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The "missing" heritability of complex traits may be partly explained by genetic variants interacting with other genes or environments that are difficult to specify, observe, and detect. We propose a new kernel-based method called Latent Interaction Testing (LIT) to screen for genetic interactions that leverages pleiotropy from multiple related traits without requiring the interacting variable to be specified or observed. Using simulated data, we demonstrate that LIT increases power to detect latent genetic interactions compared to univariate methods. We then apply LIT to obesity-related traits in the UK Biobank and detect variants with interactive effects near known obesity-related genes (URL: https://CRAN.R-project.org/package=lit ).

Most complex human traits differ by sex, but we have limited insight into the underlying mechanisms. Here, we investigated the influence of biological sex on protein expression and its genetic regulation in 1,277 human brain proteomes. We found that 13.2% (1,354) of brain proteins had sex-differentiated abundance and 1.5% (150) of proteins had sex-biased protein quantitative trait loci (sb-pQTLs). Among genes with sex-biased expression, we found 67% concordance between sex-differentiated protein and transcript levels; however, sex effects on the genetic regulation of expression were more evident at the protein level. Considering 24 psychiatric, neurologic and brain morphologic traits, we found that an average of 25% of their putatively causal genes had sex-differentiated protein abundance and 12 putatively causal proteins had sb-pQTLs. Furthermore, integrating sex-specific pQTLs with sex-stratified genome-wide association studies of six psychiatric and neurologic conditions, we uncovered another 23 proteins contributing to these traits in one sex but not the other. Together, these findings begin to provide insights into mechanisms underlying sex differences in brain protein expression and disease.

Alzheimer's disease (AD) pathology develops many years before the onset of cognitive symptoms. Two pathological processes-aggregation of the amyloid-β (Aβ) peptide into plaques and the microtubule protein tau into neurofibrillary tangles (NFTs)-are hallmarks of the disease. However, other pathological brain processes are thought to be key disease mediators of Aβ plaque and NFT pathology. How these additional pathologies evolve over the course of the disease is currently unknown. Here we show that proteomic measurements in autosomal dominant AD cerebrospinal fluid (CSF) linked to brain protein coexpression can be used to characterize the evolution of AD pathology over a timescale spanning six decades. SMOC1 and SPON1 proteins associated with Aβ plaques were elevated in AD CSF nearly 30 years before the onset of symptoms, followed by changes in synaptic proteins, metabolic proteins, axonal proteins, inflammatory proteins and finally decreases in neurosecretory proteins. The proteome discriminated mutation carriers from noncarriers before symptom onset as well or better than Aβ and tau measures. Our results highlight the multifaceted landscape of AD pathophysiology and its temporal evolution. Such knowledge will be critical for developing precision therapeutic interventions and biomarkers for AD beyond those associated with Aβ and tau.

Strength-based assessment has achieved acceptance from educational, mental health, and social service professionals as a means to measuring emotional and behavioral strengths of children. Several standardized, norm-referenced tests have been developed to assess these strengths; however, the primary mode of assessment is via informal interviews of parents and caregivers. In many cases, these interviews lack psychometric support, including basic validity and reliability. The purpose of this study was to document the multistep process used to establish the content validity of a newly developed instrument: Behavioral and Emotional Rating Scale: Strength-Based Interview. Specifically, the results of a survey of 40 U.S. professional mental health staff and educators are described where respondents rated the importance of interview questions to the construct of strength-based assessment. The findings of the survey as well as the 18 items deemed most important are reported. Research limitations, future research, and implications for mental health and educational professionals are discussed.

The present study was conducted to determine whether the problem characteristics of U.S. students school-identified with emotional disturbance (ED) have changed over two decades. We used data from a teacher rating instrument designed to measure the five problem characteristics of ED, as stated in its Individuals with Disabilities Education Act (IDEA) definition. These data were collected in the process of norming the instrument for 1998 and again for 2020. Comparison of the 1998 and 2020 students school-identified with ED showed that the 1998 group had significantly more problematic functioning on two characteristics, namely, Relationship Problems and Inappropriate Behavior, but no more problematic differences on Inability to Learn, Unhappiness or Depression, and Physical Symptoms or Fears. In addition, analyses of selected items gave more context to the main results. Study limitations, future research, and implications are discussed.

Identifying student strengths is central to transition planning. However, school personnel use few assessments that operationalize behavioral and emotional strengths, and the psychometric functioning of those measures have not been established with transition-age students. In this two-part study, we used a national sample of transition-age students to examine validity evidence for scores from the "Behavioral and Emotional Rating Scale-3: Teacher Rating Scale" (BERS-3 TRS). Study 1 evaluated the internal structure and test score reliability of the scores for 275 students with exceptionalities. Study II used a sample of 566 students to examine differences in scores between students with and without exceptionalities. Findings from these studies represent evidence for the validity and interpretation of scores for transition-age students with exceptionalities.

Provide data on the five characteristics of emotional disturbance (ED). For 503 students with ED and 2016 without disabilities, teachers rated the characteristics ("Inability to Learn;" "Relationship Problems;" "Inappropriate Behavior;" "Unhappiness or Depression;" "Physical Symptoms or Fears"), plus "Socially Maladjusted." We applied a 2 (ED, without disabilities) × 2 (female, male) × 3 (elementary, middle, high school) covariance analysis, with follow-up comparisons. Students with ED showed greater problems than students without disabilities on all five characteristics, and "Socially Maladjusted." On "Inability to Learn," among students with ED genders did not differ at elementary but males had greater problems at middle school. On "Inappropriate Behavior" and "Physical Symptoms or Fears," students with ED varied across school levels but students without disabilities did not. All five characteristics discriminated students with ED from those without disabilities. Differences between genders and school levels varied across characteristics.

Fragile X–associated tremor/ataxia syndrome (FXTAS) is a debilitating late-onset neurodegenerative disease in premutation carriers of the expanded CGG repeat in FMR1 that presents with a spectrum of neurological manifestations, such as gait ataxia, intention tremor, and parkinsonism [P. J. Hagerman, R. J. Hagerman, Ann. N. Y. Acad. Sci. 1338, 58–70 (2015); S. Jacquemont et al., JAMA 291, 460–469 (2004)]. Here, we performed whole-genome sequencing (WGS) on male premutation carriers (CGG55–200) and prioritized candidate variants to screen for candidate genetic modifiers using a Drosophila model of FXTAS. We found 18 genes that genetically modulate CGG-associated neurotoxicity in Drosophila, such as Prosbeta5 (PSMB5), pAbp (PABPC1L), e(y)1 (TAF9), and CG14231 (OSGEPL1). Among them, knockdown of Prosbeta5 (PSMB5) suppressed CGG-associated neurodegeneration in the fly as well as in N2A cells. Interestingly, an expression quantitative trait locus variant in PSMB5, PSMB5rs11543947-A, was found to be associated with decreased expression of PSMB5 and delayed onset of FXTAS in human FMR1 premutation carriers. Finally, we demonstrate evidence that PSMB5 knockdown results in suppression of CGG neurotoxicity via both the RAN translation and RNA-mediated toxicity mechanisms, thereby presenting a therapeutic strategy for FXTAS.

BACKGROUND: Cognitive trajectory varies widely and can distinguish people who develop dementia from people who remain cognitively normal. Variation in cognitive trajectory is only partially explained by traditional neuropathologies. We sought to identify novel genes associated with cognitive trajectory using DNA methylation profiles from human postmortem brain. METHODS: We performed a brain epigenome-wide association study of cognitive trajectory in 636 participants from the ROS (Religious Orders Study) and MAP (Rush Memory and Aging Project) using DNA methylation profiles of the dorsolateral prefrontal cortex. To maximize our power to detect epigenetic associations, we used the recently developed Gene Association with Multiple Traits test to analyze the 5 measured cognitive domains simultaneously. RESULTS: We found an epigenome-wide association for differential methylation of sites in the CLDN5 locus and cognitive trajectory (p = 9.96 × 10-7) that was robust to adjustment for cell type proportions (p = 8.52 × 10-7). This association was primarily driven by association with declines in episodic (p = 4.65 × 10-6) and working (p = 2.54 × 10-7) memory. This association between methylation in CLDN5 and cognitive decline was significant even in participants with no or little signs of amyloid-β and neurofibrillary tangle pathology. CONCLUSIONS: Differential methylation of CLDN5, a gene that encodes an important protein of the blood-brain barrier, is associated with cognitive trajectory beyond traditional Alzheimers disease pathologies. The association between CLDN5 methylation and cognitive trajectory in people with low pathology suggests an early role for CLDN5 and blood-brain barrier dysfunction in cognitive decline and Alzheimers disease.

Ensuring the provision of a free, appropriate public education (FAPE) to students qualified for services under the disability category of emotional disturbance (ED) has been both challenging and controversial. Examining this population in light of the five characteristics listed in the federal definition may provide useful insights to address needs and improve outcomes. The purpose of this study was to use latent class analysis to examine profiles across the five characteristics of the federal definition of ED for a sample of 491 students school-identified with ED. Key findings include that (a) students with ED are a heterogeneous group with distinct and qualitatively different subgroups; (b) latent classes representing the severe problems and the externalizing problems typologies tended to consist of younger students; (c) greater proportions of Black, Hispanic, and English-language learner students were found in the severe and externalizing latent classes; and (d) students in the externalizing and severe latent classes spent more time in special education classrooms and had worse ratings on social maladjustment. The findings highlight important implications for practice in regard to assessment, program differentiation, and preservice teacher training. Research limitations and directions for future research are also discussed.

Depression is a common condition, but current treatments are only effective in a subset of individuals. To identify new treatment targets, we integrated depression genome-wide association study (GWAS) results (N = 500,199) with human brain proteomes (N = 376) to perform a proteome-wide association study of depression followed by Mendelian randomization. We identified 19 genes that were consistent with being causal in depression, acting via their respective cis-regulated brain protein abundance. We replicated nine of these genes using an independent depression GWAS (N = 307,353) and another human brain proteomic dataset (N = 152). Eleven of the 19 genes also had cis-regulated mRNA levels that were associated with depression, based on integration of the depression GWAS with human brain transcriptomes (N = 888). Meta-analysis of the discovery and replication proteome-wide association study analyses identified 25 brain proteins consistent with being causal in depression, 20 of which were not previously implicated in depression by GWAS. Together, these findings provide promising brain protein targets for further mechanistic and therapeutic studies.

PurposeTo understand the consequences of the 3q29 deletion on medical, neurodevelopmental, psychiatric, brain structural, and neurological sequalae by systematic evaluation of affected individuals. To develop evidence-based recommendations using these data for effective clinical care.MethodsThirty-two individuals with the 3q29 deletion were evaluated using a defined phenotyping protocol and standardized data collection instruments.ResultsMedical manifestations were varied and reported across nearly every organ system. The most severe manifestations were congenital heart defects (25%) and the most common were gastrointestinal symptoms (81%). Physical examination revealed a high proportion of musculoskeletal findings (81%). Neurodevelopmental phenotypes represent a significant burden and include intellectual disability (34%), autism spectrum disorder (38%), executive function deficits (46%), and graphomotor weakness (78%). Psychiatric illness manifests across the lifespan with psychosis prodrome (15%), psychosis (20%), anxiety disorders (40%), and attention deficit-hyperactivity disorder (ADHD) (63%). Neuroimaging revealed structural anomalies of the posterior fossa, but on neurological exam study subjects displayed only mild or moderate motor vulnerabilities.ConclusionBy direct evaluation of 3q29 deletion study subjects, we document common features of the syndrome, including a high burden of neurodevelopmental and neuropsychiatric phenotypes. Evidence-based recommendations for evaluation, referral, and management are provided to help guide clinicians in the care of 3q29 deletion patients.

This study examined the internal structure of the Scales for Assessing Emotional Disturbance-3 Rating Scale (RS), a teacher-completed RS developed to measure emotional disturbance (ED). As defined in U.S. law and regulations, ED involves five characteristics or patterns of behavioral and emotional maladaptation. RS data obtained on a sample of students with ED were used to examine validity evidence based on the internal structure of the assessment. Of particular interest was the extent to which multivariate factors derived from the RS data conform to the five characteristics of ED stated in the definition. Results indicate that the RS data fit a 5-factor model reasonably well. A subsequent bifactor analysis identified a considerable proportion of common variance across factors, suggesting the presence of a strong general ED factor, two distinct group factors (Inability to Learn and Inappropriate Behavior), and three weak group factors. The findings provided evidence of the validity of the SAED-3 RS based on internal structure and pointed to support for use of the RS in contributing to the process of determining whether a student qualifies for the ED education disability. Implications for improved research on the nature of ED and how students with ED can be better served are discussed.

Community-based systems of care (SOC) provide a range of services to students with significant emotional and behavioral difficulties and their families. However, little is known about the educational characteristics and functioning of students at enrollment in SOC. The purpose of this study was to replicate and extend previous research by examining the educational characteristics and predictors of school functioning for students referred to SOC using a large and diverse national data source. Participants were 5,628 students ages 6 to 18 years who were enrolled in community-based SOC across 45 U.S. states, districts, and territories. Students' grades, discipline, and attendance (as reported by caregivers) were used as indicators of school functioning, and students' demographic characteristics, referral source, and emotional/behavioral functioning were used to predict functioning in school, including the testing of interaction effects. Findings revealed that, although many students earned average grades, a large portion of students had significant discipline and attendance problems. Results of the ordinal regression analyses indicated that most demographic variables and measures of clinical functioning significantly predicted students' grades, attendance, and discipline, and that age and special education status represented a significant interaction. Findings provide insight into the educational functioning of students at enrollment in community-based SOC and have implications for research and practice.

Genome-wide association studies (GWAS) have identified many risk loci for Alzheimers disease (AD)1,2, but how these loci confer AD risk is unclear. Here, we aimed to identify loci that confer AD risk through their effects on brain protein abundance to provide new insights into AD pathogenesis. To that end, we integrated AD GWAS results with human brain proteomes to perform a proteome-wide association study (PWAS) of AD, followed by Mendelian randomization and colocalization analysis. We identified 11 genes that are consistent with being causal in AD, acting via their cis-regulated brain protein abundance. Nine replicated in a confirmation PWAS and eight represent new AD risk genes not identified before by AD GWAS. Furthermore, we demonstrated that our results were independent of APOE e4. Together, our findings provide new insights into AD pathogenesis and promising targets for further mechanistic and therapeutic studies.

OBJECTIVE: Major depressive disorder (MDD) arises from a combination of genetic and environmental risk factors and DNA methylation is one of the molecular mechanisms through which these factors can manifest. However, little is known about the epigenetic signature of MDD in brain tissue. This study aimed to investigate associations between brain tissue-based DNA methylation and late-life MDD. METHODS: We performed a brain epigenome-wide association study (EWAS) of late-life MDD in 608 participants from the Religious Order Study and the Rush Memory and Aging Project (ROS/MAP) using DNA methylation profiles of the dorsal lateral prefrontal cortex generated using the Illumina HumanMethylation450 Beadchip array. We also conducted an EWAS of MDD in each sex separately. RESULTS: We found epigenome-wide significant associations between brain tissue-based DNA methylation and late-life MDD. The most significant and robust association was found with altered methylation levels in the YOD1 locus (cg25594636, p value = 2.55 × 10-11; cg03899372, p value = 3.12 × 10-09; cg12796440, p value = 1.51 × 10-08, cg23982678, p value = 7.94 × 10-08). Analysis of differentially methylated regions (p value = 5.06 × 10-10) further confirmed this locus. Other significant loci include UGT8 (cg18921206, p value = 1.75 × 10-08), FNDC3B (cg20367479, p value = 4.97 × 10-08) and SLIT2 (cg10946669, p value = 8.01 × 10-08). Notably, brain tissue-based methylation levels were strongly associated with late-life MDD in men more than in women. CONCLUSIONS: We identified altered methylation in the YOD1, UGT8, FNDC3B, and SLIT2 loci as new epigenetic factors associated with late-life MDD. Furthermore, our study highlights the sex-specific molecular heterogeneity of MDD.

For years, the research and policy focus on Black students with emotional disturbance (ED) has been on racial disproportionality. The disproportionality issue has sparked professional debate and raised major questions about racial bias, cultural fairness, appropriateness of assessment instruments, the adequacy of special education programs, poverty, exposure to risk factors, and research approaches. Unfortunately, minimal progress has been made on understanding the overrepresentation of Black students in ED programs. The purpose of the present study was to initiate research on the emotional and behavioral functioning of Black students with ED, by comparing the teacher-completed ratings from the "Scales for Assessing Emotional Disturbance" for Black students with ED (n = 139), Black students without ED (n = 421), White students with ED (n = 271), and White students without ED (n = 1,218). The results demonstrated that: (1) Black students with ED were judged to demonstrate significantly higher levels of emotional and behavioral problems than their Black and White peers without ED; and (2) Black students with ED differed minimally from White students with ED. Research limitations, directions for future research, and implications for assessment and service delivery are discussed.

The present study investigated evidence of the construct validity of scores from the Scales for Assessing Emotional Disturbance Rating Scale (SAED-3 RS), which is designed to help identify emotional disturbance (ED) as defined by U.S. law and regulations. The purpose of this research was to evaluate the degree to which SAED-3 RS scores differed between students with school-identified ED, students with school-identified learning disabilities (LD), and students without disabilities. The sample consisted of 2,193 K-12 students from throughout the U.S. The findings supported three hypotheses related to evidence of construct validity: (1) students with ED would differ from students without disabilities on all five dimensions of the SAED-3 RS; (2) students with ED would differ from students with LD on all dimensions of the SAED-3 RS except for the Inability to Learn dimensions; and (3) students with LD would differ from students without disabilities on all five dimensions of the SAED-3 RS, but that these differences would be smaller than the differences between students with ED and students without disabilities. Implications for practice and directions for future research are also discussed.

The present study explored the psychometric properties of ratings made using the Scales for Assessing Emotional Disturbance--Third Edition: Rating Scale (SAED-3 RS), a scale developed for use in identifying school-age students with emotional and behavioral problems. The purposes of the study were to assess differential item functioning (DIF) for SAED-3 RS items between White and Hispanic students and to assess the impact of DIF on SAED-3 RS scale scores. The sample consisted of 979 students without disabilities who were identified as White/Non-Hispanic (71.91%) and Hispanic (28.09%). The data indicated that SAED-3 RS items demonstrated small to negligible levels of DIF and that DIF did not saliently impact scores. The data suggest that items and scores yielded from the SAED-3 RS are consistent in measuring the emotional and behavioral functioning of school-age students from diverse backgrounds. Research limitations, future research directions, and practical use implications for school personnel are discussed.

The present study investigated evidence of the construct validity of scores from the Behavioral and Emotional Rating Scale (BERS-3), which is a multi-informant assessment designed to measure the behavioral and emotional strengths of school-aged youth. The purpose of this research was to evaluate the degree to which BERS-3 scores differed between students with school-identified emotional disturbance and students without disabilities. Two nationally representative samples were used in this study: (a) 1,575 students rated by teachers and (b) 793 youth who provided self-ratings. The results of multivariate multiple regression analyses supported the primary hypothesis that students with emotional disturbance would have lower scores on each of the five BERS-3 subscale scores compared to peers without disabilities. This finding held for both samples; however, differences between students with emotional disturbance and the peers without disabilities were substantially smaller for the youth self-ratings compared to teacher ratings. Implications for practice and directions for future research are also discussed.

The 22q11.2 deletion syndrome (22q11.2DS) results from non-allelic homologous recombination between low-copy repeats termed LCR22. About 60%-70% of individuals with the typical 3 megabase (Mb) deletion from LCR22A-D have congenital heart disease, mostly of the conotruncal type (CTD), whereas others have normal cardiac anatomy. In this study, we tested whether variants in the hemizygous LCR22A-D region are associated with risk for CTDs on the basis of the sequence of the 22q11.2 region from 1,053 22q11.2DS individuals. We found a significant association (FDR p < 0.05) of the CTD subset with 62 common variants in a single linkage disequilibrium (LD) block in a 350 kb interval harboring CRKL. A total of 45 of the 62 variants were associated with increased risk for CTDs (odds ratio [OR) ranges: 1.64-4.75). Associations of four variants were replicated in a meta-analysis of three genome-wide association studies of CTDs in affected individuals without 22q11.2DS. One of the replicated variants, rs178252, is located in an open chromatin region and resides in the double-elite enhancer, GH22J020947, that is predicted to regulate CRKL (CRK-like proto-oncogene, cytoplasmic adaptor) expression. Approximately 23% of patients with nested LCR22C-D deletions have CTDs, and inactivation of Crkl in mice causes CTDs, thus implicating this gene as a modifier. Rs178252 and rs6004160 are expression quantitative trait loci (eQTLs) of CRKL. Furthermore, set-based tests identified an enhancer that is predicted to target CRKL and is significantly associated with CTD risk (GH22J020946, sequence kernal association test (SKAT) p = 7.21 × 10-5) in the 22q11.2DS cohort. These findings suggest that variance in CTD penetrance in the 22q11.2DS population can be explained in part by variants affecting CRKL expression.

ObjectiveClassification of epilepsy into types and subtypes is important for both clinical care and research into underlying disease mechanisms. A quantitative, data-driven approach may augment traditional electroclinical classification and shed new light on existing classification frameworks.MethodsWe used latent class analysis, a statistical method that assigns subjects into groups called latent classes based on phenotypic elements, to classify individuals with common familial epilepsies from the Epi4K Multiplex Families study. Phenotypic elements included seizure types, seizure symptoms, and other elements of the medical history. We compared class assignments to traditional electroclinical classifications and assessed familial aggregation of latent classes.ResultsA total of 1120 subjects with epilepsy were assigned to five latent classes. Classes 1 and 2 contained subjects with generalized epilepsy, largely reflecting the distinction between absence epilepsies and younger onset (class 1) versus myoclonic epilepsies and older onset (class 2). Classes 3 and 4 contained subjects with focal epilepsies, and in contrast to classes 1 and 2, these did not adhere as closely to clinically defined focal epilepsy subtypes. Class 5 contained nearly all subjects with febrile seizures plus or unknown epilepsy type, as well as a few subjects with generalized epilepsy and a few with focal epilepsy. Family concordance of latent classes was similar to or greater than concordance of clinically defined epilepsy types.SignificanceQuantitative classification of epilepsy has the potential to augment traditional electroclinical classification by (1) combining some syndromes into a single class, (2) splitting some syndromes into different classes, (3) helping to classify subjects who could not be classified clinically, and (4) defining the boundaries of clinically defined classifications. This approach can guide future research, including molecular genetic studies, by identifying homogeneous sets of individuals that may share underlying disease mechanisms.

The transcriptome-wide association studies (TWASs) that test for association between the study trait and the imputed gene expression levels from cis-acting expression quantitative trait loci (cis-eQTL) genotypes have successfully enhanced the discovery of genetic risk loci for complex traits. By using the gene expression imputation models fitted from reference datasets that have both genetic and transcriptomic data, TWASs facilitate gene-based tests with GWAS data while accounting for the reference transcriptomic data. The existing TWAS tools like PrediXcan and FUSION use parametric imputation models that have limitations for modeling the complex genetic architecture of transcriptomic data. Therefore, to improve on this, we employ a nonparametric Bayesian method that was originally proposed for genetic prediction of complex traits, which assumes a data-driven nonparametric prior for cis-eQTL effect sizes. The nonparametric Bayesian method is flexible and general because it includes both of the parametric imputation models used by PrediXcan and FUSION as special cases. Our simulation studies showed that the nonparametric Bayesian model improved both imputation R2 for transcriptomic data and the TWAS power over PrediXcan when ≥1% cis-SNPs co-regulate gene expression and gene expression heritability ≤0.2. In real applications, the nonparametric Bayesian method fitted transcriptomic imputation models for 57.8% more genes over PrediXcan, thus improving the power of follow-up TWASs. We implement both parametric PrediXcan and nonparametric Bayesian methods in a convenient software tool TIGAR (Transcriptome-Integrated Genetic Association Resource), which imputes transcriptomic data and performs subsequent TWASs using individual-level or summary-level GWAS data.

The present study investigated the psychometric properties of the "Scales for Assessing Emotional Disturbance -- Third Edition: Rating Scale" (SAED-3 RS), which is designed for use in identifying students with emotional disturbance for special education services. The purposes of this study were to evaluate (a) the measurement invariance of SAED-3 RS scores between White and African American students and (b) the impact of differential item functioning (DIF) on test scores from the SAED-3 RS. The sample consisted of 855 K-12 students from throughout the United States. The findings suggested that SAED-3 RS items exhibited small to negligible levels of DIF and that DIF did not significantly impact scores. The results supported the SAED-3 RS, a teacher-completed rating scale, as relatively consistent in measuring the emotional and behavioral status of school-age students from different racial backgrounds. Researchers and practitioners can have confidence that scores from the SAED-3 RS are not substantially affected by DIF when assessing the emotional and behavioral functioning of African American and White school-age students. Research limitations, future research, and implications for school professionals are discussed.

The purpose of this article is to provide a qualitative review of the published research on the Scales for Assessing Emotional Disturbance-3: Screener noting the psychometric properties and overall findings. Results from 10 studies were reviewed and summarized. Across the studies, internal consistency, test-retest reliability, and inter-rater agreement were satisfactory. Unidimensionality of the tests scores was supported, and several studies reported only trivial degrees of bias across racial/ethnic and linguistic backgrounds. Diagnostic utility was acceptable as were convergent relations with other measures of psychopathology. Social validity was also satisfactory. This review indicates that the psychometric properties of the scores from the Screener meet acceptable professional standards and supports its use in school-based programs to identify at-risk students.

Gene identification in epilepsy has mainly been limited to large families segregating genes of major effect and de novo mutations in epileptic encephalopathies. Many families that present with common non-acquired focal epilepsies and genetic generalized epilepsies remain unexplained. We assembled a cohort of 'genetically enriched' common epilepsies by collecting and phenotyping families containing multiple individuals with unprovoked seizures. We aimed to determine if specific clinical epilepsy features aggregate within families, and whether this segregation of phenotypes may constitute distinct 'familial syndromes' that could inform genomic analyses. Families with three or more individuals with unprovoked seizures were studied across multiple international centres. Affected individuals were phenotyped and classified according to specific electroclinical syndromes. Families were categorized based on syndromic groupings of affected family members, examined for pedigree structure and phenotypic patterns and, where possible, assigned specific familial epilepsy syndromes. A total of 303 families were assembled and analysed, comprising 1120 affected phenotyped individuals. Of the 303 families, 117 exclusively segregated generalized epilepsy, 62 focal epilepsy, and 22 were classified as genetic epilepsy with febrile seizures plus. Over one-third (102 families) were observed to have mixed epilepsy phenotypes: 78 had both generalized and focal epilepsy features within the same individual (n = 39), or within first or second degree relatives (n = 39). Among the genetic generalized epilepsy families, absence epilepsies were found to cluster within families independently of juvenile myoclonic epilepsy, and significantly more females were affected than males. Of the 62 familial focal epilepsy families, two previously undescribed familial focal syndrome patterns were evident: 15 families had posterior quadrant epilepsies, including seven with occipito-temporal localization and seven with temporo-parietal foci, and four families displayed familial focal epilepsy of childhood with multiple affected siblings that was suggestive of recessive inheritance. The findings suggest (i) specific patterns of syndromic familial aggregation occur, including newly recognized forms of familial focal epilepsy; (ii) although syndrome-specificity usually occurs in multiplex families, the one-third of families with features of both focal and generalized epilepsy is suggestive of shared genetic determinants; and (iii) patterns of features observed across families including pedigree structure, sex, and age of onset may hold clues for future gene identification. Such detailed phenotypic information will be invaluable in the conditioning and interpretation of forthcoming sequencing data to understand the genetic architecture and inter-relationships of the common epilepsy syndromes.