Disruptive CHD8 mutations define a subtype of autism early in development.

Autism spectrum disorder (ASD) is a heterogeneous disease in which efforts to define subtypes behaviorally have met with limited success. Hypothesizing that genetically based subtype identification may prove more productive, we resequenced the ASD-associated gene CHD8 in 3,730 children with developmental delay or ASD. We identified a total of 15 independent mutations; no truncating events were identified in 8,792 controls, including 2,289 unaffected siblings. In addition to a high likelihood of an ASD diagnosis among patients bearing CHD8 mutations, characteristics enriched in this group included macrocephaly, distinct faces, and gastrointestinal complaints. chd8 disruption in zebrafish recapitulates features of the human phenotype, including increased head size as a result of expansion of the forebrain/midbrain and impairment of gastrointestinal motility due to a reduction in postmitotic enteric neurons. Our findings indicate that CHD8 disruptions define a distinct ASD subtype and reveal unexpected comorbidities between brain development and enteric innervation.

Chronic oxytocin improves neural decoupling at rest in children with autism: an exploratory RCT.

BACKGROUND: Shifts in peak frequencies of oscillatory neural rhythms are put forward as a principal mechanism by which cross-frequency coupling/decoupling is implemented in the brain. During active neural processing, functional integration is facilitated through transitory formations of "harmonic" cross-frequency couplings, whereas "nonharmonic" decoupling among neural oscillatory rhythms is postulated to characterize the resting, default state of the brain, minimizing the occurrence of spurious, noisy, background couplings. METHODS: Within this exploratory, randomized, placebo-controlled trial, we assessed whether the transient occurrence of nonharmonic and harmonic relationships between peak-frequencies in the alpha (8-14 Hz) and theta (4-8 Hz) bands is impacted by intranasal administration of oxytocin, a neuromodulator implicated in improving homeostasis and reducing stress/anxiety. To do so, resting-state electroencephalography was acquired before and after 4 weeks of oxytocin administration (12 IU twice-daily) in children with autism spectrum disorder (8-12 years, n = 33 oxytocin; n = 34 placebo). At the baseline, neural assessments of children with autism were compared with those of a matched cohort of children without autism (n = 40). RESULTS: Compared to nonautistic peers, autistic children displayed a lower incidence of nonharmonic alpha-theta cross-frequency decoupling, indicating a higher incidence of spurious "noisy" coupling in their resting brain (p = .001). Dimensionally, increased neural coupling was associated with more social difficulties (p = .002) and lower activity of the parasympathetic "rest & digest" branch of the autonomic nervous system (p = .018), indexed with high-frequency heart-rate-variability. Notably, after oxytocin administration, the transient formation of nonharmonic cross-frequency configurations was increased in the cohort of autistic children (p < .001), indicating a beneficial effect of oxytocin on reducing spurious cross-frequency-interactions. Furthermore, parallel epigenetics changes of the oxytocin receptor gene indicated that the neural effects were likely mediated by changes in endogenous oxytocinergic signaling (p = .006). CONCLUSIONS: Chronic oxytocin induced important homeostatic changes in the resting-state intrinsic neural frequency architecture, reflective of reduced noisy oscillatory couplings and improved signal-to-noise properties.

The Physiological and Clinical-Behavioral Effects of Heart Rate Variability Biofeedback in Adolescents with Autism: A Pilot Randomized Controlled Trial.

Adolescents with autism present lower levels of cardiac vagal modulation. It was hypothesized that Heart Rate Variability Biofeedback (HRVB) increases cardiac vagal modulation in adolescents with autism, resulting in positive effects on physiological and psychosocial parameters. It was also hypothesized that home-based HRVB training is feasible. In a single-blind, randomized sham-controlled pilot trial, adolescents with autism performed supervised HRVB (n = 24) or sham training (n = 20). Subsequently, half of the adolescents received HRVB training at home, whereas the other subset did not practice. Physiological, cortisol and behavioral data were collected during stress-provoking assessments before and after each training period. Supervised HRVB resulted in a late increase in cardiac vagal modulation in adolescents with autism. Heart rate increased and cortisol decreased significantly immediately after supervised HRVB, but none of these effects remained after follow-up. Following supervised HRVB, no significant change in psychosocial functioning was found. Home-based HRVB was feasible, adolescents reported lower symptoms of stress, but a significant decrease in compliance rate was found. HRVB is feasible and effective in adolescents with autism given the late-emerging increases in cardiac vagal modulation and decrease in stress symptoms. Replicating this study with a larger sample and further exploration of the working mechanisms of HRVB are recommended. ClinicalTrials.gov , NCT04628715.

Investigating the development of the autonomic nervous system in infancy through pupillometry.

We aim to investigate early developmental trajectories of the autonomic nervous system (ANS) as indexed by the pupillary light reflex (PLR) in infants with (i.e. preterm birth, feeding difficulties, or siblings of children with autism spectrum disorder) and without (controls) increased likelihood for atypical ANS development. We used eye-tracking to capture the PLR in 216 infants in a longitudinal follow-up study spanning 5 to 24 months of age, and linear mixed models to investigate effects of age and group on three PLR parameters: baseline pupil diameter, latency to constriction and relative constriction amplitude. An increase with age was found in baseline pupil diameter (F(3,273.21) = 13.15, p < 0.001, [Formula: see text] = 0.13), latency to constriction (F(3,326.41) = 3.84, p = 0.010, [Formula: see text] = 0.03) and relative constriction amplitude(F(3,282.53) = 3.70, p = 0.012, [Formula: see text] = 0.04). Group differences were found for baseline pupil diameter (F(3,235.91) = 9.40, p < 0.001, [Formula: see text] = 0.11), with larger diameter in preterms and siblings than in controls, and for latency to constriction (F(3,237.10) = 3.48, p = 0.017, [Formula: see text] = 0.04), with preterms having a longer latency than controls. The results align with previous evidence, with development over time that could be explained by ANS maturation. To better understand the cause of the group differences, further research in a larger sample is necessary, combining pupillometry with other measures to further validate its value.

Can repeated intranasal oxytocin administration affect reduced neural sensitivity towards expressive faces in autism? A randomized controlled trial.

BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by difficulties in social communication and interaction. Crucial for efficient social interaction is the ability to quickly and accurately extract information from a person's face. Frequency-tagging electroencephalography (EEG) is a novel tool to quantify face-processing sensitivity in a robust and implicit manner. In terms of intervention approaches, intranasal administration of oxytocin (OT) is increasingly considered as a potential pharmacological approach for improving socio-communicative difficulties in ASD, through enhancing social salience and/or reducing (social) stress and anxiety. METHODS: In this randomized, double-blind, placebo-controlled, mechanistic pharmaco-neuroimaging clinical trial, we implemented frequency-tagging EEG to conduct an exploratory investigation into the impact of repeated OT administration (4 weeks, 12 IU, twice daily) on neural sensitivity towards happy and fearful facial expressions in children with ASD (8-12 years old; OT: n = 29; placebo: n = 32). Neural effects were assessed at baseline, post-nasal spray (24 hr after the last nasal spray) and at a follow-up session, 4 weeks after the OT administration period. At baseline, neural assessments of children with ASD were compared with those of an age- and gender-matched cohort of neurotypical (NT) children (n = 39). RESULTS: Children with ASD demonstrated reduced neural sensitivity towards expressive faces, as compared to NT children. Upon nasal spray administration, children with ASD displayed a significant increase in neural sensitivity at the post- and follow-up sessions, but only in the placebo group, likely reflecting an implicit learning effect. Strikingly, in the OT group, neural sensitivity remained unaffected from the baseline to the post-session, likely reflecting a dampening of an otherwise typically occurring implicit learning effect. CONCLUSIONS: First, we validated the robustness of the frequency-tagging EEG approach to assess reduced neural sensitivity towards expressive faces in children with ASD. Furthermore, in contrast to social salience effects observed after single-dose administrations, repeated OT administration dampened typically occurring learning effects in neural sensitivity. In line with OT's social anxiolytic account, these observations possibly reflect a predominant (social) stress regulatory effect towards emotionally evocative faces after repeated OT administration.

At the Head and Heart of Oxytocin's Stress-Regulatory Neural and Cardiac Effects: A Chronic Administration RCT in Children with Autism.

INTRODUCTION: Intranasal administration of oxytocin presents a promising new approach to reduce disability associated with an autism spectrum disorder diagnosis. Previous investigations have emphasized the amygdala as the neural foundation for oxytocin's acute effects. However, to fully understand oxytocin's therapeutic potential, it is crucial to gain insight into the neuroplastic changes in amygdala circuitry induced from chronic oxytocin administrations, particularly in pediatric populations. OBJECTIVE: We aimed to examine the impact of a 4-week course of intranasal oxytocin on amygdala functional connectivity in children with autism, compared to placebo. Additionally, we investigated whether oxytocin improves cardiac autonomic arousal, as indexed by high-frequency heart rate variability. METHODS: Fifty-seven children with autism aged 8-12 years (45 boys, 12 girls) participated in a double-blind, randomized pharmaco-neuroimaging trial involving twice-daily administrations of intranasal oxytocin or placebo. Resting-state fMRI scans and simultaneous, in-scanner heart rate recordings were obtained before, immediately after, and 4 weeks after the nasal spray administration period. RESULTS: Significant reductions in intrinsic amygdala-orbitofrontal connectivity were observed, particularly at the 4-week follow-up session. These reductions were correlated with improved social symptoms and lower cardiac autonomic arousal. Further, oxytocin's neural and cardiac autonomic effects were modulated by epigenetic modifications of the oxytocin receptor gene. The effects were more pronounced in children with reduced epigenetic methylation, signifying heightened expression of the oxytocin receptor. CONCLUSION: These findings underscore that a 4-week oxytocin administration course decreases amygdala connectivity and improves cardiac autonomic balance. Epigenetic modulators may explain inter-individual variation in responses to oxytocin.

Exploring the perception of stress in childhood and early adolescence.

Stressful life experiences may jeopardize the healthy development of children. To improve interventions, more knowledge is needed on the perception of stress by children. In adults, stress is regarded as a state of low valence and high arousal. It is unclear whether children perceive stress similarly. In the current study, 35 children of the general population completed three tasks aiming to provide insight into their knowledge of the concept stress. In the first task, participants were asked about their verbal knowledge of the concept stress. In the second task, they rated the valence and arousal of eight emotion-evoking vignettes. In the final task, participants completed an experience sampling survey for at least 1 day, consisting of a stress thermometer and pictorial scales of valence and arousal. Participants' perception of stress was found to be mainly valence focused. Age and sex were found to play a role in the degree of arousal focus. Older participants differentiated more in arousal levels than younger participants, as did girls in comparison with boys. Because the perception of stress depends on developmental and other individual factors, using stress as a single measurement dimension in a survey is not recommended.

De novo missense variants in the E3 ubiquitin ligase adaptor KLHL20 cause a developmental disorder with intellectual disability, epilepsy, and autism spectrum disorder.

PURPOSE: KLHL20 is part of a CUL3-RING E3 ubiquitin ligase involved in protein ubiquitination. KLHL20 functions as the substrate adaptor that recognizes substrates and mediates the transfer of ubiquitin to the substrates. Although KLHL20 regulates neurite outgrowth and synaptic development in animal models, a role in human neurodevelopment has not yet been described. We report on a neurodevelopmental disorder caused by de novo missense variants in KLHL20. METHODS: Patients were ascertained by the investigators through Matchmaker Exchange. Phenotyping of patients with de novo missense variants in KLHL20 was performed. RESULTS: We studied 14 patients with de novo missense variants in KLHL20, delineating a genetic syndrome with patients having mild to severe intellectual disability, febrile seizures or epilepsy, autism spectrum disorder, hyperactivity, and subtle dysmorphic facial features. We observed a recurrent de novo missense variant in 11 patients (NM_014458.4:c.1069G>A p.[Gly357Arg]). The recurrent missense and the 3 other missense variants all clustered in the Kelch-type ß-propeller domain of the KLHL20 protein, which shapes the substrate binding surface. CONCLUSION: Our findings implicate KLHL20 in a neurodevelopmental disorder characterized by intellectual disability, febrile seizures or epilepsy, autism spectrum disorder, and hyperactivity.

8p21.3 deletions are rare causes of non-syndromic autism spectrum disorder.

A de novo 0.95 Mb 8p21.3 deletion had been identified in an individual with non-syndromic autism spectrum disorder (ASD) through high-resolution copy number variant analysis. Subsequent screening of in-house and publicly available databases resulted in the identification of six additional individuals with 8p21.3 deletions. Through case-based reasoning, we conclude that 8p21.3 deletions are rare causes of non-syndromic neurodevelopmental and neuropsychiatric disorders. Based on literature data, we highlight six genes within the region of minimal overlap as potential ASD genes or genes for neuropsychiatric disorders: DMTN, EGR3, FGF17, LGI3, PHYHIP, and PPP3CC.

Ethics of returning children's individual research findings: from principles to practice.

Little ethical recommendations on returning children's individual research findings are available for researchers in behavioral sciences, especially when compared to genetic research. Anecdotic evidence suggests that since parents are often interested in their child's individual research findings, researchers tend to offer this information as a form of compensation for research participation. Despite good intentions, these practices are not without potential harmful consequences for children. We were confronted with these difficulties and with the paucity of available guidance on this topic, being involved in a longitudinal, infant development study, i.e. tracking infants at risk for autism (TIARA). First, we review current ethical recommendations and discuss their limitations in the light of the TIARA study. Second, we will suggest to revise these recommendations, by identifying and applying the relevant bioethical principles and concepts at hand. Third, as an example of practical implementation, the adopted 'return of research findings'-policy for the TIARA-study is presented. The principles and concepts we engage with are the ancillary care responsibilities of the researcher, non-maleficence and beneficence, the right to an open future of the child, and the avoidance of therapeutic misconception. Ultimately, we present the concrete return of research findings policy implemented in the TIARA-study. Here, we suggest restricting the systematic return of children's individual research findings to cases where findings are considered clinically significant and actionable for the child. We discuss the broader implications for designing and conducting research in behavioral sciences with children.

How well are DSM-5 diagnostic criteria for ASD represented in standardized diagnostic instruments?

Five years after the publication of DSM-5 in 2013, three widely used diagnostic instruments have published algorithms designed to represent its (sub-)criteria for Autism Spectrum Disorder (ASD) in children and adolescents. This study aimed to: (1) establish the content validity of these three DSM-5-adapted algorithms, and (2) identify problems with the operationalization of DSM-5 diagnostic criteria in measurable and observable behaviors. Algorithm items of the Autism Diagnostic Observation Schedule-Second Edition (ADOS-2), Developmental, Dimensional and Diagnostic Interview (3di) and Diagnostic Interview for Social and Communication Disorders-11th edition (DISCO-11) were mapped onto DSM-5 sub-criteria. The development and decision-making rules integrated in their algorithms were then compared with DSM-5. Results demonstrated significant variability in the number and nature of sub-criteria covered by the ADOS-2, 3di and DISCO-11. In addition to differences in the development of algorithms and cut-off scores, instruments also differed in the extent to which they follow DSM-5 decision-making rules for diagnostic classification. We conclude that such differences in interpretation of DSM-5 criteria provide a challenge for symptom operationalization which will be most effectively overcome by consensus, testing and reformulation.

Structural and genomic decoding of human and plant myristoylomes reveals a definitive recognition pattern.

An organism's entire protein modification repertoire has yet to be comprehensively mapped. N-myristoylation (MYR) is a crucial eukaryotic N-terminal protein modification. Here we mapped complete Homo sapiens and Arabidopsis thaliana myristoylomes. The crystal structures of human modifier NMT1 complexed with reactive and nonreactive target-mimicking peptide ligands revealed unexpected binding clefts and a modifier recognition pattern. This information allowed integrated mapping of myristoylomes using peptide macroarrays, dedicated prediction algorithms, and in vivo mass spectrometry. Global MYR profiling at the genomic scale identified over a thousand novel, heterogeneous targets in both organisms. Surprisingly, MYR involved a non-negligible set of overlapping targets with N-acetylation, and the sequence signature marks for a third proximal acylation-S-palmitoylation-were genomically imprinted, allowing recognition of sequences exhibiting both acylations. Together, the data extend the N-end rule concept for Gly-starting proteins to subcellular compartmentalization and reveal the main neighbors influencing protein modification profiles and consequent cell fate.

Rapid neural categorization of angry and fearful faces is specifically impaired in boys with autism spectrum disorder.

BACKGROUND: Difficulties with facial expression processing may be associated with the characteristic social impairments in individuals with autism spectrum disorder (ASD). Emotional face processing in ASD has been investigated in an abundance of behavioral and EEG studies, yielding, however, mixed and inconsistent results. METHODS: We combined fast periodic visual stimulation (FPVS) with EEG to assess the neural sensitivity to implicitly detect briefly presented facial expressions among a stream of neutral faces, in 23 boys with ASD and 23 matched typically developing (TD) boys. Neutral faces with different identities were presented at 6 Hz, periodically interleaved with an expressive face (angry, fearful, happy, sad in separate sequences) every fifth image (i.e., 1.2 Hz oddball frequency). These distinguishable frequency tags for neutral and expressive stimuli allowed direct and objective quantification of the expression-categorization responses, needing only four sequences of 60 s of recording per condition. RESULTS: Both groups show equal neural synchronization to the general face stimulation and similar neural responses to happy and sad faces. However, the ASD group displays significantly reduced responses to angry and fearful faces, compared to TD boys. At the individual subject level, these neural responses allow to predict membership of the ASD group with an accuracy of 87%. Whereas TD participants show a significantly lower sensitivity to sad faces than to the other expressions, ASD participants show an equally low sensitivity to all the expressions. CONCLUSIONS: Our results indicate an emotion-specific processing deficit, instead of a general emotion-processing problem: Boys with ASD are less sensitive than TD boys to rapidly and implicitly detect angry and fearful faces. The implicit, fast, and straightforward nature of FPVS-EEG opens new perspectives for clinical diagnosis.

Parents' multi-layered expectations when requesting an Autism Spectrum Disorder assessment of their young child: an in-depth interview study.

BACKGROUND: Parents are valued stakeholders in research, clinical practice and policy development concerning autism spectrum disorder (ASD). However, little is known about what drives and moves parents besides their obvious worries and help request when they ask for a diagnostic ASD assessment of their child. METHODS: Seventeen Flemish parents of 11 young children participated in a longitudinal study consisting of three in-depth interviews before and after their child's diagnostic ASD assessment. Data were analysed in Nvivo 11 according to the procedures of Interpretative Phenomenological Analysis. RESULTS: In this paper we report the results of the first series of interviews which were conducted after parents had asked for an ASD assessment of their young child, and before this assessment started. The pre-assessment experiences of the parents were dominated by the anticipation of various implications of an ASD diagnosis, comprising both positive and negative expectations. The theme of positive expectations consisted of two equally prominent subthemes: treatment-related implications but also expectations pertaining to their psychological and relational experiences. CONCLUSIONS: This study suggests important issues for clinicians to bear in mind during a consultation with parents who request an ASD assessment of their young child. We argue that attending to and communicating about parents' expectations prior to their child's ASD assessment may help clinicians to better understand parents' requests for help, and to address their needs more effectively.

Parents' views and experiences of the autism spectrum disorder diagnosis of their young child: a longitudinal interview study.

Parents are valuable stakeholders in research, clinical practice and policy development concerning autism spectrum disorder (ASD). Little is known, however, about how parents view and experience an ASD diagnosis. We investigated the evolution of parents' views and experiences of the ASD diagnosis before, right after and 12 months after their child was diagnosed. Seventeen Flemish parents waiting for their young child's diagnostic ASD assessment participated in a longitudinal study consisting of three in-depth interviews. They described their views and experiences concerning their child's ASD diagnosis at three separate moments: (T1) prior to a diagnostic ASD assessment; (T2) immediately after their final feedback session at the end of the assessment; and (T3) 12 months later. Interviews were digitally recorded, transcribed and analysed in Nvivo 11 according to the procedures of interpretative phenomenological analysis. We extracted three themes from the interview material throughout the parental journey: (T1) expecting certainty and exculpation; (T2) vulnerabilisation of the child; and (T3) pragmatic attitude and some disappointment. At T3, the parents overall had come to value the diagnosis because of two reasons: they were satisfied with their child's entitlement to ASD-related support at school, and with the diagnosis' impact on the child's relationships with parents and teachers. Many parents experienced their child with an ASD diagnosis as vulnerable, and themselves as acutely responsible for his development and future. Our findings may lead to a higher satisfaction with the clinical trajectory in both clinician and parents by inspiring a conversation between them about parents' evolving views, hopes and concerns related to their child's ASD diagnosis.

How the Warburg effect supports aggressiveness and drug resistance of cancer cells?

Cancer cells employ both conventional oxidative metabolism and glycolytic anaerobic metabolism. However, their proliferation is marked by a shift towards increasing glycolytic metabolism even in the presence of O2 (Warburg effect). HIF1, a major hypoxia induced transcription factor, promotes a dissociation between glycolysis and the tricarboxylic acid cycle, a process limiting the efficient production of ATP and citrate which otherwise would arrest glycolysis. The Warburg effect also favors an intracellular alkaline pH which is a driving force in many aspects of cancer cell proliferation (enhancement of glycolysis and cell cycle progression) and of cancer aggressiveness (resistance to various processes including hypoxia, apoptosis, cytotoxic drugs and immune response). This metabolism leads to epigenetic and genetic alterations with the occurrence of multiple new cell phenotypes which enhance cancer cell growth and aggressiveness. In depth understanding of these metabolic changes in cancer cells may lead to the development of novel therapeutic strategies, which when combined with existing cancer treatments, might improve their effectiveness and/or overcome chemoresistance.

Gaze-Contingent Display Changes as New Window on Analytical and Holistic Face Perception in Children With Autism Spectrum Disorder.

The strength of holistic face perception in children with autism spectrum disorder (ASD) was evaluated by applying the gaze-contingent mask and window technique to a face matching and discrimination task in 6- to 14-year-old children with (n = 36) and without ASD (n = 47), and by examining fixation patterns. Behavioral results suggested a slower and less efficient face processing in the ASD sample compared with the matched control group. Comparing the moving mask and window conditions revealed a reduced holistic face processing bias in the younger age group but not in the older sample. Preferential viewing patterns revealed both similarities and differences between both participant groups.

Mechanical stress increases brain amyloid ß, tau, and α-synuclein concentrations in wild-type mice.

INTRODUCTION: Exposure to traumatic brain injury is a core risk factor that predisposes an individual to sporadic neurodegenerative diseases. We provide evidence that mechanical stress increases brain levels of hallmark proteins associated with neurodegeneration. METHODS: Wild-type mice were exposed to multiple regimens of repetitive mild traumatic brain injury, generating a range of combinations of impact energies, frequencies, and durations of exposure. Brain concentrations of amyloid ß 1-42 (Aß1-42), total tau, and α-synuclein were measured by sandwich enzyme-linked immunosorbent assay. RESULTS: There was a highly significant main effect of impact energy, frequency, and duration of exposure on Aß1-42, tau, and α-synuclein levels (P < .001), and a significant interaction between impact energy and duration of exposure for Aß1-42 and tau (P < .001), but not for α-synuclein. DISCUSSION: Dose-dependent and cumulative influence of repetitive mild traumatic brain injury-induced mechanical stress may trigger and/or accelerate neurodegeneration by pushing protein concentration over the disease threshold.

Executive functioning and local-global visual processing: candidate endophenotypes for autism spectrum disorder?

BACKGROUND: Heterogeneity within autism spectrum disorder (ASD) hampers insight in the etiology and stimulates the search for endophenotypes. Endophenotypes should meet several criteria, the most important being the association with ASD and the higher occurrence rate in unaffected ASD relatives than in the general population. We evaluated these criteria for executive functioning (EF) and local-global (L-G) visual processing. METHODS: By administering an extensive cognitive battery which increases the validity of the measures, we examined which of the cognitive anomalies shown by ASD probands also occur in their unaffected relatives (n = 113) compared to typically developing (TD) controls (n = 100). Microarrays were performed, so we could exclude relatives from probands with a de novo mutation in a known ASD susceptibility copy number variant, thus increasing the probability that genetic risk variants are shared by the ASD relatives. An overview of studies investigating EF and L-G processing in ASD relatives was also provided. RESULTS: For EF, ASD relatives - like ASD probands - showed impairments in response inhibition, cognitive flexibility and generativity (specifically, ideational fluency), and EF impairments in daily life. For L-G visual processing, the ASD relatives showed no anomalies on the tasks, but they reported more attention to detail in daily life. Group differences were similar for siblings and for parents of ASD probands, and yielded larger effect sizes in a multiplex subsample. The group effect sizes for the comparison between ASD probands and TD individuals were generally larger than those of the ASD relatives compared to TD individuals. CONCLUSIONS: Impaired cognitive flexibility, ideational fluency and response inhibition are strong candidate endophenotypes for ASD. They could help to delineate etiologically more homogeneous subgroups, which is clinically important to allow assigning ASD probands to different, more targeted, interventions.