Background Deletion of the recurrent ~600 kb BP4-BP5 chromosomal region 16p11.2 has been associated with a wide range of neurodevelopmental outcomes. Method To clarify the phenotype of 16p11.2 deletion, we examined psychiatric and developmental presentation of predominantly clinically referred individuals, with a particular emphasis on broader autism phenotype characteristics in individuals with recurrent ~600 kb chromosome 16p11.2 deletions. 85 Individuals with the 16p11.2 deletion, and 153 familial controls, were evaluated for symptom presentation and clinical diagnosis using an extensive standardized assessment battery across 3 clinical sites. Results Individuals with the 16p11.2 deletion presented with a high frequency of psychiatric and developmental disorders (>90%). The most commonly diagnosed conditions were developmental coordination disorder, phonological processing disorder, expressive and receptive language disorders (71% of individuals over 3 years of age with a speech and language related disorder), and autism spectrum disorder (ASD). Individuals with the 16p11.2 deletion not meeting diagnostic criteria for ASD had significantly higher prevalence of autism-related characteristics compared to the familial non-carrier control group. Individuals with the 16p11.2 deletion had a range of intellectual ability, but IQ scores were 26 points lower than non-carrier family members on average. Conclusion Clinically referred individuals with the 16p11.2 deletion have high rates of psychiatric and developmental disorders and provide a genetically well-defined group to study the emergence of developmental difficulties, particularly those associated with the broader autism phenotype.

The two head domains of the budding yeast Kinesin-14 Kar3Vik1 bind adjacent protofilaments at the start of the motility cycle, followed by release of Vik1 from one protofilament to allow the motor’s powerstroke.

BACKGROUND: 16p11.2 breakpoint 4 to 5 copy number variants (CNVs) increase the risk for developing autism spectrum disorder, schizophrenia, and language and cognitive impairment. In this multisite study, we aimed to quantify the effect of 16p11.2 CNVs on brain structure. METHODS: Using voxel-and surface-based brain morphometric methods, we analyzed structural magnetic resonance imaging collected at seven sites from 78 individuals with a deletion, 71 individuals with a duplication, and 212 individuals without a CNV. RESULTS: Beyond the 16p11.2-related mirror effect on global brain morphometry, we observe regional mirror differences in the insula (deletion . control . duplication). Other regions are preferentially affected by either the deletion or the duplication: the calcarine cortex and transverse temporal gyrus (deletion . control; Cohen's d . 1), the superior and middle temporal gyri (deletion , control; Cohen's d , 21), and the caudate and hippocampus (control . duplication; 20.5 . Cohen's d . 21). Measures of cognition, language, and social responsiveness and the presence of psychiatric diagnoses do not influence these results. CONCLUSIONS: The global and regional effects on brain morphometry due to 16p11.2 CNVs generalize across site, computational method, age, and sex. Effect sizes on neuroimaging and cognitive traits are comparable. Findings partially overlap with results of meta-analyses performed across psychiatric disorders. However, the lack of correlation between morphometric and clinical measures suggests that CNV-associated brain changes contribute to clinical manifestations but require additional factors for the development of the disorder. These findings highlight the power of genetic risk factors as a complement to studying groups defined by behavioral criteria. Autism spectrum disorder (ASD) and related neurodevelopmental disorders are defined behaviorally and characterized by a significant clinical and etiologic heterogeneity. As a consequence, investigating ASD under the assumption of an underlying homogeneous condition has resulted in controversial findings in the field of neuroimaging (1). Increased brain growth early in development (2-4) and alterations of many regional brain volumes (5) have been implicated in ASD, but results have proven difficult to replicate (1,(6)(7)(8).To mitigate some of these issues, cohorts of individuals with shared genetic risk factors have been assembled to minimize the noise introduced by etiologic and biological heterogeneity (9). Such a "genetic-first" study design provides the opportunity to investigate a given neurodevelopmental risk (and associated mechanism) shared by individuals who carry the same genetic etiology irrespective of the psychiatric diagnosis.Copy number variants (CNVs) at the 16p11.2 (breakpoints 4-5, 29.6-30.2 Mb-hg19) (10) are among the most frequent risk factors for neurodevelopmental and psychiatric conditions.

Chronic traumatic encephalopathy is a disease afflicting individuals exposed to repetitive neurotrauma. Unfortunately, diagnosis is made by postmortem pathologic analysis, and treatment options are primarily symptomatic. In this clinical update, we review clinical and pathologic diagnostic criteria and recommended symptomatic treatments. We also review animal models and recent discoveries from pre-clinical studies. Furthermore, we highlight the recent advances in diagnosis using diffusor tensor imaging, functional magnetic resonance imaging, positron emission tomography, and the fluid biomarkers t-tau, sTREM2, CCL11, NFL, and GFAP. We also provide an update on emerging pharmaceutical treatments, including immunotherapies and those that target tau acetylation, tau phosphorylation, and inflammation. Lastly, we highlight the current literature gaps and guide future directions to further improve clinical diagnosis and management of patients suffering from this condition.

Many copy number variants (CNVs) confer risk for the same range of neurodevelopmental symptoms and psychiatric conditions including autism and schizophrenia. Yet, to date neuroimaging studies have typically been carried out one mutation at a time, showing that CNVs have large effects on brain anatomy. Here, we aimed to characterize and quantify the distinct brain morphometry effects and latent dimensions across 8 neuropsychiatric CNVs. We analyzed T1-weighted MRI data from clinically and non-clinically ascertained CNV carriers (deletion/duplication) at the 1q21.1 (n = 39/28), 16p11.2 (n = 87/78), 22q11.2 (n = 75/30), and 15q11.2 (n = 72/76) loci as well as 1296 non-carriers (controls). Case-control contrasts of all examined genomic loci demonstrated effects on brain anatomy, with deletions and duplications showing mirror effects at the global and regional levels. Although CNVs mainly showed distinct brain patterns, principal component analysis (PCA) loaded subsets of CNVs on two latent brain dimensions, which explained 32 and 29% of the variance of the 8 Cohen’s d maps. The cingulate gyrus, insula, supplementary motor cortex, and cerebellum were identified by PCA and multi-view pattern learning as top regions contributing to latent dimension shared across subsets of CNVs. The large proportion of distinct CNV effects on brain morphology may explain the small neuroimaging effect sizes reported in polygenic psychiatric conditions. Nevertheless, latent gene brain morphology dimensions will help subgroup the rapidly expanding landscape of neuropsychiatric variants and dissect the heterogeneity of idiopathic conditions.