Explore the vast range of titles available.

The genetic etiology of autism spectrum disorder (ASD) is multifactorial, but how combinations of genetic factors determine risk is unclear. In a large family sample, we show that genetic loads of rare and polygenic risk are inversely correlated in cases and greater in females than in males, consistent with a liability threshold that differs by sex. De novo mutations (DNMs), rare inherited variants and polygenic scores were associated with various dimensions of symptom severity in children and parents. Parental age effects on risk for ASD in offspring were attributable to a combination of genetic mechanisms, including DNMs that accumulate in the paternal germline and inherited risk that influences behavior in parents. Genes implicated by rare variants were enriched in excitatory and inhibitory neurons compared with genes implicated by common variants. Our results suggest that a phenotypic spectrum of ASD is attributable to a spectrum of genetic factors that impact different neurodevelopmental processes. Integrated analyses in a large collection of families provide insights into the combined effects of rare variants and polygenic risk on autism spectrum disorder.

Across Europe, there is increased awareness of the frequency and importance of autism spectrum disorder (ASD), which is now recognised not only as a childhood disorder but as a heterogeneous, neurodevelopmental condition that persists throughout life. Services for individuals with autism and their families vary widely, but in most European countries, provision is limited. In 2018, European Society of Child and Adolescent Psychiatry (ESCAP) identified the need for a Practice Guidance document that would help to improve knowledge and practice, especially for individuals in underserviced areas. The present document, prepared by the ASD Working Party and endorsed by the ESCAP Board on October 3, 2019, summarises current information on autism and focuses on ways of detecting, diagnosing, and treating this condition.

About one-quarter of genetic variants that are associated with autism spectrum disorder (ASD) are due to de novo mutations in protein-coding genes. Brandler et al. wanted to determine whether changes in noncoding regions of the genome are associated with autism. They applied whole-genome sequencing to ∼2600 families with at least one affected child. Children with ASD had inherited structural variants in noncoding regions from their father. Regulatory regions of some specific genes were disrupted among multiple families, supporting the idea that a component of autism risk involves inherited noncoding variation. Science , this issue p. 327 Whole-genome sequencing identifies inherited noncoding variants in families affected by autism spectrum disorder. The genetic basis of autism spectrum disorder (ASD) is known to consist of contributions from de novo mutations in variant-intolerant genes. We hypothesize that rare inherited structural variants in cis-regulatory elements (CRE-SVs) of these genes also contribute to ASD. We investigated this by assessing the evidence for natural selection and transmission distortion of CRE-SVs in whole genomes of 9274 subjects from 2600 families affected by ASD. In a discovery cohort of 829 families, structural variants were depleted within promoters and untranslated regions, and paternally inherited CRE-SVs were preferentially transmitted to affected offspring and not to their unaffected siblings. The association of paternal CRE-SVs was replicated in an independent sample of 1771 families. Our results suggest that rare inherited noncoding variants predispose children to ASD, with differing contributions from each parent.

Theoretical and empirical accounts suggest that adolescence is associated with heightened reward learning and impulsivity. Experimental tasks and computational models that can dissociate reward learning from the tendency to initiate actions impulsively (action initiation bias) are thus critical to characterise the mechanisms that drive developmental differences. However, existing work has rarely quantified both learning ability and action initiation, or it has relied on small samples. Here, using computational modelling of a learning task collected from a large sample ( N  = 742, 9-18 years, 11 countries), we test differences in reward and punishment learning and action initiation from childhood to adolescence. Computational modelling reveals that whilst punishment learning rates increase with age, reward learning remains stable. In parallel, action initiation biases decrease with age. Results are similar when considering pubertal stage instead of chronological age. We conclude that heightened reward responsivity in adolescence can reflect differences in action initiation rather than enhanced reward learning. Adolescence is often associated with heightened reward learning and impulsivity. Here the authors show in 742 people aged 9-18 that reward learning in fact remains stable with age, whilst punishment learning increases and action initiation decreases.

Conduct Disorder (CD) is an impairing psychiatric disorder of childhood and adolescence characterized by aggressive and dissocial behavior. Environmental factors such as maternal smoking during pregnancy, socio-economic status, trauma, or early life stress are associated with CD. Although the number of females with CD is rising in Western societies, CD is under-researched in female cohorts. We aimed at exploring the epigenetic signature of females with CD and its relation to psychosocial and environmental risk factors. We performed HpaII sensitive genome-wide methylation sequencing of 49 CD girls and 50 matched typically developing controls and linear regression models to identify differentially methylated CpG loci (tags) and regions. Significant tags and regions were mapped to the respective genes and tested for enrichment in pathways and brain developmental processes. Finally, epigenetic signatures were tested as mediators for CD-associated risk factors. We identified a 12% increased methylation 5’ of the neurite modulator SLITRK5 ( FDR = 0.0046) in cases within a glucocorticoid receptor binding site. Functionally, methylation positively correlated with gene expression in lymphoblastoid cell lines. At systems-level, genes (uncorr. P < 0.01) were associated with development of neurons, neurite outgrowth or neuronal developmental processes. At gene expression level, the associated gene-networks are activated perinatally and during early childhood in neocortical regions, thalamus and striatum, and expressed in amygdala and hippocampus. Specifically, the epigenetic signatures of the gene network activated in the thalamus during early childhood correlated with the effect of parental education on CD status possibly mediating its protective effect. The differential methylation patterns identified in females with CD are likely to affect genes that are expressed in brain regions previously indicated in CD. We provide suggestive evidence that protective effects are likely mediated by epigenetic mechanisms impairing specific brain developmental networks and therefore exerting a long-term effect on neural functions in CD. Our results are exploratory and thus, further replication is needed.

Objective To interpret the current evidence on the prevalence of neurodevelopmental disorders (NDDs) through a systematic review based on both DSM-5 (2013) and PRISMA criteria. Method Empirical studies complying with the PRISMA guidelines were identified from four databases (PubMed, Scopus, Science Direct, and ProQuest) and systematically reviewed. In total, 17 articles were selected for the study. Results In the scientific literature, there have been only a few studies measuring the prevalence of NDDs according to the DSM-5 (2013) criteria in people under 18 years old. The reported prevalence rates were as follows: intellectual disability (ID), 0.63%; attention-deficit/hyperactivity disorder (ADHD), 5–11%; autism spectrum disorder (ASD), 0.70–3%; specific learning disorder (SLD), 3–10%; communication disorders (CDs), 1–3.42%; and motor disorders (MDs), 0.76–17%. Although there is extensive literature on specific disorders, NDDs have rarely been assessed as a whole. All of the reviewed studies support the idea that such disorders can be considered chronic, heterogeneous, underdiagnosed conditions and that comorbidity of multiple NDDs is the norm. Likewise, it is estimated that the prevalence of the most studied disorders, such as ADHD, ASD and SLD, remains stable over time and is consistent in different cultures, ages, ethnicities and sexes. Conclusion The studies reviewed lead us to conclude that the prevalence rate of NDDs fluctuates globally between 4.70 and 88.50%; these variations depend on methodological aspects such as estimation procedures, as well as on sociocontextual phenomena. It is also important to consider that the prevalence found is probably highly influenced by the activity of the countries in the diagnosis and training of professionals who care for children and adolescents. Hence, there is a need for a secondary intervention in the fields of public health and education to minimize socioemotional consequences, prevent academic failure, and reduce the economic cost to society.

Conduct disorder (CD) with high levels of callous-unemotional traits (CD/HCU) has been theoretically linked to specific difficulties with fear and sadness recognition, in contrast to CD with low levels of callous-unemotional traits (CD/LCU). However, experimental evidence for this distinction is mixed, and it is unclear whether these difficulties are a reliable marker of CD/HCU compared to CD/LCU. In a large sample ( N  = 1263, 9–18 years), we combined univariate analyses and machine learning classifiers to investigate whether CD/HCU is associated with disproportionate difficulties with fear and sadness recognition over other emotions, and whether such difficulties are a reliable individual-level marker of CD/HCU. We observed similar emotion recognition abilities in CD/HCU and CD/LCU. The CD/HCU group underperformed relative to typically developing (TD) youths, but difficulties were not specific to fear or sadness. Classifiers did not distinguish between youths with CD/HCU versus CD/LCU (52% accuracy), although youths with CD/HCU and CD/LCU were reliably distinguished from TD youths (64% and 60%, respectively). In the subset of classifiers that performed well for youths with CD/HCU, fear and sadness were the most relevant emotions for distinguishing them from youths with CD/LCU and TD youths, respectively. We conclude that non-specific emotion recognition difficulties are common in CD/HCU, but are not reliable individual-level markers of CD/HCU versus CD/LCU. These findings highlight that a reduced ability to recognise facial expressions of distress should not be assumed to be a core feature of CD/HCU.

Evidence of alterations in emotion processing in maltreated youth has been hypothesized to reflect latent vulnerability for psychopathology. However, previous studies have not systematically examined the influence of psychopathology on the results. Here, we examined emotion recognition and learning in youth who differed in terms of presence vs. absence of maltreatment and psychopathology and tested for potential sex effects. Maltreatment and psychopathology were assessed in 828 youth (514 females) aged 9–18 years using diagnostic interviews and self- and parent-report questionnaires. Emotion recognition was assessed via identification of morphed facial expressions of six universal emotions. For emotion learning, reward and punishment values were assigned to novel stimuli and participants had to learn to correctly respond/withhold response to stimuli to maximize points. A three-way interaction of maltreatment by psychopathology by emotion indicated that when psychopathology was low, maltreated youth were less accurate than non-maltreated youth for happy, fear and disgust. A three-way interaction of sex, maltreatment and emotion indicated that maltreated girls and boys were impaired for fear, but girls showed an impairment for happy, while boys for disgust. There were no effects of maltreatment, psychopathology, or sex on reward learning. However, a two-way interaction between sex and maltreatment showed that maltreated girls were worse at learning from punishment relative to non-maltreated girls, while maltreated boys were better than non-maltreated boys. The study provides the first clear evidence of latent-vulnerability in emotion recognition in maltreated youth and suggests that girls and boys might be characterized by distinct profiles of emotion recognition and learning following maltreatment.

BACKGROUND: Autistic spectrum disorders (ASD) are severe neurodevelopmental alterations characterised by deficits in social communication and repetitive and restricted behaviours. About a third of patients receive pharmacological treatment for comorbid symptoms. However, 30–50% do not respond adequately and/or present severe and long-lasting side effects. METHODS: Genetic variants in CYP1A2, CYP2C19, CYP2D6 and SLC6A4 were investigated in N = 42 ASD sufferers resistant to pharmacological treatment. Clinical recommendations based on their pharmacogenetic profiles were provided within 24–48 h of receiving a biological sample. RESULTS: A total of 39 participants (93%) improved after the pharmacogenetic intervention according to their CGI scores (difference in basal-final scores: 2.26, SD 1.55) and 37 participants (88%) according to their CGAS scores (average improvement of 20.29, SD 11.85). Twenty-three of them (55%) achieved symptom stability (CGI ≤ 3 and CGAS improvement ≥ 20 points), requiring less frequent visits to their clinicians and hospital stays. Furthermore, the clinical improvement was higher than that observed in a control group (N = 62) with no pharmacogenetic interventions, in which 66% responded to treatment (difference in CGI scores: −0.87, SD 9.4, p = 1 × 10−5; difference in CGAS scores: 6.59, SD 7.76, p = 5 × 10−8). CONCLUSIONS: The implementation of pharmacogenetic interventions has the potential to significantly improve the clinical outcomes in severe comorbid ASD populations with drug treatment resistance and poor prognosis.

Background Youth with conduct disorder (CD) and high callous‐unemotional (CU) traits are not a homogenous group and can be disaggregated into primary and secondary subgroups. However, there are inconsistencies in defining primary and secondary subgroups, with some studies using anxiety, others using maltreatment and still others using both features to identify subgroups. There is a paucity of work comparing primary and secondary subgroups with typically developing (TD) youth on experiences of maltreatment and parenting as well as a lack of studies investigating sex differences. Methods In a large sample of TD youth (n = 946, 66% female) and youth with CD (n = 885, 60% female), we used latent profile analysis in youth with CD aged between 9 and 18 years to address four aims: (i) to demonstrate how primary and secondary subgroup membership differs when anxiety, maltreatment, or both are used as continuous indicators, (ii) to compare primary and secondary subgroups with TD youth on abuse and neglect measures, and (iii) to compare primary and secondary subgroups with TD youth on parenting experiences, and (iv) to examine whether the results were consistent across sexes. Results Anxiety without maltreatment yielded the best fitting and most theoretically interpretable classification of primary and secondary subgroups across both sexes (Bayesian information criterion = 17832.33, Entropy = 0.75, Lo‐Mendell‐Rubin: p < 0.01). Compared with TD youth, youth with primary and secondary CU traits experienced greater levels of abuse and neglect (p < 0.001, η2p = 0.04−0.16) and maladaptive parenting practices (p < 0.001, η2p = 0.04−0.13). Youth with primary and secondary CU traits were equally high on levels of abuse, neglect, and maladaptive parenting (all p values >0.05). Conclusions We provide evidence that anxiety and maltreatment cannot be used interchangeably to identify youth with primary versus secondary CU traits. Anxiey yielded the best fitting and most theoretically interpretable classifications across both sexes. Our results signify the need for researchers and clinicians to adopt a unified approach to defining primary and secondary subgroups of CU traits using anxiety in both sexes. We investigated latent classes of typically developing youth with subgroups of primary and secondary callous‐unemotional youth. Sex differences were also explored. The groups were then compared on maltreatment histories (abuse and neglect) and experiences of parenting.