology-associated databases displayed differing rates of variation by exon of NF2. The highest rate of NF2 disease-associated variants was observed in exon 7, while lower rates were observed toward the C-terminus of the NF2 protein, merlin. Further phenotypic information associated with variants, alongside variant-specific functional analysis, is necessary for more definitive variant interpretation. Our data identified differences in frequency of NF2 missense variants by exon between gnomAD population data and NF2 disease-associated variants, suggesting a potential genotype-phenotype correlation; further work is necessary to substantiate this.

Schwannomatosis comprises a group of hereditary tumor predisposition syndromes characterized by, usually benign, multiple nerve sheath tumors, which frequently cause severe pain that does not typically respond to drug treatments. The most common schwannomatosis-associated gene is NF2, but SMARCB1 and LZTR1 are also associated. There are still many cases in which no pathogenic variants (PVs) have been identified, suggesting the existence of as yet unidentified genetic risk factors. In this study, we performed extended genetic screening of 75 unrelated schwannomatosis patients without identified germline PVs in NF2, LZTR1, or SMARCB1. Screening of the coding region of DGCR8, COQ6, CDKN2A, and CDKN2B was carried out, based on previous reports that point to these genes as potential candidate genes for schwannomatosis. Deletions or duplications in CDKN2A, CDKN2B, and adjacent chromosome 9 region were assessed by multiplex ligation-dependent probe amplification analysis. Sequencing analysis of a patient with multiple schwannomas and melanomas identified a novel duplication in the coding region of CDKN2A, disrupting both p14ARF and p16INK4a. Our results suggest that none of these genes are major contributors to schwannomatosis risk but the possibility remains that they may have a role in more complex mechanisms for tumor predisposition.

ObjectivesCases of sporadic vestibular schwannoma (sVS) have a low rate of association with germline pathogenic variants. However, some individuals with sVS can represent undetected cases of neurofibromatosis type 2 (NF2) or schwannomatosis. Earlier identification of patients with these syndromes can facilitate more accurate familial risk prediction and prognosis.MethodsCases of sVS were ascertained from a local register at the Manchester Centre for Genomic Medicine. Genetic analysis was conducted in NF2 on blood samples for all patients, and tumour DNA samples when available. LZTR1 and SMARCB1 screening was also performed in patient subgroups.ResultsAge at genetic testing for vestibular schwannoma (VS) presentation was younger in comparison with previous literature, a bias resulting from updated genetic testing recommendations. Mosaic or constitutional germline NF2 variants were confirmed in 2% of patients. Pathogenic germline variants in LZTR1 were found in 3% of all tested patients, with a higher rate of 5% in patients SMARCB1 variants were identified within the cohort. Considering all individuals who received tumour DNA analysis, 69% of patients were found to possess two somatic pathogenic NF2 variants, including those with germline LZTR1 pathogenic variants.ConclusionsUndiagnosed schwannoma predisposition may account for a significant minority of apparently sVS cases, especially at lower presentation ages. Loss of NF2 function is a common event in VS tumours and may represent a targetable common pathway in VS tumourigenesis. These data also support the multi-hit mechanism of LZTR1-associated VS tumourigenesis.

To evaluate the incidence of mosaicism in de novo neurofibromatosis 2 (NF2).Patients fulfilling NF2 criteria, but with no known affected family member from a previous generation (n = 1055), were tested for NF2 variants in lymphocyte DNA and where available tumor DNA. The proportion of individuals with a proven or presumed mosaic NF2 variant was assessed and allele frequencies of identified variants evaluated using next-generation sequencing.The rate of proven/presumed mosaicism was 232/1055 (22.0%). However, nonmosaic heterozygous pathogenic variants were only identified in 387/1055 (36.7%). When variant detection rates in second generation nonmosaics were applied to de novo cases, we assessed the overall probable mosaicism rate to be 59.7%. This rate differed by age from 21.7% in those presenting with bilateral vestibular schwannoma20 years to 80.7% in those aged ≥60 years. A mosaic variant was detected in all parents of affected children with a single-nucleotide pathogenic NF2 variant.This study has identified a very high probable mosaicism rate in de novo NF2, probably making NF2 the condition with the highest expressed rate of mosaicism in de novo dominant disease that is nonlethal in heterozygote form. Risks to offspring are small and probably correlate with variant allele frequency detected in blood.

The principal novel feature of this paper is the notion that a coherent memory can be synthesised from a set of partially coherent memory fragments by maximising a particular function, Harmony (Smolensky, 1986). The appeal of Harmony is that it fulfils two functions: it is at the heart of the synthesis algorithm and it provides a natural measure for "feeling-of-knowing". The model is applied to feeling-of-knowing data, flashbulb memories, flashbacks, repression, dissociation, memory stability across repeated recalls, and the effects of cue size on retrieval.

Understanding the relationship between age and prospective memory may be increased by studying the distribution and constituents of incorrect responses. Failure to perform the right activity at the right time may manifest itself as an 'error of omission', in which no response is made at the critical moment, or an 'error of commission', in which the intended action is replaced by a related one. These may, in turn, result from breakdown of encoding/storage or from retrieval failure. Which error is made may depend on the nature of the task, the context or the available processing resources of the performer. Responses of a group of elderly people to the appointment item of the Rivermead Behavioural Memory Test were examined for frequency of occurrence of different types of error and their relationship to other variables. Logistic regression analysis was used to explore the contribution made by variables of anxiety, age and current intelligence to performance on the task. The results suggest that the relationship is a complex one, in which there is an inverse relationship between anxiety and intelligence, and error type is differentially related to low and high anxiety and to age.

We report two studies of the distinct effects that a word's age of acquisition (AoA) and frequency have on the mental lexicon. In the first study, a purely statistical analysis, we show that AoA and frequency are related in different ways to the phonological form and imageability of different words. In the second study, three groups of participants (34 seven-year-olds, 30 ten-year-olds, and 17 adults) took part in an auditory lexical decision task, with stimuli varying in AoA, frequency, length, neighbourhood density, and imageability. The principal result is that the influence of these different variables changes as a function of AoA: Neighbourhood density effects are apparent for early and late AoA words, but not for intermediate AoA, whereas imageability effects are apparent for intermediate AoA words but not for early or late AoA. These results are discussed from the perspective that AoA affects a word's representation, but frequency affects processing biases.

The study investigated the relationship between depressive feelings and coping amongst older widowed men and women. Participants were interviewed about their affective experiences of widowhood and completed two depression questionnaire assessments, the Symptoms of Anxiety and Depression Scale (SAD) and the Hospital Anxiety and Depression Scale (HADS). Participants were assessed as either coping or not coping. The results showed that both measures were effective at differentiating those who coped (Copers) from those who did not (Non-Copers) in the sample as a whole. Amongst the widows the HADS significantly differentiated the two groups. Amongst men, neither measure significantly distinguished Copers from Non-Copers. However, an examination of the interviews suggested that widowers reported depressive feelings significantly more often than widows. The results suggest that depressive feelings are associated with non-coping in older widowed people. There is also evidence to suggest that widows and widowers respond differentially to assessment measures.

The effect of long-term knowledge upon performance in short-term memory tasks was examined for children from 5 to 10 years of age. The emergence of a lexicality effect, in which familiar words were recalled more accurately than unfamiliar words, was found to depend upon the nature of the memory task. Lexicality effects were interpreted as reflecting the use of redintegration, or reconstruction processes, in short-term memory. Redintegration increased with age for tasks requiring spoken item recall and decreased with age when position information but not naming was required. In a second experiment, redintegration was found in a recognition task when some of the foils rhymed with the target. Older children were able to profit from a rhyming foil, whereas younger children were confused by it, suggesting that the older children make use of sublexical phonological information in reconstructing the target. It was proposed that redintegrative processes in their mature form support the reconstruction of detailed phonological knowledge of words.

Performance on the Rivermead Behavioural Memory Test (RBMT) of 43 residents of Part III homes was compared with performance on Raven's Coloured Progressive Matrices and the National Adult Reading Test (NART). Health, medication, self-care and social activity were also measured. Results show that although Raven's score was the best predictor of memory test performance, it had a high refusal rate. Age was not a significant predictor of overall memory test score but results were complicated by age of entry into Part III, with older people performing better on some items. Medication, in particular drugs acting on the central nervous system, enhanced performance on some items.

Two experiments investigated the development of the word length effect in children aged 4 to 10 years, comparing auditory and visual stimuli. The question addressed was whether word length effects emerged earlier with auditory presentation or visual presentation, or whether they emerged at the same age regardless of presentation modality. Results provided evidence that word length effects emerge earlier with visual than auditory presentation. The implication of our results is that with visual presentation, 4-year-olds engage in some form of verbalisation strategy that involves obtaining phonological representations of picture names and mapping them on to articulatory output plans. This strategy is clearly verbal in nature, but is not necessarily characterised as cumulative verbal rehearsal.

A short memory test that provides analogs of everyday activities was used to investigate the relationship between everyday memory, cognitive abilities, participation in social, domestic, and leisure pursuits, and health status among 94 community-dwelling people aged between 70 and 93 years. Multiple regression analysis revealed that while fluid intelligence was a significant predictor of performance on most of the memory items, age was also a significant predictor of performance on prospective and verbal memory items, over and above the effects of intelligence. Crystallized intelligence and years of formal education showed little predictive power, but an index of participation in social and domestic activities was a good predictor of verbal, visual, and spatial memory items. It is concluded that cognitive decline in aging involves more than a simple decline in fluid intelligence.

The Frenchay Activities Index (FAI), a brief scale developed to measure lifestyle in stroke patients, was given to 119 community-dwelling people, aged 70 years or older, in order to obtain a baseline estimate of social, domestic, and leisure activity among older people. Factor analysis identified three main factors, similar in composition to those previously reported. A general linear models regression analysis of selected variables indicated that both fluid intelligence and memory test performance were significantly associated with level of activity. There was no significant association with age or crystallized intelligence in this sample. An apparently strong bias towards higher levels of activity among female respondents was diluted when marital status was included in the equation. This study suggests that the FAI is appropriate for measuring levels of activity in community-dwelling older people and that such activity is related to current cognitive abilities.

Four models of the organization of feature-testing units in the perception of phonemes are developed and tested against data drawn from a number of published studies. The independence model, which asserts that features are tested independently of each other, is conclusively rejected. The response-conditional and stimulus-conditional models require individual feature-testing units to be dependent, respectively, on the responses of other feature-testing units and on the other features present in the stimulus. Both these models handle perceptual confusions very well among stop and nasal consonants, but are less satisfactory for fricatives. Finally, the correct-conditional model requires individual feature-testing units to be dependent on the correctness of the decisions made by other feature-testing units; this model is very poor for perceptual confusions but quite good for mnemonic confusions. In addition, some of the distinctive features currently favoured by linguists are shown to provide unsatisfactory descriptions. The implications of this study are that perceptual and mnemonic processes are different in certain basic respects, and that many current scaling models are ignoring important types of structure in the data they analyse.

Two studies of stress assignment rules are reported. In both studies speakers found to base their pronunciations partly on general rules and partly on comparisons with particular English words: word length, syntactic category and position of primary stress all influenced performance. In the second study, the distinctions between pronounced polysyllabic nonsense words, and similarity to real English words, as well as phonemic and syntactic structure, was controlled. In the first study, speakers were lax and tense vowels, and strong and weak clusters, which are central to Chomsky and Halle's (1968) formulation of stress assignment rules, were found to influence performance, but not only in the ways predicted by Chomsky and Halle. A probabilistic performance model is proposed: part of this model incorporates Chomsky and Halle's rules, but other linguistic influences are also taken into account.