Systematic identification of disease-causing promoter and untranslated region variants in 8,040 undiagnosed individuals with rare disease.

Background: Both promoters and untranslated regions (UTRs) have critical regulatory roles, yet variants in these regions are largely excluded from clinical genetic testing due to difficulty in interpreting pathogenicity. The extent to which these regions may harbour diagnoses for individuals with rare disease is currently unknown. Methods: We present a framework for the identification and annotation of potentially deleterious proximal promoter and UTR variants in known dominant disease genes. We use this framework to annotate de novo variants (DNVs) in 8,040 undiagnosed individuals in the Genomics England 100,000 genomes project, which were subject to strict region-based filtering, clinical review, and validation studies where possible. In addition, we performed region and variant annotation-based burden testing in 7,862 unrelated probands against matched unaffected controls. Results: We prioritised eleven DNVs and identified an additional variant overlapping one of the eleven. Ten of these twelve variants (82%) are in genes that are a strong match to the individual's phenotype and six had not previously been identified. Through burden testing, we did not observe a significant enrichment of potentially deleterious promoter and/or UTR variants in individuals with rare disease collectively across any of our region or variant annotations. Conclusions: Overall, we demonstrate the value of screening promoters and UTRs to uncover additional diagnoses for previously undiagnosed individuals with rare disease and provide a framework for doing so without dramatically increasing interpretation burden.

An evaluation of the applicability of the tripartite constructs to social anxiety in adolescents.

The current study examined the tripartite model of anxiety and depression in relation to social phobia in a nonclinical sample of adolescents (ages 13-17). Adolescent/parent dyads participated in a semistructured interview and completed self-report measures of the tripartite constructs and social anxiety. Adolescents gave an impromptu speech, and heart rate was monitored. Low positive affect, high negative affect, and high physiological hyperarousal were characteristic of adolescents diagnosed with social phobia; adolescents with elevated social anxiety symptoms who did not meet criteria for social phobia did not evidence low positive affect. Heart rate reactivity during the speech was not significantly correlated with social anxiety symptomatology or with self-reported physiological hyperarousal.

Race/ethnicity and internalizing disorders in youth: a review.

This review examines the impact of race/ethnicity and cultural differences in the presentation and prevalence rates of internalizing disorders in youth, as well as a variety of associated factors. There is robust support for higher prevalence rates of depression and anxiety in ethnic minority youth living in the United States. Gender differences are consistent across ethnicity, but symptom presentation, biological factors, and family processes vary somewhat by ethnic group. Environmental factors and acculturation are considered in relation to internalizing disorders in ethnic minority youth. Several problems with the literature are outlined. Several recommendations are made including better operationalization of internalizing disorders in the DSM and key issues that warrant being added to background text in the DSM. A research agenda is outlined to address possible mechanisms by which culture and race/ethnicity impact internalizing symptomatology.

An examination of the MASC Social Anxiety Scale in a non-referred sample of adolescents.

Social phobia is prevalent during adolescence and is associated with negative outcomes. Two self-report instruments are empirically validated to specifically assess social phobia symptomatology in youth: the Social Phobia and Anxiety Inventory for Children and the Social Anxiety Scale for Adolescents. The Multidimensional Anxiety Scale for Children is a broad-band measure of anxiety containing a scale assessing the social phobia construct. The present study investigated the MASC Social Anxiety Scale in relation to other well-established measures of social phobia and depression in a non-referred sample of adolescents. Results support the convergent validity of the MASC Social Anxiety Scale and provide some support for its discriminant validity, suggesting its utility in the initial assessment of social phobia. Receiver Operating Characteristics (ROCs) calculated the sensitivity and specificity of the MASC Social Anxiety Scale. Binary logistic regression analyses determined the predictive utility of the MASC Social Anxiety Scale. Implications for assessment are discussed.

Brave men and timid women? A review of the gender differences in fear and anxiety.

Substantial evidence indicates that women report greater fear and are more likely to develop anxiety disorders than men. Women's greater vulnerability for anxiety disorders can be partly understood by examining gender differences in the etiological factors known to contribute to anxiety. This review examines evidence for gender differences across a broad range of relevant factors, including biological influences, temperamental factors, stress and trauma, cognitive factors, and environmental factors. Gender differences are observed with increasing consistency as the scope of analysis broadens to molar levels of functioning. Socialization processes cultivate and promote processes related to anxiety, and moderate gender differences across levels of analysis.

The relationship among social phobia, objective and perceived physiological reactivity, and anxiety sensitivity in an adolescent population.

Physiological theories may be important in the development and maintenance of social phobia in youth. A limited literature base indicates that youth with social phobia experience increases in objective physiological arousal during social-evaluative situations and are more aware of such increases compared to nonanxious youth. Recent research suggests that youth with social phobia also evidence heightened levels of anxiety sensitivity, which may lead to interpretation of physiological arousal as dangerous or distressing, and, as a result, in avoidance of situations which produce increased physiological arousal. The purpose of the current study was to examine interaction among objective physiological arousal, perceived physiological arousal, and anxiety sensitivity among adolescents diagnosed with social phobia. A sample of community adolescents participated in two anxiety-provoking tasks during which objective physiological arousal was monitored, and after which perceived physiological arousal and anxiety sensitivity were evaluated. Results from this study evidenced no differences between social phobic and nonanxious adolescents with regard to objective physiological arousal during either anxiety-provoking tasks. Adolescents with social phobia, however, were more aware of measured increases in physiological arousal, as well as more afraid of the potential social implications of that arousal compared to nonanxious adolescents. Implications for theory and treatment are discussed.

A review of the tripartite model for understanding the link between anxiety and depression in youth.

Although research from numerous investigations indicates that there is substantial overlap in anxiety and depressive symptoms and comorbid diagnoses in youth, these constructs can be adequately differentiated. Clark and Watson [Clark, L. A. & Watson, D., (1991). Tripartite model of anxiety and depression: Psychometric evidence and taxonomic implications. Journal of Abnormal Psychology, 100, 316-336] proposed a tripartite model to account for the symptom overlap and diagnostic comorbidity between anxiety and depression. This tripartite model posits that anxiety and depression share a common component of negative affect, but can be differentiated by low positive affect associated with depression and high physiological hyperarousal associated with anxiety. The present article reviews initial research which has supported the utility of the tripartite model for explaining the association between anxiety and depression in adult and youth samples. Following that review, more recent investigations which have called into question the applicability of the tripartite constructs for youth are presented. Finally, the paper reviews evidence suggesting that the tripartite factors may not function similarly across all anxiety and depressive disorders. This article concludes by suggesting that more research is necessary with children and adolescents in order to determine the functioning of tripartite constructs across anxiety disorders in youth.

Subjective versus objective behavioral ratings following two analogue tasks: a comparison of socially phobic and non-anxious adolescents.

Although results regarding objective social skills deficits in adults are inconsistent, research with youth have consistently demonstrated such deficits. Furthermore, research has consistently demonstrated subjective appraisal of social skill deficit in both youth and adults with social phobia or social anxiety. As a result, research has begun to examine the presence of a negative perceptual bias in individuals with social phobia and social anxiety. The purpose of the present study was to extend the findings of social skill deficits to an adolescent sample by investigating differences between adolescents with social phobia and non-anxious peers with regard to objective and subjective behavioral ratings. In addition, the presence of a negative perceptual bias was investigated by examining discrepancy scores between these ratings. The results of the current study provide support for the presence of social skill deficits in a socially phobic adolescent population and are the first to suggest that a limited negative bias exists in this population.

The Social Phobia Inventory: validity and reliability in an adolescent community sample.

Social anxiety disorder and social anxiety are highly prevalent psychological conditions in youth. Because of the known risks associated with the spectrum of social anxiety in youth, early detection with valid and reliable assessment measures is imperative. Self-report measures have become the most widely used method of assessment for child and adolescent social anxiety. Because research to date on self-report measures of social anxiety disorder in adolescents is limited, the primary objective of the present study was to contribute to the literature by examining the validity and reliability of a new self-report measure, the Social Phobia Inventory (SPIN), in a community sample of adolescents. The SPIN is a 17-item measure purported to assess the full spectrum of social anxiety disorder symptomatology. Previously, psychometric research on the SPIN in adult populations has demonstrated its validity and reliability. In the current psychometric examination, results revealed strong support for the temporal stability, internal consistency, and construct validity of the SPIN, suggesting it is an appropriate screening measure for the assessment of social anxiety disorder in adolescents.

Understanding and treating trichotillomania: what we know and what we don't know.

This article reviews current issues in the understanding and clinical management of trichotillomania (TTM). After diagnostic considerations and epidemiology are discussed, a brief update on biologic and environmental precipitants is provided, and emerging research on possible TTM subtypes is discussed. Current strategies for assessing TTM and t heir applicability to clinical practice are reviewed, as is the current state of pharmacologic and nonpharmacologic treatments for the disorder. The article concludes with suggestions for future research and descriptions of the authors'research agenda.