BackgroundPhelan-McDermid syndrome (PMS) is a neurodevelopmental disorder characterized by psychiatric and neurological features. Most reported cases are caused by 22q13.3 deletions, leading to SHANK3 haploinsufficiency, but also usually encompassing many other genes. While the number of point mutations identified in SHANK3 has increased in recent years due to large-scale sequencing studies, systematic studies describing the phenotype of individuals harboring such mutations are lacking.MethodsWe provide detailed clinical and genetic data on 17 individuals carrying mutations in SHANK3. We also review 60 previously reported patients with pathogenic or likely pathogenic SHANK3 variants, often lacking detailed phenotypic information.ResultsSHANK3 mutations in our cohort and in previously reported cases were distributed throughout the protein; the majority were truncating and all were compatible with de novo inheritance. Despite substantial allelic heterogeneity, four variants were recurrent (p.Leu1142Valfs*153, p.Ala1227Glyfs*69, p.Arg1255Leufs*25, and c.2265+1G>A), suggesting that these are hotspots for de novo mutations. All individuals studied had intellectual disability, and autism spectrum disorder was prevalent (73%). Severe speech deficits were common, but in contrast to individuals with 22q13.3 deletions, the majority developed single words, including 41% with at least phrase speech. Other common findings were consistent with reports among individuals with 22q13.3 deletions, including hypotonia, motor skill deficits, regression, seizures, brain abnormalities, mild dysmorphic features, and feeding and gastrointestinal problems.ConclusionsHaploinsufficiency of SHANK3 resulting from point mutations is sufficient to cause a broad range of features associated with PMS. Our findings expand the molecular and phenotypic spectrum of PMS caused by SHANK3 point mutations and suggest that, in general, speech impairment and motor deficits are more severe in the case of deletions. In contrast, renal abnormalities associated with 22q13.3 deletions do not appear to be related to the loss of SHANK3.Electronic supplementary materialThe online version of this article (10.1186/s13229-018-0205-9) contains supplementary material, which is available to authorized users.

BackgroundHaploinsufficiency of the forkhead-box protein P1 (FOXP1) gene leads to a neurodevelopmental disorder termed FOXP1 syndrome. Previous studies in individuals carrying FOXP1 mutations and deletions have described the presence of autism spectrum disorder (ASD) traits, intellectual disability, language impairment, and psychiatric features. The goal of the present study was to comprehensively characterize the genetic and clinical spectrum of FOXP1 syndrome. This is the first study to prospectively examine the genotype-phenotype relationship in multiple individuals with FOXP1 syndrome, using a battery of standardized clinical assessments.MethodsGenetic and clinical data was obtained and analyzed from nine children and adolescents between the ages of 5–17 with mutations in FOXP1. Phenotypic characterization included gold standard ASD testing and norm-referenced measures of cognition, adaptive behavior, language, motor, and visual-motor integration skills. In addition, psychiatric, medical, neurological, and dysmorphology examinations were completed by a multidisciplinary team of clinicians. A comprehensive review of reported cases was also performed. All missense and in-frame mutations were mapped onto the three-dimensional structure of DNA-bound FOXP1.ResultsWe have identified nine de novo mutations, including three frameshift, one nonsense, one mutation in an essential splice site resulting in frameshift and insertion of a premature stop codon, three missense, and one in-frame deletion. Reviewing prior literature, we found seven instances of recurrent mutations and another 34 private mutations. The majority of pathogenic missense and in-frame mutations, including all four missense mutations in our cohort, lie in the DNA-binding domain. Through structural analyses, we show that the mutations perturb amino acids necessary for binding to the DNA or interfere with the domain swapping that mediates FOXP1 dimerization. Individuals with FOXP1 syndrome presented with delays in early motor and language milestones, language impairment (expressive language > receptive language), ASD symptoms, visual-motor integration deficits, and complex psychiatric presentations characterized by anxiety, obsessive-compulsive traits, attention deficits, and externalizing symptoms. Medical features included non-specific structural brain abnormalities and dysmorphic features, endocrine and gastrointestinal problems, sleep disturbances, and sinopulmonary infections.ConclusionsThis study identifies novel FOXP1 mutations associated with FOXP1 syndrome, identifies recurrent mutations, and demonstrates significant clustering of missense mutations in the DNA-binding domain. Clinical findings confirm the role FOXP1 plays in development across multiple domains of functioning. The genetic findings can be incorporated into clinical genetics practice to improve accurate genetic diagnosis of FOXP1 syndrome and the clinical findings can inform monitoring and treatment of individuals with FOXP1 syndrome.Electronic supplementary materialThe online ver...

Adults prefer fair processes (“procedural justice”) over equal outcomes (“distributive justice”). This preference impacts their judgments of others in addition to their willingness to cooperate, raising questions about whether similar preferences drive judgments and behavior in children. The present study examines the development of this preference for procedural justice by testing children’s attitudes towards procedural justice using a resource allocation task in both first- and third-party contexts, and in contexts in which the procedurally just process does versus does not create distributional injustice. Results from children 4 to 8 years of age demonstrate that children robustly attend to and prefer procedural justice over distributive justice. However, younger children are less likely to prefer methods that are procedurally just or that create distributively just outcomes in first-party contexts, when distributive injustice might favor them. Results suggest an interplay between abstract justice concerns and the emerging ability to override selfishness.

Adolescence and later childhood are critical periods for developing attitudes toward legal authorities, a process known as legal socialization. Traditionally, scholars have understood contact with local police officers and experiences with the juvenile justice system to drive legal socialization. These interactions, and in particular how fair they are perceived to be, influence long-term views about the legitimacy of the legal system and future criminal behavior. In recent years, however, the potential for adolescent contact with police has increased exponentially through their presence in a new context: schools. In a survey of high schoolers, we explored how school-based police, school resource officers (SROs), function as an emerging nexus of legal socialization. We found that SROs' influence extends beyond school grounds: the more procedurally just students perceived SROs to be, the more they were willing to follow their directives and to obey police outside of school. Further, procedural justice perceptions of SROs were correlated with school climate outcomes, including self-reported academic success, anxiety, and identification with the school community. Our results speak to the connection between legal socialization and other developmental processes like community engagement and support expanding robust theories of legal socialization to consider arenas that intermingle legal and non-legal authority.

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The firearms data infrastructure in the United States is severely limited in scope and fragmented in nature. Improved data systems are needed in order to address gun violence and promote productive conversation about gun policy. In the absence of federal leadership in firearms data systems improvement, motivated states may take proactive steps to stitch gaps in data systems. We propose that states evaluate the gaps in their systems, expand data collection, and improve data presentation and availability.

Rates of firearm injury and mortality are far higher in the United States compared to other high-income nations. Patterns of firearm injury have complex causal pathways; different social contexts may be differentially affected by firearm legislation. In the context of the diversity of social, political, and legal approaches at the state level, we suggest the application of the social ecological model as a conceptual public health framework to guide future policy interventions in the U.S.

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