A framework for an evidence-based gene list relevant to autism spectrum disorder.

Autism spectrum disorder (ASD) is often grouped with other brain-related phenotypes into a broader category of neurodevelopmental disorders (NDDs). In clinical practice, providers need to decide which genes to test in individuals with ASD phenotypes, which requires an understanding of the level of evidence for individual NDD genes that supports an association with ASD. Consensus is currently lacking about which NDD genes have sufficient evidence to support a relationship to ASD. Estimates of the number of genes relevant to ASD differ greatly among research groups and clinical sequencing panels, varying from a few to several hundred. This Roadmap discusses important considerations necessary to provide an evidence-based framework for the curation of NDD genes based on the level of information supporting a clinically relevant relationship between a given gene and ASD.

Episignatures Stratifying Helsmoortel-Van Der Aa Syndrome Show Modest Correlation with Phenotype.

Helsmoortel-Van der Aa syndrome (HVDAS) is a neurodevelopmental condition associated with intellectual disability/developmental delay, autism spectrum disorder, and multiple medical comorbidities. HVDAS is caused by mutations in activity-dependent neuroprotective protein (ADNP). A recent study identified genome-wide DNA methylation changes in 22 individuals with HVDAS, adding to the group of neurodevelopmental disorders with an epigenetic signature. This methylation signature segregated those with HVDAS into two groups based on the location of the mutations. Here, we conducted an independent study on 24 individuals with HVDAS and replicated the existence of the two mutation-dependent episignatures. To probe whether the two distinct episignatures correlate with clinical outcomes, we used deep behavioral and neurobiological data from two prospective cohorts of individuals with a genetic diagnosis of HVDAS. We found limited phenotypic differences between the two HVDAS-affected groups and no evidence that individuals with more widespread methylation changes are more severely affected. Moreover, in spite of the methylation changes, we observed no profound alterations in the blood transcriptome of individuals with HVDAS. Our data warrant caution in harnessing methylation signatures in HVDAS as a tool for clinical stratification, at least with regard to behavioral phenotypes.

Impact of autism genetic risk on brain connectivity: a mechanism for the female protective effect.

The biological mechanisms underlying the greater prevalence of autism spectrum disorder in males than females remain poorly understood. One hypothesis posits that this female protective effect arises from genetic load for autism spectrum disorder differentially impacting male and female brains. To test this hypothesis, we investigated the impact of cumulative genetic risk for autism spectrum disorder on functional brain connectivity in a balanced sample of boys and girls with autism spectrum disorder and typically developing boys and girls (127 youth, ages 8-17). Brain connectivity analyses focused on the salience network, a core intrinsic functional connectivity network which has previously been implicated in autism spectrum disorder. The effects of polygenic risk on salience network functional connectivity were significantly modulated by participant sex, with genetic load for autism spectrum disorder influencing functional connectivity in boys with and without autism spectrum disorder but not girls. These findings support the hypothesis that autism spectrum disorder risk genes interact with sex differential processes, thereby contributing to the male bias in autism prevalence and proposing an underlying neurobiological mechanism for the female protective effect.

Pubertal maturation and timing effects on resting state electroencephalography in autistic and comparison youth.

Autistic and comparison individuals differ in resting-state electroencephalography (EEG), such that sex and age explain variability within and between groups. Pubertal maturation and timing may further explain variation, as previous work has suggested alterations in pubertal timing in autistic youth. In a sample from two studies of 181 autistic and 94 comparison youth (8 years to 17 years and 11 months), mixed-effects linear regressions were conducted to assess differences in EEG (midline power for theta, alpha, and beta frequency bands). Alpha power was analyzed as a mediator in the relation between pubertal maturation and timing with autistic traits in the autistic groups to understand the role of puberty in brain-based changes that contribute to functional outcomes. Individuals advanced in puberty exhibited decreased power in all bands. Those who experienced puberty relatively early showed decreased power in theta and beta bands, controlling for age, sex, and diagnosis. Autistic individuals further along in pubertal development exhibited lower social skills. Alpha mediated the relation between puberty and repetitive behaviors. Pubertal maturation and timing appear to play unique roles in the development of cognitive processes for autistic and comparison youth and should be considered in research on developmental variation in resting-state EEG.

Sex-Based Analysis of De Novo Variants in Neurodevelopmental Disorders.

While genes with an excess of de novo mutations (DNMs) have been identified in children with neurodevelopmental disorders (NDDs), few studies focus on DNM patterns where the sex of affected children is examined separately. We considered ∼8,825 sequenced parent-child trios (n ∼26,475 individuals) and identify 54 genes with a DNM enrichment in males (n = 18), females (n = 17), or overlapping in both the male and female subsets (n = 19). A replication cohort of 18,778 sequenced parent-child trios (n = 56,334 individuals) confirms 25 genes (n = 3 in males, n = 7 in females, n = 15 in both male and female subsets). As expected, we observe significant enrichment on the X chromosome for females but also find autosomal genes with potential sex bias (females, CDK13, ITPR1; males, CHD8, MBD5, SYNGAP1); 6.5% of females harbor a DNM in a female-enriched gene, whereas 2.7% of males have a DNM in a male-enriched gene. Sex-biased genes are enriched in transcriptional processes and chromatin binding, primarily reside in the nucleus of cells, and have brain expression. By downsampling, we find that DNM gene discovery is greatest when studying affected females. Finally, directly comparing de novo allele counts in NDD-affected males and females identifies one replicated genome-wide significant gene (DDX3X) with locus-specific enrichment in females. Our sex-based DNM enrichment analysis identifies candidate NDD genes differentially affecting males and females and indicates that the study of females with NDDs leads to greater gene discovery consistent with the female-protective effect.

The Human-Specific BOLA2 Duplication Modifies Iron Homeostasis and Anemia Predisposition in Chromosome 16p11.2 Autism Individuals.

Human-specific duplications at chromosome 16p11.2 mediate recurrent pathogenic 600 kbp BP4-BP5 copy-number variations, which are among the most common genetic causes of autism. These copy-number polymorphic duplications are under positive selection and include three to eight 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 carriers 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, which included 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, our data showed 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 Bola2-deficient mice and the mice carrying the deletion 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.

Coding and noncoding variants in EBF3 are involved in HADDS and simplex autism.

BACKGROUND: Previous research in autism and other neurodevelopmental disorders (NDDs) has indicated an important contribution of protein-coding (coding) de novo variants (DNVs) within specific genes. The role of de novo noncoding variation has been observable as a general increase in genetic burden but has yet to be resolved to individual functional elements. In this study, we assessed whole-genome sequencing data in 2671 families with autism (discovery cohort of 516 families, replication cohort of 2155 families). We focused on DNVs in enhancers with characterized in vivo activity in the brain and identified an excess of DNVs in an enhancer named hs737. RESULTS: We adapted the fitDNM statistical model to work in noncoding regions and tested enhancers for excess of DNVs in families with autism. We found only one enhancer (hs737) with nominal significance in the discovery (p = 0.0172), replication (p = 2.5 × 10-3), and combined dataset (p = 1.1 × 10-4). Each individual with a DNV in hs737 had shared phenotypes including being male, intact cognitive function, and hypotonia or motor delay. Our in vitro assessment of the DNVs showed they all reduce enhancer activity in a neuronal cell line. By epigenomic analyses, we found that hs737 is brain-specific and targets the transcription factor gene EBF3 in human fetal brain. EBF3 is genome-wide significant for coding DNVs in NDDs (missense p = 8.12 × 10-35, loss-of-function p = 2.26 × 10-13) and is widely expressed in the body. Through characterization of promoters bound by EBF3 in neuronal cells, we saw enrichment for binding to NDD genes (p = 7.43 × 10-6, OR = 1.87) involved in gene regulation. Individuals with coding DNVs have greater phenotypic severity (hypotonia, ataxia, and delayed development syndrome [HADDS]) in comparison to individuals with noncoding DNVs that have autism and hypotonia. CONCLUSIONS: In this study, we identify DNVs in the hs737 enhancer in individuals with autism. Through multiple approaches, we find hs737 targets the gene EBF3 that is genome-wide significant in NDDs. By assessment of noncoding variation and the genes they affect, we are beginning to understand their impact on gene regulatory networks in NDDs.

A neurogenetic analysis of female autism.

Females versus males are less frequently diagnosed with autism spectrum disorder (ASD), and while understanding sex differences is critical to delineating the systems biology of the condition, female ASD is understudied. We integrated functional MRI and genetic data in a sex-balanced sample of ASD and typically developing youth (8-17 years old) to characterize female-specific pathways of ASD risk. Our primary objectives were to: (i) characterize female ASD (n = 45) brain response to human motion, relative to matched typically developing female youth (n = 45); and (ii) evaluate whether genetic data could provide further insight into the potential relevance of these brain functional differences. For our first objective we found that ASD females showed markedly reduced response versus typically developing females, particularly in sensorimotor, striatal, and frontal regions. This difference between ASD and typically developing females does not resemble differences between ASD (n = 47) and typically developing males (n = 47), even though neural response did not significantly differ between female and male ASD. For our second objective, we found that ASD females (n = 61), versus males (n = 66), showed larger median size of rare copy number variants containing gene(s) expressed in early life (10 postconceptual weeks to 2 years) in regions implicated by the typically developing female > female functional MRI contrast. Post hoc analyses suggested this difference was primarily driven by copy number variants containing gene(s) expressed in striatum. This striatal finding was reproducible among n = 2075 probands (291 female) from an independent cohort. Together, our findings suggest that striatal impacts may contribute to pathways of risk in female ASD and advocate caution in drawing conclusions regarding female ASD based on male-predominant cohorts.

Response Dissociation in Hierarchical Cortical Circuits: a Unique Feature of Autism Spectrum Disorder.

A prominent hypothesis regarding the pathophysiology of autism is that an increase in the balance between neural excitation and inhibition results in an increase in neural responses. However, previous reports of population-level response magnitude in individuals with autism have been inconsistent. Critically, network interactions have not been considered in previous neuroimaging studies of excitation and inhibition imbalance in autism. In particular, a defining characteristic of cortical organization is its hierarchical and interactive structure; sensory and cognitive systems are comprised of networks where later stages inherit and build upon the processing of earlier input stages, and also influence and shape earlier stages by top-down modulation. Here we used the well established connections of the human visual system to examine response magnitudes in a higher-order motion processing region [middle temporal area (MT+)] and its primary input region (V1). Simple visual stimuli were presented to adult individuals with autism spectrum disorders (ASD; n = 24, mean age 23 years, 8 females) and neurotypical controls (n = 24, mean age 22, 8 females) during fMRI scanning. We discovered a strong dissociation of fMRI response magnitude between region MT+ and V1 in individuals with ASD: individuals with high MT+ responses had attenuated V1 responses. The magnitude of MT+ amplification and of V1 attenuation was associated with autism severity, appeared to result from amplified suppressive feedback from MT+ to V1, and was not present in neurotypical controls. Our results reveal the potential role of altered hierarchical network interactions in the pathophysiology of ASD.SIGNIFICANCE STATEMENT An imbalance between neural excitation and inhibition, resulting in increased neural responses, has been suggested as a pathophysiological pathway to autism, but direct evidence from humans is lacking. In the current study we consider the role of interactions between stages of sensory processing when testing increased neural responses in individuals with autism. We used the well known hierarchical structure of the visual motion pathway to demonstrate dissociation in the fMRI response magnitude between adjacent stages of processing in autism: responses are attenuated in a primary visual area but amplified in a subsequent higher-order area. This response dissociation appears to rely on enhanced suppressive feedback between regions and reveals a previously unknown cortical network alteration in autism.

Truncating Variants in NAA15 Are Associated with Variable Levels of Intellectual Disability, Autism Spectrum Disorder, and Congenital Anomalies.

N-alpha-acetylation is a common co-translational protein modification that is essential for normal cell function in humans. We previously identified the genetic basis of an X-linked infantile lethal Mendelian disorder involving a c.109T>C (p.Ser37Pro) missense variant in NAA10, which encodes the catalytic subunit of the N-terminal acetyltransferase A (NatA) complex. The auxiliary subunit of the NatA complex, NAA15, is the dimeric binding partner for NAA10. Through a genotype-first approach with whole-exome or genome sequencing (WES/WGS) and targeted sequencing analysis, we identified and phenotypically characterized 38 individuals from 33 unrelated families with 25 different de novo or inherited, dominantly acting likely gene disrupting (LGD) variants in NAA15. Clinical features of affected individuals with LGD variants in NAA15 include variable levels of intellectual disability, delayed speech and motor milestones, and autism spectrum disorder. Additionally, mild craniofacial dysmorphology, congenital cardiac anomalies, and seizures are present in some subjects. RNA analysis in cell lines from two individuals showed degradation of the transcripts with LGD variants, probably as a result of nonsense-mediated decay. Functional assays in yeast confirmed a deleterious effect for two of the LGD variants in NAA15. Further supporting a mechanism of haploinsufficiency, individuals with copy-number variant (CNV) deletions involving NAA15 and surrounding genes can present with mild intellectual disability, mild dysmorphic features, motor delays, and decreased growth. We propose that defects in NatA-mediated N-terminal acetylation (NTA) lead to variable levels of neurodevelopmental disorders in humans, supporting the importance of the NatA complex in normal human development.

Sex Differences in Functional Connectivity of the Salience, Default Mode, and Central Executive Networks in Youth with ASD.

Autism spectrum disorder (ASD) is associated with the altered functional connectivity of 3 neurocognitive networks that are hypothesized to be central to the symptomatology of ASD: the salience network (SN), default mode network (DMN), and central executive network (CEN). Due to the considerably higher prevalence of ASD in males, however, previous studies examining these networks in ASD have used primarily male samples. It is thus unknown how these networks may be differentially impacted among females with ASD compared to males with ASD, and how such differences may compare to those observed in neurotypical individuals. Here, we investigated the functional connectivity of the SN, DMN, and CEN in a large, well-matched sample of girls and boys with and without ASD (169 youth, ages 8-17). Girls with ASD displayed greater functional connectivity between the DMN and CEN than boys with ASD, whereas typically developing girls and boys differed in SN functional connectivity only. Together, these results demonstrate that youth with ASD exhibit altered sex differences in these networks relative to what is observed in typical development, and highlight the importance of considering sex-related biological factors and participant sex when characterizing the neural mechanisms underlying ASD.

Glutamatergic facilitation of neural responses in MT enhances motion perception in humans.

There is large individual variability in human neural responses and perceptual abilities. The factors that give rise to these individual differences, however, remain largely unknown. To examine these factors, we measured fMRI responses to moving gratings in the motion-selective region MT, and perceptual duration thresholds for motion direction discrimination. Further, we acquired MR spectroscopy data, which allowed us to quantify an index of neurotransmitter levels in the region of area MT. These three measurements were conducted in separate experimental sessions within the same group of male and female subjects. We show that stronger Glx (glutamate + glutamine) signals in the MT region are associated with both higher fMRI responses and superior psychophysical task performance. Our results suggest that greater baseline levels of glutamate within MT facilitate motion perception by increasing neural responses in this region.

Disruption of POGZ Is Associated with Intellectual Disability and Autism Spectrum Disorders.

Intellectual disability (ID) and autism spectrum disorders (ASD) are genetically heterogeneous, and a significant number of genes have been associated with both conditions. A few mutations in POGZ have been reported in recent exome studies; however, these studies do not provide detailed clinical information. We collected the clinical and molecular data of 25 individuals with disruptive mutations in POGZ by diagnostic whole-exome, whole-genome, or targeted sequencing of 5,223 individuals with neurodevelopmental disorders (ID primarily) or by targeted resequencing of this locus in 12,041 individuals with ASD and/or ID. The rarity of disruptive mutations among unaffected individuals (2/49,401) highlights the significance (p = 4.19 × 10(-13); odds ratio = 35.8) and penetrance (65.9%) of this genetic subtype with respect to ASD and ID. By studying the entire cohort, we defined common phenotypic features of POGZ individuals, including variable levels of developmental delay (DD) and more severe speech and language delay in comparison to the severity of motor delay and coordination issues. We also identified significant associations with vision problems, microcephaly, hyperactivity, a tendency to obesity, and feeding difficulties. Some features might be explained by the high expression of POGZ, particularly in the cerebellum and pituitary, early in fetal brain development. We conducted parallel studies in Drosophila by inducing conditional knockdown of the POGZ ortholog row, further confirming that dosage of POGZ, specifically in neurons, is essential for normal learning in a habituation paradigm. Combined, the data underscore the pathogenicity of loss-of-function mutations in POGZ and define a POGZ-related phenotype enriched in specific features.

Genome sequencing identifies multiple deleterious variants in autism patients with more severe phenotypes.

PURPOSE: To maximize the discovery of potentially pathogenic variants to better understand the diagnostic utility of genome sequencing (GS) and to assess how the presence of multiple risk events might affect the phenotypic severity in autism spectrum disorders (ASD). METHODS: GS was applied to 180 simplex and multiplex ASD families (578 individuals, 213 patients) with exome sequencing and array comparative genomic hybridization further applied to a subset for validation and cross-platform comparisons. RESULTS: We found that 40.8% of patients carried variants with evidence of disease risk, including a de novo frameshift variant in NR4A2 and two de novo missense variants in SYNCRIP, while 21.1% carried clinically relevant pathogenic or likely pathogenic variants. Patients with more than one risk variant (9.9%) were more severely affected with respect to cognitive ability compared with patients with a single or no-risk variant. We observed no instance among the 27 multiplex families where a pathogenic or likely pathogenic variant was transmitted to all affected members in the family. CONCLUSION: The study demonstrates the diagnostic utility of GS, especially for multiple risk variants that contribute to the phenotypic severity, shows the genetic heterogeneity in multiplex families, and provides evidence for new genes for follow up.

Linking social motivation with social skill: The role of emotion dysregulation in autism spectrum disorder.

Autism spectrum disorder (ASD) is associated with pervasive social deficits as well as marked emotion dysregulation across the life span. Decreased social motivation accounts in part for social difficulties, but factors moderating its influence are not fully understood. In this paper, we (a) characterize social and emotional functioning among children and adolescents with ASD, (b) explore contributions of social motivation and emotion dysregulation to social skill, and (c) consider biological sex and intellectual functioning as moderators of these associations. In a sample of 2,079 children and adolescents with ASD from the Simons Simplex Collection, we document direct effects of social motivation, internalizing symptoms, aggression, attention problems, irritability, and self-injurious behavior on children's social skills. Furthermore, dysregulation in several domains moderated the association between social motivation and social skill, suggesting a blunting effect on social motivation in the context of emotional difficulties. Moreover, when considering only individuals with intellectual skills in the average range or higher, biological sex further moderated these associations. Findings add to our understanding of social-emotional processes in ASD, suggest emotion dysregulation as a target of intervention in the service of social skill improvements, and build on efforts to understand sources of individual difference that contribute to heterogeneity among individuals with ASD.

denovo-db: a compendium of human de novo variants.

Whole-exome and whole-genome sequencing have facilitated the large-scale discovery of de novo variants in human disease. To date, most de novo discovery through next-generation sequencing focused on congenital heart disease and neurodevelopmental disorders (NDDs). Currently, de novo variants are one of the most significant risk factors for NDDs with a substantial overlap of genes involved in more than one NDD. To facilitate better usage of published data, provide standardization of annotation, and improve accessibility, we created denovo-db (http://denovo-db.gs.washington.edu), a database for human de novo variants. As of July 2016, denovo-db contained 40 different studies and 32,991 de novo variants from 23,098 trios. Database features include basic variant information (chromosome location, change, type); detailed annotation at the transcript and protein levels; severity scores; frequency; validation status; and, most importantly, the phenotype of the individual with the variant. We included a feature on our browsable website to download any query result, including a downloadable file of the full database with additional variant details. denovo-db provides necessary information for researchers to compare their data to other individuals with the same phenotype and also to controls allowing for a better understanding of the biology of de novo variants and their contribution to disease.

Comorbid symptoms of inattention, autism, and executive cognition in youth with putative genetic risk.

BACKGROUND: Symptoms of autism spectrum disorder (ASD) and inattention (IA) are highly comorbid and associated with deficits in executive cognition. Cognitive deficits have been posited as candidate endophenotypes of psychiatric traits, but few studies have conceptualized cognitive deficits as psychiatric comorbidities. The latter model is consistent with a latent factor reflecting broader liability to neuropsychological dysfunction, and explains heterogeneity in the cognitive profile of individuals with ASD and IA. METHODS: We tested competing models of covariance among symptoms of ASD, IA, and cognition in a sample of 73 youth with a known genetic mutation. RESULTS: A common executive factor fit best as a cognitive comorbidity, rather than endophenotype, of the shared variance between measures of IA and ASD symptoms. Known genetic risk explained a third of the shared variance among psychiatric and cognitive measures. CONCLUSIONS: Comorbid symptoms of ASD, IA, and cognitive deficits are likely influenced by common neurogenetic factors. Known genetic risk in ASD may inform future investigation of putative genetic causes of IA.

Early enhanced processing and delayed habituation to deviance sounds in autism spectrum disorder.

Children with autism spectrum disorder (ASD) exhibit difficulties processing and encoding sensory information in daily life. Cognitive response to environmental change in control individuals is naturally dynamic, meaning it habituates or reduces over time as one becomes accustomed to the deviance. The origin of atypical response to deviance in ASD may relate to differences in this dynamic habituation. The current study of 133 children and young adults with and without ASD examined classic electrophysiological responses (MMN and P3a), as well as temporal patterns of habituation (i.e., N1 and P3a change over time) in response to a passive auditory oddball task. Individuals with ASD showed an overall heightened sensitivity to change as exhibited by greater P3a amplitude to novel sounds. Moreover, youth with ASD showed dynamic ERP differences, including slower attenuation of the N1 response to infrequent tones and the P3a response to novel sounds. Dynamic ERP responses were related to parent ratings of auditory sensory-seeking behaviors, but not general cognition. As the first large-scale study to characterize temporal dynamics of auditory ERPs in ASD, our results provide compelling evidence that heightened response to auditory deviance in ASD is largely driven by early sensitivity and prolonged processing of auditory deviance.

Infants' grip strength predicts mu rhythm attenuation during observation of lifting actions with weighted blocks.

Research has established that the body is fundamentally involved in perception: bodily experience influences activation of the shared neural system underlying action perception and production during action observation, and bodily characteristics influence perception of the spatial environment. However, whether bodily characteristics influence action perception and its underlying neural system is unknown, particularly in early ontogeny. We measured grip strength in 12-month-old infants and investigated relations with mu rhythm attenuation, an electroencephalographic correlate of the neural system underlying action perception, during observation of lifting actions performed with differently weighted blocks. We found that infants with higher grip strength exhibited significant mu attenuation during observation of lifting actions, whereas infants with lower grip strength did not. Moreover, a progressively strong relation between grip strength and mu attenuation during observation of lifts was found with increased block weight. We propose that this relation is attributable to differences in infants' ability to recognize the effort associated with lifting objects of different weights, as a consequence of their developing strength. Together, our results extend the body's role in perception by demonstrating that bodily characteristics influence action perception by shaping the activation of its underlying neural system.

Social motivation by self- and caregiver-report: Reporter concordance and social correlates among autistic and neurotypical youth.

Differences in social motivation underlie the core social-communication features of autism according to several theoretical models, with decreased social motivation among autistic youth relative to neurotypical peers. However, research on social motivation often relies on caregiver reports and rarely includes firsthand perspectives of children and adolescents with autism. Furthermore, social motivation is typically assumed to be constant across social settings when it may actually vary by social context. Among a sample of 58 verbally fluent youth (8-13 years old; 22 with autism, 36 neurotypical), we examined correspondence between youth and caregiver reports of social motivation with peers and with adults, as well as diagnostic group differences and associations with social outcomes. Results suggest youth and caregivers provide overlapping but distinct information. Autistic youth had lower levels of social motivation relative to neurotypical youth, and reported relatively consistent motivation toward peers and adults. Youth self- and caregiver-report were correlated for motivation toward adults, but not toward peers. Despite low correspondence between self- and caregiver-reported motivation toward peers, autistic youths' self-report corresponded to caregiver-reported social skills and difficulties whereas caregiver-report of peer motivation did not. For neurotypical youth, self- and caregiver-reported motivation toward adults was correlated, but motivation by both reporters was largely independent of broader social outcomes. Findings highlight the unique value of self-report among autistic children and adolescents, and warrant additional work exploring the development, structure, and correlates of social motivation among autistic and neurotypical youth.