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Purpose: Genome-wide sequencing is increasingly being performed during pregnancy to identify the genetic cause of congenital anomalies. The interpretation of prenatally identified variants can be challenging and is hampered by our often limited knowledge of prenatal phenotypes. To better delineate the prenatal phenotype of Coffin-Siris syndrome (CSS), we collected clinical data from patients with a prenatal phenotype and a pathogenic variant in one of the CSS-associated genes. Methods: Clinical data was collected through an extensive web-based survey. Results: We included 44 patients with a variant in a CSS-associated gene and a prenatal phenotype; 9 of these patients have been reported before. Prenatal anomalies that were frequently observed in our cohort include hydrocephalus, agenesis of the corpus callosum, hypoplastic left heart syndrome, persistent left vena cava, diaphragmatic hernia, renal agenesis, and intrauterine growth restriction. Anal anomalies were frequently identified after birth in patients with ARID1A variants (6/14, 43%). Interestingly, pathogenic ARID1A variants were much more frequently identified in the current prenatal cohort (16/44, 36%) than in postnatal CSS cohorts (5%-9%). Conclusion: Our data shed new light on the prenatal phenotype of patients with pathogenic variants in CSS genes. (C) 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.

Rare genomic disorders (RGDs) confer elevated risk for neurodevelopmental psychiatric disorders. In this era of intense genomics discoveries, the landscape of RGDs is rapidly evolving. However, there has not been comparable progress to date in scalable, harmonized phenotyping methods. As a result, beyond associations with categorical diagnoses, the effects on dimensional traits remain unclear for many RGDs. The nature and specificity of RGD effects on cognitive and behavioral traits is an area of intense investigation: RGDs are frequently associated with more than one psychiatric condition, and those studied to date affect, to varying degrees, a broad range of developmental and cognitive functions. Although many RGDs have large effects, phenotypic expression is typically influenced by additional genomic and environmental factors. There is emerging evidence that using polygenic risk scores in individuals with RGDs offers opportunities to refine prediction, thus allowing for the identification of those at greatest risk of psychiatric illness. However, translation into the clinic is hindered by roadblocks, which include limited genetic testing in clinical psychiatry, and the lack of guidelines for following individuals with RGDs, who are at high risk of developing psychiatric symptoms. The Genes to Mental Health Network (G2MH) is a newly funded National Institute of Mental Health initiative that will collect, share, and analyze large-scale data sets combining genomics and dimensional measures of psychopathology spanning diverse populations and geography. The authors present here the most recent understanding of the effects of RGDs on dimensional behavioral traits and risk for psychiatric conditions and discuss strategies that will be pursued within the G2MH network, as well as how expected results can be translated into clinical practice to improve patient outcomes.

Stress granules (SGs) are cytoplasmic assemblies in response to a variety of stressors. We report a new neurodevelopmental disorder (NDD) with common features of language problems, intellectual disability, and behavioral issues caused by de novo likely gene-disruptive variants in UBAP2L , which encodes an essential regulator of SG assembly. Ubap2l haploinsufficiency in mouse led to social and cognitive impairments accompanied by disrupted neurogenesis and reduced SG formation during early brain development. On the basis of data from 40,853 individuals with NDDs, we report a nominally significant excess of de novo variants within 29 genes that are not implicated in NDDs, including 3 essential genes ( G3BP1 , G3BP2 , and UBAP2L ) in the core SG interaction network. We validated that NDD-related de novo variants in newly implicated and known NDD genes, such as CAPRIN1 , disrupt the interaction of the core SG network and interfere with SG formation. Together, our findings suggest the common SG pathology in NDDs.

PAX5 is a transcription factor associated with abnormal posterior midbrain and cerebellum development in mice. PAX5 is highly loss-of-function intolerant and missense constrained, and has been identified as a candidate gene for autism spectrum disorder (ASD). We describe 16 individuals from 12 families who carry deletions involving PAX5 and surrounding genes, de novo frameshift variants that are likely to trigger nonsense-mediated mRNA decay, a rare stop-gain variant, or missense variants that affect conserved amino acid residues. Four of these individuals were published previously but without detailed clinical descriptions. All these individuals have been diagnosed with one or more neurodevelopmental phenotypes including delayed developmental milestones (DD), intellectual disability (ID), and/or ASD. Seizures were documented in four individuals. No recurrent patterns of brain magnetic resonance imaging (MRI) findings, structural birth defects, or dysmorphic features were observed. Our findings suggest that PAX5 haploinsufficiency causes a neurodevelopmental disorder whose cardinal features include DD, variable ID, and/or ASD.

Purpose: Pathogenic variants in ARID1B are one of the most frequent causes of intellectual disability (ID) as determined by large-scale exome sequencing studies. Most studies published thus far describe clinically diagnosed Coffin-Siris patients (ARID1BCSS) and it is unclear whether these data are representative for patients identified through sequencing of unbiased ID cohorts (ARID1B-ID). We therefore sought to determine genotypic and phenotypic differences between ARID1B-ID and ARID1B-CSS. In parallel, we investigated the effect of different methods of phenotype reporting. Methods: Clinicians entered clinical data in an extensive webbased survey. Results: 79 ARID1B-CSS and 64 ARID1B-ID patients were included. CSS-associated dysmorphic features, such as thick eyebrows, long eyelashes, thick alae nasi, long and/or broad philtrum, small nails and small or absent fifth distal phalanx and hypertrichosis, were observed significantly more often (p < 0.001) in ARID1B-CSS patients. No other significant differences were identified. Conclusion: There are only minor differences between ARID1BID and ARID1B-CSS patients. ARID1B-related disorders seem to consist of a spectrum, and patients should be managed similarly. We demonstrated that data collection methods without an explicit option to report the absence of a feature (such as most Human Phenotype Ontology-based methods) tended to underestimate gene-related features., We are grateful for the assistance of Pepijn Cox in setting up the website www.arid1bgene.com. This study has made use of data generated by the Human Disease Genes website series, www.humandiseasegenes.com. This work was financially supported by grants from the Netherlands Organisation for Health Research and Development (917-86-319 to B.B.A.d.V., 912-12-109 to B.B.A.d.V.)

Contains fulltext : 231702.pdf (Publisher’s version ) (Closed access) Deletion 1p36 (del1p36) syndrome is the most common human disorder resulting from a terminal autosomal deletion. This condition is molecularly and clinically heterogeneous. Deletions involving two non-overlapping regions, known as the distal (telomeric) and proximal (centromeric) critical regions, are sufficient to cause the majority of the recurrent clinical features, although with different facial features and dysmorphisms. SPEN encodes a transcriptional repressor commonly deleted in proximal del1p36 syndrome and is located centromeric to the proximal 1p36 critical region. Here, we used clinical data from 34 individuals with truncating variants in SPEN to define a neurodevelopmental disorder presenting with features that overlap considerably with those of proximal del1p36 syndrome. The clinical profile of this disease includes developmental delay/intellectual disability, autism spectrum disorder, anxiety, aggressive behavior, attention deficit disorder, hypotonia, brain and spine anomalies, congenital heart defects, high/narrow palate, facial dysmorphisms, and obesity/increased BMI, especially in females. SPEN also emerges as a relevant gene for del1p36 syndrome by co-expression analyses. Finally, we show that haploinsufficiency of SPEN is associated with a distinctive DNA methylation episignature of the X chromosome in affected females, providing further evidence of a specific contribution of the protein to the epigenetic control of this chromosome, and a paradigm of an X chromosome-specific episignature that classifies syndromic traits. We conclude that SPEN is required for multiple developmental processes and SPEN haploinsufficiency is a major contributor to a disorder associated with deletions centromeric to the previously established 1p36 critical regions.

Sleep difficulties are pervasive in autism spectrum disorder (ASD), yet how sleep problems relate to underlying biological mechanisms such as genetic etiology is unclear, despite recent reports of profound sleep problems in children with ASD-associated de novo likely gene disrupting (dnLGD) mutations, CHD8, DYRK1A, and ADNP. We aimed to inform etiological contributions to ASD and sleep by characterizing sleep problems in individuals with dnLGD mutations. Participants (N = 2886) were families who completed dichotomous questions about sleep problems within a medical history interview for their child with ASD (age 3–28 years). Confirmatory factor analyses compared between those with ASD and a dnLGD mutation and those with idiopathic ASD (i.e., no known genetic event, NON) highlighted four domains (sleep onset, breathing issues, nighttime awakenings, and daytime tiredness) with sleep onset as a strong factor for both groups. Overall, participant predictors indicated that internalizing behavioral problems and lower cognitive scores were related to increased sleep problems. Internalizing problems were also related to increase nighttime awakenings in the dnLGD group. As an exploratory aim, patterns of sleep issues are described for genetic subgroups with unique patterns including more overall sleep issues in ADNP (n = 19), problems falling asleep in CHD8 (n = 22), and increased daytime naps in DYRK1A (n = 23). Implications for considering genetically defined subgroups when approaching sleep problems in children with ASD are discussed.

Autism-associated CHD8/CHD7/kismet deficiency in blood-brain barrier glia causes developmental hyperserotonemia and sleep defects., Sleep disturbances in autism and neurodevelopmental disorders are common and adversely affect patient’s quality of life, yet the underlying mechanisms are understudied. We found that individuals with mutations in CHD8, among the highest-confidence autism risk genes, or CHD7 suffer from disturbed sleep maintenance. These defects are recapitulated in Drosophila mutants affecting kismet, the sole CHD8/CHD7 ortholog. We show that Kismet is required in glia for early developmental and adult sleep architecture. This role localizes to subperineurial glia constituting the blood-brain barrier. We demonstrate that Kismet-related sleep disturbances are caused by high serotonin during development, paralleling a well-established but genetically unsolved autism endophenotype. Despite their developmental origin, Kismet’s sleep architecture defects can be reversed in adulthood by a behavioral regime resembling human sleep restriction therapy. Our findings provide fundamental insights into glial regulation of sleep and propose a causal mechanistic link between the CHD8/CHD7/Kismet family, developmental hyperserotonemia, and autism-associated sleep disturbances.

Background Persistent occiput posterior position in labor is associated with adverse maternal and perinatal outcomes. Prophylactic manual rotation from the occiput posterior position to the occiput anterior position in the second stage of labor is considered a safe and easy to perform procedure that in observational studies has shown promise as a method for preventing operative deliveries. Objective This study aimed to determine the efficacy of prophylactic manual rotation in the management of occiput posterior position for preventing operative delivery. The hypothesis was that among women who are at least 37 weeks pregnant and whose baby is in the occiput posterior position early in the second stage of labor, manual rotation will reduce the rate of operative delivery compared with the “sham” rotation. Study Design A double-blinded, parallel, superiority, multicenter, randomized controlled clinical trial in 4 tertiary hospitals was conducted in Australia. A total of 254 nulliparous and parous women with a term pregnancy and a baby in the occiput posterior position in the second stage of labor were randomly assigned to receive either a prophylactic manual rotation (n=127) or a sham rotation (n=127). The primary outcome was operative delivery (cesarean, forceps, or vacuum delivery). Secondary outcomes were cesarean delivery, combined maternal mortality and serious morbidity, and combined perinatal mortality and serious morbidity. Analysis was by intention to treat. Proportions were compared using chi-square tests adjusted for stratification variables using the Mantel-Haenszel method or the Fisher exact test. Planned subgroup analyses by operator experience and by manual rotation technique (digital or whole-hand rotation) were performed. Results Operative delivery occurred in 79 of 127 women (62%) assigned to prophylactic manual rotation and 90 of 127 women (71%) assigned to sham rotation (common risk difference, 12; 95% confidence interval, −1.7 to 26; P=.09). Among more experienced operators or investigators, operative delivery occurred in 46 of 74 women (62%) assigned to manual rotation and 52 of 71 women (73%) assigned to a sham rotation (common risk difference, 18; 95% confidence interval, −0.5 to 36; P=.07). Cesarean delivery occurred in 22 of 127 women (17%) in both groups. Instrumental delivery (forceps or vacuum) occurred in 57 of 127 women (45%) assigned to prophylactic manual rotation and 68 of 127 women (54%) assigned to sham rotation (common risk difference, 10; 95% confidence interval, −3.1 to 22; P=.14). There was no significant difference in the combined maternal and perinatal outcomes. Conclusion Prophylactic manual rotation did not result in a reduction in the rate of operative delivery. Given manual rotation was associated with a nonsignificant reduction in operative delivery, more randomized trials are needed, as our trial might have been underpowered. In addition, further research is required to further explore the potential impact of operator or investigator experience.

Self-injurious behaviors (SIB) are elevated in autism spectrum disorder (ASD) and related genetic disorders, but the genetic and biological mechanisms that contribute to SIB in ASD are poorly understood. This study examined rates and predictors of SIB in 112 individuals with disruptive mutations to ASD-risk genes. Current SIB were reported in 30% of participants and associated with poorer cognitive and adaptive skills. History of severe abdominal pain predicted higher rates of SIB and SIB severity after controlling for age and adaptive behavior; individuals with a history of severe abdominal pain were eight times more likely to exhibit SIB than those with no history. Future research is needed to examine associations between genetic risk, pain, and SIB in this population.

Most genes associated with neurodevelopmental disorders (NDDs) were identified with an excess of de novo mutations (DNMs) but the significance in case-control mutation burden analysis is unestablished. Here, we sequence 63 genes in 16,294 NDD cases and an additional 62 genes in 6,211 NDD cases. By combining these with published data, we assess a total of 125 genes in over 16,000 NDD cases and compare the mutation burden to nonpsychiatric controls from ExAC. We identify 48 genes (25 newly reported) showing significant burden of ultra-rare (MAF 0.01%) gene-disruptive mutations (FDR 5%), six of which reach family-wise error rate (FWER) significance (p 1.25E-06). Among these 125 targeted genes, we also reevaluate DNM excess in 17,426 NDD trios with 6,499 new autism trios. We identify 90 genes enriched for DNMs (FDR 5%; e.g., GABRG2 and UIMC1); of which, 61 reach FWER significance (p 3.64E-07; e.g., CASZ1). In addition to doubling the number of patients for many NDD risk genes, we present phenotype-genotype correlations for seven risk genes (CTCF, HNRNPU, KCNQ3, ZBTB18, TCF12, SPEN, and LEO1) based on this large-scale targeted sequencing effort.

Background: Disruptive mutations to GRIN2B are considered a high-confidence genetic factor of autism spectrum disorder (ASD), yet only ~25% of patients with GRIN2B mutations are given a formal ASD diagnosis. Here, we generate a comprehensive understanding of the ASD profile in children with de novo disruptive GRIN2B variants, including social communication deficits and restricted and repetitive behaviors (RRBs).Methods: The ASD profile was measured in 34 children with disruptive GRIN2B variants, including clinically assessed ASD severity (subset of 16 children) and parental reports of ASD symptomology. GRIN2B ASD profiles were compared to 96 children with a different pathogenic ASD-associated mutation, as well as 55 children with ASD stratified based upon low (n = 14) or average (n = 41) nonverbal cognition. Following statistical group comparisons, unique GRIN2B ASD features were further characterized using qualitative analysis of clinical observations and case reports. Results: Both GRIN2B and pathogenic groups exhibited similar proportions of formal ASD diagnoses and clinically assessed ASD severity was similar across comparison groups. Parents endorsed fewer problematic social behaviors and impairing RRBs in certain categories, highlighting relative strengths in socioemotional reciprocity and fewer reported problems with rigidity or restricted interests. Contextualization of behaviors based upon clinical observations indicated a unique GRIN2B profile describing high motivation to approach others, but often inappropriate social responses. Atypical nonverbal communication and sensory seeking were evident. Limitations: This study is limited by the small sample size for the clinically assessed GRIN2B subset. Second, the ASD comparison group was older than the GRIN2B or Pathogenic groups. Lastly, we focus on ASD symptomology and do not fully characterize other psychiatric, behavioral, or medical comorbidities or link the ASD profile to the specific function of GRIN2B variants (e.g., loss or gain of function), which may be a critical next step for developing targeted interventions.Conclusions: We identify a unique ASD profile for children with disruptive GRIN2B variants involving strengths in social motivation/approach and reduced impairing RRBs. Continued work phenotyping GRIN2B should incorporate nuanced examination of these strengths in the context of the challenges faced by individuals with disruptive GRIN2B variants.

Autism is a highly heritable complex disorder in which de novo mutation (DNM) variation contributes significantly to risk. Using whole-genome sequencing data from 3,474 families, we investigate another source of large-effect risk variation, ultra-rare variants. We report and replicate a transmission disequilibrium of private, likely gene-disruptive (LGD) variants in probands but find that 95% of this burden resides outside of known DNM-enriched genes. This variant class more strongly affects multiplex family probands and supports a multi-hit model for autism. Candidate genes with private LGD variants preferentially transmitted to probands converge on the E3 ubiquitin–protein ligase complex, intracellular transport and Erb signaling protein networks. We estimate that these variants are approximately 2.5 generations old and significantly younger than other variants of similar type and frequency in siblings. Overall, private LGD variants are under strong purifying selection and appear to act on a distinct set of genes not yet associated with autism. Analysis of whole-genome sequence data from 3,474 families finds an excess of private, likely gene-disrupting variants in individuals with autism. These variants are under purifying selection and suggest candidate genes not previously associated with autism.

Autism is a highly heritable, complex disorder where de novo mutation (DNM) variation contributes significantly to disease risk. Using whole-genome sequencing data from 3,474 families, we investigate another source of large-effect risk variation, ultra-rare mutations. We report and replicate a transmission disequilibrium of private likely-gene disruptive (LGD) mutations in probands but find that 95% of this burden resides outside of known DNM-enriched genes. This variant class more strongly affects multiplex family probands and supports a multi-hit model for autism. Candidate genes with private LGD variants preferentially transmitted to probands converge on the E3 ubiquitin-protein ligase complex, intracellular transport, and Erb signaling protein networks. We estimate these mutations are ~2.5 generations old and significantly younger than other mutations of similar type and frequency in siblings. Overall, private LGD variants are under strong purifying selection and act on a distinct set of genes not yet associated with autism.One sentence summaryUltra-rare autism variants preferentially transmitted to probands are younger and identify distinct gene candidates and functional networks.

BACKGROUND The fetal occiput transverse position in the second stage of labor is associated with adverse maternal and perinatal outcomes. Prophylactic manual rotation in the second stage of labor is considered a safe and easy to perform procedure that has been used to prevent operative deliveries. OBJECTIVE This study aimed to determine the efficacy of prophylactic manual rotation in the management of the occiput transverse position for preventing operative delivery. We hypothesized that among women who are at ≥37 weeks’ gestation with a baby in the occiput transverse position early in the second stage of labor, manual rotation compared with a “sham” rotation will reduce the rate of operative delivery. STUDY DESIGN A double-blinded, parallel, superiority, multicenter, randomized controlled clinical trial in 3 tertiary hospitals was conducted in Australia. The primary outcome was operative (cesarean, forceps, or vacuum) delivery. Secondary outcomes were cesarean delivery, serious maternal morbidity and mortality, and serious perinatal morbidity and mortality. Outcomes were analyzed by intention to treat. Proportions were compared using χ2 tests adjusted for stratification variables using the Mantel-Haenszel method or Fisher exact test. Planned subgroup analyses by operator experience and technique of manual rotation (digital or whole hand rotation) were performed. The planned sample size was 416 participants (trial registration: ACTRN12613000005752). RESULTS Here, 160 women with a term pregnancy and a baby in the occiput transverse position in the second stage of labor, confirmed by ultrasound, were randomly assigned to receive either a prophylactic manual rotation (n=80) or a sham procedure (n=80), which was less than our original intended sample size. Operative delivery occurred in 41 of 80 women (51%) assigned to prophylactic manual rotation and 40 of 80 women (50%) assigned to a sham rotation (common risk difference, −4.2% [favors sham rotation]; 95% confidence interval, −21 to 13; P=.63). Among more experienced proceduralists, operative delivery occurred in 24 of 47 women (51%) assigned to manual rotation and 29 of 46 women (63%) assigned to a sham rotation (common risk difference, 11%; 95% confidence interval, −11 to 33; P=.33). Cesarean delivery occurred in 6 of 80 women (7.5%) in the manual rotation group and 7 of 80 women (8.7%) in the sham group. Instrumental (forceps or vacuum) delivery occurred in 35 of 80 women (44%) in the manual rotation group and 33 of 80 women (41%) in the sham group. There was no significant difference in the combined maternal and perinatal outcomes. The trial was terminated early because of limited resources. CONCLUSION Planned prophylactic manual rotation did not result in fewer operative deliveries. More research is needed in the use of manual rotation from the occiput transverse position for preventing operative deliveries.

Empirical investigations of trauma and post-traumatic stress disorder (PTSD) in individuals with autism spectrum disorder (ASD) are lacking despite indications of increased risk for exposure to potentially traumatic events in this population. Research on the treatment of traumatic stress psychopathology in ASD is even more limited and suggests a critical need for guidance in the area of ASD-specific treatment adaptations. The current paper provides preliminary recommendations for adapting current evidenced-based, trauma-specific interventions, specifically trauma-focused cognitive behavioral therapy (TF-CBT), for individuals with ASD based on well-established and evidence-based practices for working with this population. These adaptations highlight the need to incorporate treatment goals related to ASD core symptoms and associated characteristics during treatment targeting traumatic stress symptoms. Future directions are discussed, including the development of instruments measuring trauma reactions in ASD, empirical investigations of modified trauma interventions for children with ASD to evaluate effectiveness, and collaboration between professionals specializing in ASD and trauma/PTSD to advance research and facilitate effective care for this community.

Human-specific duplications at chromosome 16p11.2 mediate recurrent pathogenic 600 kbp BP4-BP5 copy number variations, one of the most common genetic causes of autism. These copy number polymorphic duplications are under positive selection and include 3–8 copies of BOLA2, a gene involved in the maturation of cytosolic iron-sulfur proteins. To investigate the potential advantage provided by the rapid expansion of BOLA2, we assessed hematological traits and anemia prevalence in 379,385 controls and individuals who have lost or gained copies of BOLA2: 89 chromosome 16p11.2 BP4-BP5 deletion and 56 reciprocal duplication carriers in the UK Biobank. We found that the 16p11.2 deletion is associated with anemia (18/89 carriers, 20%, P=4e-7, OR=5), particularly iron-deficiency anemia. We observed similar enrichments in two clinical 16p11.2 deletion cohorts, with 6/63 (10%) and 7/20 (35%) unrelated individuals with anemia, microcytosis, low serum iron, or low blood hemoglobin. Upon stratification by BOLA2 copy number, we found an association between low BOLA2 dosage and the above phenotypes (8/15 individuals with three copies, 53%, P=1e-4). In parallel, we analyzed hematological traits in mice carrying the 16p11.2 orthologous deletion or duplication, as well as Bola2+/- and Bola2-/- animals. The deletion and Bola2-deficient mice showed early evidence of iron deficiency, including a mild decrease in hemoglobin, lower plasma iron, microcytosis, and an increased red blood cell zinc protoporphyrin to heme ratio. Our results indicate that BOLA2 participates in iron homeostasis in vivo and its expansion has a potential adaptive role in protecting against iron deficiency.

The original version of this Article contained an error in the spelling of the author Pleuntje J. van der Sluijs, which was incorrectly given as Eline (P. J.) van der Sluijs. This has now been corrected in both the PDF and HTML versions of the Article.

Between 6 and 12 months, typically developing infants undergo a socio-cognitive ‘revolution’. The Interactive Specialization (IS) theory of brain development predicts that these behavioral changes will be underpinned by developmental increases in the power and topographic extent of socially selective cortical responses. To test this hypothesis, we used EEG to examine developmental changes in cortical selectivity for ecologically valid dynamic social versus non-social stimuli in a large cohort of 6- and 12-month-old infants. Consistent with the Interactive Specialization model, results showed that differences in EEG theta activity between social and non-social stimuli became more pronounced and widespread with age. Differences in EEG activity were most clearly elicited by a live naturalistic interaction, suggesting that measuring brain activity in ecologically valid contexts is central to mapping social brain development in infancy.

Internalizing disorders among youths represent a significant public health concern due to associated risk for future psychopathology, physical health costs, and the likelihood that affected children will experience difficulty transitioning to adult life. Despite the troubling aspects of internalizing disorders, there is a dearth of selective, Tier 2 interventions that educators can implement for students with identified internalizing problems as part of their school’s multi-tiered system of support. To fill this void, the purpose this study was to evaluate the efficacy, acceptability, and integrity of a structured mentor-based program, the Courage and Confidence Mentor Program (CCMP), which represented a modified version of the Check-In/Check-out program. Single-case experimental methods, consisting of a multiple baseline across participants design, were used to evaluate the efficacy of the CCMP with five students. The results of visual analysis and single-case effect size estimates revealed that all participants demonstrated noticeable reductions in internalizing problems as measured by self-ratings of subjective units of discomfort and teacher reports on a standardized behavior rating scale. Limitations of the methods and directions for future research involving Tier 2 interventions for students with internalizing problems are discussed.

Background As a neurodevelopmental disorder, symptoms of ASD likely emerge from a complex interaction between preexisting genetic vulnerabilities and the child's environment. One way to understand causal paths to ASD is to identify dimensional ASD-related traits that vary in the general population and that predispose individuals with other risk factors toward ASD. Moving beyond behavioral traits to explore underlying neurocognitive processes may further constrain the underlying genetics. Endophenotypes are quantitative, heritable, trait-related differences that are generally assessed with laboratory-based methods, can be identified in the general population, and may be more closely tied to particular causal chains that have a more restricted set of genetic roots. The most fruitful endophenotypes may be those observed in infancy, prior to the emergence of behavioral symptoms that they are hypothesized to cause. Social motivation is an ASD-related trait that is highly heritable. In this study, we investigate whether infant endophenotypes of social attention relate to familial risk for lower social motivation in the general population. Methods We examined whether infant social attention (measured using habituation, EEG power, and event-related potential tasks previously used in infants/toddlers with ASD) varies quantitatively with parental social motivation in 117 six-month-old and 106 twelve-month-old typically developing infants assessed cross-sectionally. To assess heritable aspects of social motivation, primary caregiver biological parents completed two self-report measures of social avoidance and discomfort that have shown high heritability in previous work. Results Parents with higher social discomfort and avoidance had infants who showed shorter looks to faces but not objects; reduced theta power during naturalistic social attention; and smaller P400 responses to faces versus objects. Conclusions Early reductions in social attention are continuously related to lower parental social motivation. Alterations in social attention may be infant endophenotypes of social motivation traits related to ASD.

Copy number variation at 16p11.2 is associated with diverse phenotypes but little is known about the early developmental trajectories and emergence of the phenotype. This longitudinal study followed 56 children with the 16p11.2 BP4-BP5 deletion or duplication between the ages of 6 months and 8 years with diagnostic characterization and dimensional assessment across cognitive, adaptive, and behavioral domains. Linear mixed modeling revealed distinct developmental trajectories with deletions showing VIQ gains but declines in motor and social abilities while duplications showed VIQ gains and steady development across other domains. Nonparametric analyses suggest distinct trajectories and early cognitive abilities for deletion carriers who are ultimately diagnosed with intellectual disability and developmental coordination disorder as well as distinct trajectories and early social communication and cognitive abilities for duplication carriers diagnosed with ASD and intellectual disability. Findings provide predictions for patient developmental trajectories, insight into mean functioning of individuals with 16p11.2 at early ages, and highlight the need for ongoing monitoring of social and motor functioning and behavioral symptomatology to improve treatment planning. © 2017 Wiley Periodicals, Inc.

Background Autism spectrum disorder (ASD) is a neurodevelopmental disorder that affects more than 1 % of the population and close to 20 % of prospectively studied infants with an older sibling with ASD. Although significant progress has been made in characterizing the emergence of behavioral symptoms of ASD, far less is known about the underlying disruptions to early learning. Recent models suggest that core aspects of the causal path to ASD may only be apparent in early infancy. Here, we investigated social attention in 6- and 12-month-old infants who did and did not meet criteria for ASD at 24 months using both cognitive and electrophysiological methods. We hypothesized that a reduction in attention engagement to faces would be associated with later ASD. Methods In a prospective longitudinal design, we used measures of both visual attention (habituation) and brain function (event-related potentials to faces and objects) at 6 and 12 months and investigated the relationship to ASD outcome at 24 months. Results High-risk infants who met criteria for ASD at 24 months showed shorter epochs of visual attention, faster but less prolonged neural activation to faces, and delayed sensitization responses (increases in looking) to faces at 6 months; these differences were less apparent at 12 months. These findings are consistent with disrupted engagement of sustained attention to social stimuli. Conclusions These findings suggest that there may be fundamental early disruptions to attention engagement that may have cascading consequences for later social functioning. Electronic supplementary material The online version of this article (doi:10.1186/s11689-016-9139-8) contains supplementary material, which is available to authorized users.

Complex diseases are caused by a combination of genetic and environmental factors, creating a difficult challenge for diagnosis and defining subtypes. This review article describes how distinct disease subtypes can be identified through integration and analysis of clinical and multi-omics data. A broad shift toward molecular subtyping of disease using genetic and omics data has yielded successful results in cancer and other complex diseases. To determine molecular subtypes, patients are first classified by applying clustering methods to different types of omics data, then these results are integrated with clinical data to characterize distinct disease subtypes. An example of this molecular-data-first approach is in research on Autism Spectrum Disorder (ASD), a spectrum of social communication disorders marked by tremendous etiological and phenotypic heterogeneity. In the case of ASD, omics data such as exome sequences and gene and protein expression data are combined with clinical data such as psychometric testing and imaging to enable subtype identification. Novel ASD subtypes have been proposed, such as CHD8, using this molecular subtyping approach. Broader use of molecular subtyping in complex disease research is impeded by data heterogeneity, diversity of standards, and ineffective analysis tools. The future of molecular subtyping for ASD and other complex diseases calls for an integrated resource to identify disease mechanisms, classify new patients, and inform effective treatment options. This in turn will empower and accelerate precision medicine and personalized healthcare.