Rare and de novo duplications containing TCF20 are associated with a neurodevelopmental disorder.

Transcriptor co-activator factor 20 gene (TCF20) encodes a nuclear chromatin-binding protein involved in regulation of gene expression. In human pathology, pathogenic variants or deletions in TCF20 were identified in patients with developmental delay, variable intellectual disability and behavioral impairment (OMIM: 618430). The shared core phenotype includes developmental delay, hypotonia, motor delay, autism spectrum disorders, neurobehavioral anomalies, neurological features such as ataxia, seizures, movement disorders, structural brain anomalies, craniofacial features and various congenital anomalies. Most pathogenic variants are loss-of-function variants. Duplication including TCF20 was suspected to cause a neurodevelopmental disorder (NDD) with mirror traits compared to patients with TCF20 deletions. In the present study, we report three patients from three unrelated families with NDD with a de novo duplication at 22q13.2 encompassing TCF20. We propose that the TCF20 duplication could be involved in a new 22q13.2 microduplication syndrome with high penetrance, enlarging the genotype-phenotype knowledge of TCF20-associated NDDs.

Increased risk of ADHD in families with ASD.

Attention Deficit and Hyperactive Disorder (ADHD) and Autism Spectrum Disorders (ASD) are frequent comorbid neurodevelopmental conditions and the overlap between both disorders remains to be delineated. A more complete understanding of the shared genetic and environmental factors is needed. Using a family-based method, we evaluated the risk of ADHD in a group of relatives with an ASD proband (ASD-) and a group of relatives with an ASD and ADHD proband (ASD+). We enrolled 1245 individuals in the study: 499 probands, their 746 first-degree relatives and 140 controls. We used a multivariate generalized estimating equation (GEE) model, in which the dependent variable was the ADHD diagnosis in the relatives and the independent variable the ASD+ or ASD- in probands. We adjusted for sociodemographic factors (age, sex, IQ) and for the nature of the familial relationship with the affected proband (parent or sibling). Among the probands, there were 287 ASD- and 212 ASD+ individuals. ADHD was more frequent in relatives (19%) than in the control group (7%) (p = 0.001). The risk of ADHD was higher in the ASD+ relatives group than in the ASD- relatives group (GEE model OR 1.58 [95% CI 1.04-2.38], p = 0.032). This result was found in parents (OR 1.96 [95% CI 1.14-3.36], but not in siblings (OR 1.28 [95% CI 0.84-1.94], p = 0.434). Our study provides a representative estimate of the family distribution of ADHD in relatives of ASD probands but supports the modest effect of shared genetic and environmental factors between both disorders.

11q24.2-25 micro-rearrangements in autism spectrum disorders: Relation to brain structures.

Jacobsen syndrome (JS) is characterized by intellectual disability and higher risk for autism spectrum disorders (ASD). All patients with JS are carriers of contiguous de novo deletions of 11q24.2-25, but the causative genes remain unknown. Within the critical interval, we hypothesized that haploinsufficiency of the neuronal cell adhesion molecule Neurotrimin (NTM) might increase the risk for ASD and could affect brain structure volumes. We searched for deleterious mutations affecting NTM in 1256 ASD patients and 1287 controls, using SNP arrays, and by direct sequencing of 250 ASD patients and 180 controls. We compared our results to those obtained from independent cohorts of ASD patients and controls. We identified two patients with Copy Number Variants (CNV) encompassing NTM, one with a large de novo deletion, and a clinical phenotype of JS (including macrocephaly), and a second with a paternally inherited duplication, not consistent with JS. Interestingly, no similar CNVs were observed in controls. We did not observe enrichment for deleterious NTM mutations in our cohort. We then explored if the macrocephaly in the patient with JS was associated with a homogeneous increase of brain structures volumes using automatic segmentation. Compared to subjects without NTM micro-rearrangements (n=188), the patient had an increased volume of the sub-cortical structures but a decrease of the occipital gray matter. Finally our explorations could not incriminate NTM as a susceptibility gene for ASD, but provides new information on the impact of the 11q24.2-25 deletion on brain anatomy.

Autism spectrum disorder in young patients with congenital central hypoventilation syndrome: role of the autonomic nervous system dysfunction.

BACKGROUND: Congenital central hypoventilation syndrome (CCHS) is a rare condition characterized by alveolar hypoventilation and autonomic nervous system (ANS) dysfunction requiring long-term ventilation. CCHS could constitute a risk factor of autism spectrum disorder (ASD) due to birth injury related to respiratory failure, which remains to be determined. ANS dysfunction has also been described in ASD and there are indications for altered contribution of ANS-central nervous system interaction in processing of social information; thus, CCHS could be a risk factor for ASD based on pathophysiological background also. Our study aimed to determine the prevalence of ASD among CCHS patients, identify risk factors, and explore the relationship between the ANS, evaluated by heart rate variability indices, and adaptative functioning. RESULTS: Our retrospective study, based on the analysis of records of a French national center of patients with CCHS under 20 years of age, determined that the prevalence of ASD (diagnosed by a psychiatrist, following the criteria of DSM-4 or DSM-5) was 6/69 patients, 8.7% (95% confidence interval: 3.3-18.0%). In a case (CCHS with ASD, n = 6) - control (CCHS without ASD, n = 12) study with matching on sex, longer neonatal hospitalization stay and glycemic dysfunction were associated with ASD. Adaptative functioning was assessed using Vineland Adaptative behavioral scales (VABS) and heart rate variability indices (including daytime RMSSD as an index of parasympathetic modulation) were obtained from ECG Holter performed the same day. In 19 young subjects with CCHS who had both ECG Holter and VABS, significant positive correlations were observed between RMSSD and three of four sub-domains of the VABS (communication: R = 0.50, p = 0.028; daily living skills: R = 0.60, p = 0.006; socialization: R = 0.52, p = 0.021). CONCLUSION: Our study suggests a high prevalence of ASD in patients with CCHS. Glycemic dysfunction and longer initial hospitalization stays were associated with ASD development. A defect in parasympathetic modulation was associated with worse adaptative functioning.

Familial KCNQ2 mutation: a psychiatric perspective.

KCNQ2 mutations are a common cause of early-onset epileptic syndromes. They are associated with heterogeneous developmental profiles, from mild to severe cognitive and social impairments that need better characterization. We report a case of an inherited KCNQ2 mutation due to a deletion c.402delC in a heterozygous state, in the exon 3 of the KCNQ2 gene. A 5-year-old boy presented a cluster of sudden-onset generalized tonic-clonic seizures at three months of age, after an unremarkable postnatal period. Multiplex ligation-dependent probe amplification identified a familial mutation after an investigation in the family revealed that this mutation was present on the father's side. The patient was diagnosed with autism and intellectual deficiency in a context of KCNQ2 -encephalopathy. We describe his clinical features in light of current literature. This report highlights the importance of appropriate genetic counseling and psychiatric assessment in planning the medical and social follow-up of a disorder with complex socio-behavioral features.

Global Sensory Features are Linked to Executive and Attentional Impairments in Autism Spectrum Disorders.

Sensory features, executive and attentional impairments are frequently reported in individuals with autism spectrum disorders (ASD). However, little is known about their complex relationships. In this study, we aim to examine the executive and attentional difficulties related to distinct sensory profiles. We identified sensory profiles with a Latent Profile Analysis (LPA) based on scores on the Short Sensory Profile (SSP) questionnaire in 95 children with ASD aged 6 to 17 years. Executive and attention functions were assessed using the Behavior Rating Inventory of Executive Functions (BRIEF) questionnaire and Attention-Deficit Hyperactivity Disorder Rating Scale (ADHD-RS). A three-cluster solution based on raw SSP scores identified a "high'', a "medium" and a "low'' SSP profile. We found a significant relationship between executive functions, attentional skills and the global severity of sensory features, reinforcing findings of previous studies in the literature. A two-cluster solution based on normalized SSP (i.e. equalized for the global severity) identified distinct sensory profiles, mainly discriminated by the score of underresponsive/seeks sensation. We found no significant difference between these two clusters for the BRIEF and ADHD-RS related scores. Our study suggests that the heterogeneity of sensory features in ASD may not be explained by differences in executive and attention functions. Future studies are needed to refine the link between sensory features and executive functions in autism.

Heterozygous FA2H mutations in autism spectrum disorders.

BACKGROUND: Widespread abnormalities in white matter development are frequently reported in cases of autism spectrum disorders (ASD) and could be involved in the disconnectivity suggested in these disorders. Homozygous mutations in the gene coding for fatty-acid 2-hydroxylase (FA2H), an enzyme involved in myelin synthesis, are associated with complex leukodystrophies, but little is known about the functional impact of heterozygous FA2H mutations. We hypothesized that rare deleterious heterozygous mutations of FA2H might constitute risk factors for ASD. METHODS: We searched deleterious mutations affecting FA2H, by genotyping 1256 independent patients with ASD genotyped using Genome Wide SNP arrays, and also by sequencing in independent set of 186 subjects with ASD and 353 controls. We then explored the impact of the identified mutations by measuring FA2H enzymatic activity and expression, in transfected COS7 cells. RESULTS: One heterozygous deletion within 16q22.3-q23.1 including FA2H was observed in two siblings who share symptoms of autism and severe cognitive impairment, axial T2-FLAIR weighted MRI posterior periventricular white matter lesions. Also, two rare non-synonymous mutations (R113W and R113Q) were reported. Although predictive models suggested that R113W should be a deleterious, we did not find that FA2H activity was affected by expression of the R113W mutation in cultured COS cells. CONCLUSIONS: While our results do not support a major role for FA2H coding variants in ASD, a screening of other genes related to myelin synthesis would allow us to better understand the role of non-neuronal elements in ASD susceptibility.

Consensus recommendations on mental health issues in Phelan-McDermid syndrome.

Phelan-McDermid syndrome is a rare genetic condition caused by a deletion encompassing the 22q13.3 region or a pathogenic variant of the gene SHANK3. The clinical presentation is variable, but main characteristics include global developmental delay/intellectual disability (ID), marked speech impairment or delay, along with other features like hypotonia and somatic or psychiatric comorbidities. This publication delineates mental health, developmental and behavioural themes across the lifetime of individuals with PMS as informed by parents/caregivers, experts, and other key professionals involved in PMS care. We put forward several recommendations based on the available literature concerning mental health and behaviour in PMS. Additionally, this article aims to improve our awareness of the importance of considering developmental level of the individual with PMS when assessing mental health and behavioural issues. Understanding how the discrepancy between developmental level and chronological age may impact concerning behaviours offers insight into the meaning of those behaviours and informs care for individuals with PMS, enabling clinicians to address unmet (mental health) care needs and improve quality of life.

Abnormal neutrophil-to-lymphocyte ratio in children with autism spectrum disorder and history of maternal immune activation.

Maternal immune activation (MIA), related to autoimmune/inflammatory diseases or acute infections, during the two first trimesters of pregnancy is a risk factor for autism spectrum disorders (ASD) in offspring. In mice, MIA has a long-term impact on offspring's immune equilibrium resulting in a pro-inflammatory phenotype. We therefore hypothesized that children with ASD and a history of MIA could display a similar phenotype specifically assessed by a higher neutrophil to lymphocyte ratio (NLR). In this study, we used a retrospective sample of 231 dyads involving children with ASD and their mothers. Among ASD patients, 12% had a history of MIA. The multivariate analysis revealed a significant association between NLR in children with ASD and maternal history of MIA (F = 2.27, p = 0.03). Using a categorical approach, we observed an abnormal NLR (over 3) in 7.4% of children with ASD MIA+ compared to 1.9% for MIA-. Our study supports the hypothesis suggesting an impact of MIA on the risk of ASD. Further studies could contribute to the development of biomarkers in MIA+ ASD and enable the development of targeted immunomodulatory therapies.

Dissecting the 22q13 region to explore the genetic and phenotypic diversity of patients with Phelan-McDermid syndrome.

SHANK3-related Phelan-McDermid syndrome (PMS) is caused by a loss of the distal part of chromosome 22, including SHANK3, or by a pathological SHANK3 variant. There is an important genetic and phenotypic diversity among patients who can present with developmental delay, language impairments, autism, epilepsy, and other symptoms. SHANK3, encoding a synaptic scaffolding protein, is deleted in the majority of patients with PMS and is considered a major gene involved in the neurological impairments of the patients. However, differences in deletion size can influence clinical features, and in some rare cases, deletions at the 22q13 locus in individuals with SHANK3-unrelated PMS do not encompass SHANK3. These individuals with SHANK3-unrelated PMS still display a PMS-like phenotype. This suggests the participation of other 22q13 genes in the pathogenesis of PMS. Here, we review the biological function and potential implication in PMS symptoms of 110 genes located in the 22q13 region, focusing on 35 genes with evidence for association with neurodevelopmental disorders, including 13 genes for epilepsy and 11 genes for microcephaly and/or macrocephaly. Our review is restricted to the 22q13 region, but future large-scale studies using whole genome sequencing and deep-phenotyping are warranted to develop predictive models of clinical trajectories and to target specific medical and educational care for each individual with PMS.

Questioning cognitive heterogeneity and intellectual functioning in fetal alcohol spectrum disorders from the Wechsler intelligence scale for children.

Introduction: Fetal Alcohol Spectrum Disorders (FASD) are characterized by a variety of multiple cognitive and behavioral impairments, with intellectual, attentional, and executive impairments being the most commonly reported. In populations with multiple neurodevelopmental disorders, the Full Scale Intelligence Quotient (FSIQ) may not be a proper measure of intellectual abilities, rarely interpreted in FASD clinical practice because the heterogeneity of the cognitive profile is deemed too strong. We propose a quantitative characterization of this heterogeneity, of the strengths and weaknesses profile, and a differential analysis between global cognitive (FSIQ) and elementary reasoning abilities in a large retrospective monocentric FASD sample. Methods: Using clinical and cognitive data (Wechsler Intelligence Scale for Children) from 107 children with FASD, we characterized subject heterogeneity (variance and scatter of scaled/composite scores), searched for strengths and weaknesses, and specified intellectual functioning in terms of FSIQ and elementary reasoning (General Abilities Index, Highest Reasoning Scaled Score), in comparison with standardization norms and a Monte-Carlo-simulated sample from normalization data. Results: Performance of children with FASD was lower on all subtests, with a significant weakness in working memory and processing speed. We found no increase in the variance and scatter of the scores, but a discordance between the assessment of global cognitive functioning (28% borderline, 23% deficient) and that of global and elementary reasoning abilities (23-9% borderline, 15-14% deficient). Conclusion: Our results question the notion of WISC profile heterogeneity in FASD and point to working memory and processing speed over-impairment, with global repercussions but most often preserved elementary reasoning abilities.

Cortico-Cerebellar neurodynamics during social interaction in Autism Spectrum Disorders.

BACKGROUND: Exploring neural network dynamics during social interaction could help to identify biomarkers of Autism Spectrum Disorders (ASD). A cerebellar involvement in autism has long been suspected and recent methodological advances now enable studying cerebellar functioning in a naturalistic setting. Here, we investigated the electrophysiological activity of the cerebro-cerebellar network during real-time social interaction in ASD. We focused our analysis on theta oscillations (3-8 Hz), which have been associated with large-scale coordination of distant brain areas and might contribute to interoception, motor control, and social event anticipation, all skills known to be altered in ASD. METHODS: We combined the Human Dynamic Clamp, a paradigm for studying realistic social interactions using a virtual avatar, with high-density electroencephalography (HD-EEG). Using source reconstruction, we investigated power in the cortex and the cerebellum, along with coherence between the cerebellum and three cerebral-cortical areas, and compared our findings in a sample of participants with ASD (n = 107) and with typical development (TD) (n = 33). We developed an open-source pipeline to analyse neural dynamics at the source level from HD-EEG data. RESULTS: Individuals with ASD showed a significant increase in theta band power over the cerebellum and the frontal and temporal cortices during social interaction compared to resting state, along with significant coherence increases between the cerebellum and the sensorimotor, frontal and parietal cortices. However, a phase-based connectivity measure did not support a strict activity increase in the cortico-cerebellar functional network. We did not find any significant differences between the ASD and the TD group. CONCLUSIONS: This exploratory study uncovered increases in the theta band activity of participants with ASD during social interaction, pointing at the presence of neural interactions between the cerebellum and cerebral networks associated with social cognition. It also emphasizes the need for complementary functional connectivity measures to capture network-level alterations. Future work will focus on optimizing artifact correction to include more participants with TD and increase the statistical power of group-level contrasts.

Tackling hypo and hyper sensory processing heterogeneity in autism: From clinical stratification to genetic pathways.

As an integral part of autism spectrum symptoms, sensory processing issues including both hypo and hyper sensory sensitivities. These sensory specificities may result from an excitation/inhibition imbalance with a poorly understood of their level of convergence with genetic alterations in GABA-ergic and glutamatergic pathways. In our study, we aimed to characterize the hypo/hyper-sensory profile among autistic individuals. We then explored its link with the burden of deleterious mutations in a subset of individuals with available whole-genome sequencing data. To characterize the hypo/hyper-sensory profile, the differential Short Sensory Profile (dSSP) was defined as a normalized and centralized hypo/hypersensitivity ratio from the Short Sensory Profile (SSP). Including 1136 participants (533 autistic individuals, 210 first-degree relatives, and 267 controls) from two independent study samples (PARIS and LEAP), we observed a statistically significant dSSP mean difference between autistic individuals and controls, driven mostly by a high dSSP variability, with an intermediated profile represented by relatives. Our genetic analysis tended to associate the dSSP and the hyposensitivity with mutations of the GABAergic pathway. The major limitation was the dSSP difficulty to discriminate subjects with a similar quantum of hypo- and hyper-sensory symptoms to those with no such symptoms, resulting both in a similar ratio score of 0. However, the dSSP could be a relevant clinical score, and combined with additional sensory descriptions, genetics and endophenotypic substrates, will improve the exploration of the underlying neurobiological mechanisms of sensory processing differences in autism spectrum.

Exploring the multidimensional nature of repetitive and restricted behaviors and interests (RRBI) in autism: neuroanatomical correlates and clinical implications.

BACKGROUND: Repetitive and restricted behaviors and interests (RRBI) are core symptoms of autism with a complex entity and are commonly categorized into 'motor-driven' and 'cognitively driven'. RRBI symptomatology depends on the individual's clinical environment limiting the understanding of RRBI physiology, particularly their associated neuroanatomical structures. The complex RRBI heterogeneity needs to explore the whole RRBI spectrum by integrating the clinical context [autistic individuals, their relatives and typical developing (TD) individuals]. We hypothesized that different RRBI dimensions would emerge by exploring the whole spectrum of RRBI and that these dimensions are associated with neuroanatomical signatures-involving cortical and subcortical areas. METHOD: A sample of 792 individuals composed of 267 autistic subjects, their 370 first-degree relatives and 155 TD individuals was enrolled in the study. We assessed the whole patterns of RRBI in each individual by using the Repetitive Behavior Scale-Revised and the Yale-Brown Obsessive Compulsive Scale. We estimated brain volumes using MRI scanner for a subsample of the subjects (n = 152, 42 ASD, 89 relatives and 13 TD). We first investigated the dimensionality of RRBI by performing a principal component analysis on all items of these scales and included all the sampling population. We then explored the relationship between RRBI-derived factors with brain volumes using linear regression models. RESULTS: We identified 3 main factors (with 30.3% of the RRBI cumulative variance): Factor 1 (FA1, 12.7%) reflected mainly the 'motor-driven' RRBI symptoms; Factor 2 and 3 (respectively, 8.8% and 7.9%) gathered mainly Y-BOCS related items and represented the 'cognitively driven' RRBI symptoms. These three factors were significantly associated with the right/left putamen volumes but with opposite effects: FA1 was negatively associated with an increased volume of the right/left putamen conversely to FA2 and FA3 (all uncorrected p < 0.05). FA1 was negatively associated with the left amygdala (uncorrected p < 0.05), and FA2 was positively associated with the left parietal structure (uncorrected p = 0.001). CONCLUSION: Our results suggested 3 coherent RRBI dimensions involving the putamen commonly and other structures according to the RRBI dimension. The exploration of the putamen's integrative role in RSBI needs to be strengthened in further studies.

Phenotypic effects of genetic variants associated with autism.

While over 100 genes have been associated with autism, little is known about the prevalence of variants affecting them in individuals without a diagnosis of autism. Nor do we fully appreciate the phenotypic diversity beyond the formal autism diagnosis. Based on data from more than 13,000 individuals with autism and 210,000 undiagnosed individuals, we estimated the odds ratios for autism associated to rare loss-of-function (LoF) variants in 185 genes associated with autism, alongside 2,492 genes displaying intolerance to LoF variants. In contrast to autism-centric approaches, we investigated the correlates of these variants in individuals without a diagnosis of autism. We show that these variants are associated with a small but significant decrease in fluid intelligence, qualification level and income and an increase in metrics related to material deprivation. These effects were larger for autism-associated genes than in other LoF-intolerant genes. Using brain imaging data from 21,040 individuals from the UK Biobank, we could not detect significant differences in the overall brain anatomy between LoF carriers and non-carriers. Our results highlight the importance of studying the effect of the genetic variants beyond categorical diagnosis and the need for more research to understand the association between these variants and sociodemographic factors, to best support individuals carrying these variants.

Maternal immune activation during pregnancy is associated with more difficulties in socio-adaptive behaviors in autism spectrum disorder.

Autism spectrum disorder (ASD) are neurodevelopmental conditions characterised by deficits in social communication and interaction and repetitive behaviours. Maternal immune activation (MIA) during the mid-pregnancy is a known risk factor for ASD. Although reported in 15% of affected individuals, little is known about the specificity of their clinical profiles. Adaptive skills represent a holistic approach to a person's competencies and reflect specifically in ASD, their strengths and difficulties. In this study, we hypothesised that ASD individual with a history of MIA (MIA+) could be more severely socio-adaptively impaired than those without MIA during pregnancy (MIA-). To answer this question, we considered two independent cohorts of individuals with ASD (PARIS study and FACE ASD) screened for pregnancy history, and used supervised and unsupervised machine learning algorithms. We included 295 mother-child dyads with 14% of them with MIA+. We found that ASD-MIA+ individuals displayed more severe maladaptive behaviors, specifically in their socialization abilities. MIA+ directly influenced individual's socio-adaptive skills, independent of other covariates, including ASD severity. Interestingly, MIA+ affect persistently the socio-adaptive behavioral trajectories of individuals with ASD. The current study has a retrospective design with possible recall bias regarding the MIA event and, even if pooled from two cohorts, has a relatively small population. In addition, we were limited by the number of covariables available potentially impacted socio-adaptive behaviors. Larger prospective study with additional dimensions related to ASD is needed to confirm our results. Specific pathophysiological pathways may explain these clinical peculiarities of ASD- MIA+ individuals, and may open the way to new perspectives in deciphering the phenotypic complexity of ASD and for the development of specific immunomodulatory strategies.

The different clinical facets of SYN1-related neurodevelopmental disorders.

Synapsin-I (SYN1) is a presynaptic phosphoprotein crucial for synaptogenesis and synaptic plasticity. Pathogenic SYN1 variants are associated with variable X-linked neurodevelopmental disorders mainly affecting males. In this study, we expand on the clinical and molecular spectrum of the SYN1-related neurodevelopmental disorders by describing 31 novel individuals harboring 22 different SYN1 variants. We analyzed newly identified as well as previously reported individuals in order to define the frequency of key features associated with these disorders. Specifically, behavioral disturbances such as autism spectrum disorder or attention deficit hyperactivity disorder are observed in 91% of the individuals, epilepsy in 82%, intellectual disability in 77%, and developmental delay in 70%. Seizure types mainly include tonic-clonic or focal seizures with impaired awareness. The presence of reflex seizures is one of the most representative clinical manifestations related to SYN1. In more than half of the cases, seizures are triggered by contact with water, but other triggers are also frequently reported, including rubbing with a towel, fever, toothbrushing, fingernail clipping, falling asleep, and watching others showering or bathing. We additionally describe hyperpnea, emotion, lighting, using a stroboscope, digestive troubles, and defecation as possible triggers in individuals with SYN1 variants. The molecular spectrum of SYN1 variants is broad and encompasses truncating variants (frameshift, nonsense, splicing and start-loss variants) as well as non-truncating variants (missense substitutions and in-frame duplications). Genotype-phenotype correlation revealed that epileptic phenotypes are enriched in individuals with truncating variants. Furthermore, we could show for the first time that individuals with early seizures onset tend to present with severe-to-profound intellectual disability, hence highlighting the existence of an association between early seizure onset and more severe impairment of cognitive functions. Altogether, we present a detailed clinical description of the largest series of individuals with SYN1 variants reported so far and provide the first genotype-phenotype correlations for this gene. A timely molecular diagnosis and genetic counseling are cardinal for appropriate patient management and treatment.

Discriminant value of repetitive behaviors in families with autism spectrum disorder and obsessional compulsive disorder probands.

Repetitive behaviors (RB) represent a wide spectrum of symptoms ranging from sensory-motor stereotypies to complex cognitive rituals, frequently dichotomized as low- and high-order sub-groups of symptoms. Even though these subgroups are considered as phenomenologically distinct in autism spectrum disorder (ASD) and obsessive-compulsive disorder (OCD), brain imaging and genetic studies suggest that they have common mechanisms and pathways. This discrepancy may be explained by the frequent intellectual disability reported in ASD, which blurs the RB expressivity. Given the high heritability of RB, that is, the diversity of symptoms expressed in the relatives are dependent on those expressed in their probands, we hypothesize that if RB expressed in ASD or OCD are two distinct entities, then the RB expressed in relatives will also reflect these two dimensions. We thus conduct a linear discriminant analysis on RB in both the relatives of probands with ASD and OCD and subjects from the general population (n = 1023). The discriminant analysis results in a classification of 81.1% of the controls (p < 10-4 ), but poorly differentiated the ASD and OCD relatives (≈46%). The stepwise analysis reveals that five symptoms attributed to high-order RB and two related to low-order RB (including hypersensitivity) are the most discriminant. Our results support the idea that the difference of RB patterns in the relatives is mild compared with the distribution of symptoms in controls. Our findings reinforce the evidence of a common biological pattern of RB both in ASD and OCD but with minor differences, specific to each of these two neuro-developmental disorders. LAY SUMMARY: Repetitive behaviors (RB), a key symptom in the classification of both OCD and ASD, are phenomenologically considered as distinct in the two disorders, which is in contrast with brain imaging studies describing a common neural circuit. Intellectual disability, which is frequently associated with ASD, makes RB in ASD more difficult to understand as it affects the expression of the RB symptoms. To avoid this bias, we propose to consider the familial aggregation in ASD and OCD by exploring RB in the first-degree relatives of ASD and OCD. Our results highlight the existence of RB expressed in relatives compared to the general population, with a common pattern of symptoms in relatives of both ASD and OCD but also minor differences, specific to each of these two neuro-developmental disorders.

Interactive Psychometrics for Autism With the Human Dynamic Clamp: Interpersonal Synchrony From Sensorimotor to Sociocognitive Domains.

The human dynamic clamp (HDC) is a human-machine interface designed on the basis of coordination dynamics for studying realistic social interaction under controlled and reproducible conditions. Here, we propose to probe the validity of the HDC as a psychometric instrument for quantifying social abilities in children with autism spectrum disorder (ASD) and neurotypical development. To study interpersonal synchrony with the HDC, we derived five standardized scores following a gradient from sensorimotor and motor to higher sociocognitive skills in a sample of 155 individuals (113 participants with ASD, 42 typically developing participants; aged 5 to 25 years; IQ > 70). Regression analyses were performed using normative modeling on global scores according to four subconditions (HDC behavior "cooperative/competitive," human task "in-phase/anti-phase," diagnosis, and age at inclusion). Children with ASD had lower scores than controls for motor skills. HDC motor coordination scores were the best candidates for stratification and diagnostic biomarkers according to exploratory analyses of hierarchical clustering and multivariate classification. Independently of phenotype, sociocognitive skills increased with developmental age while being affected by the ongoing task and HDC behavior. Weaker performance in ASD for motor skills suggests the convergent validity of the HDC for evaluating social interaction. Results provided additional evidence of a relationship between sensorimotor and sociocognitive skills. HDC may also be used as a marker of maturation of sociocognitive skills during real-time social interaction. Through its standardized and objective evaluation, the HDC not only represents a valid paradigm for the study of interpersonal synchrony but also offers a promising, clinically relevant psychometric instrument for the evaluation and stratification of sociomotor dysfunctions.

Synesthesia & autistic features in a large family: Evidence for spatial imagery as a common factor.

BACKGROUND: Autism and synesthesia are neurodevelopmental conditions associated with variants of perceptual processing. They also share some genetic variants and include a large magnitude of intra-categorical variation: 60 types for synesthesia, as well as a spectrum for autism. In order to investigate the relationship between these two phenomena, we investigated the family of FC, an autistic individual who also possess savant abilities and synesthesia manifestations. METHOD: Autistic symptoms were assessed for the entire sample of participants entering the study (39 individuals) using the SRS. Participants above threshold were evaluated with standardized diagnostic tools. Synesthesia was explored in the entire participating sample using a self-reported questionnaire. Consistency tests were used for participants who reported synesthetic manifestations. RESULTS: In addition to FC, four individuals with ASD were detected. Fifteen participants self-reported synesthesia (15 sequence-space, 4 sound-shape, 4 day-color), among which nine sequence-space synesthetes satisfied the consistency criteria. Two participants possess both autism and synesthesia. CONCLUSION: This family illustrates the co-segregation of autism and synesthesia. This co-segregation is in favour of a partially overlapping genetic predisposition for both conditions, but also authorizes a large variety of manifestations in both conditions. The high prevalence of sequence-space synesthesia in this family strengthens the previous assumption that this form of synesthesia may be linked to autism. We discuss the potential role of spatial imagery in the development of this form of synesthesia and savant abilities.