A syndrome of severe intellectual disability, hypotonia, failure to thrive, dysmorphism, and thinning of corpus callosum maps to chromosome 7q21.13-q21.3.

Six individuals of consanguineous Bedouin kindred presented at infancy with an autosomal recessive syndrome of severe global developmental delay, positive pyramidal signs, unique dysmorphism, skeletal abnormalities, and severe failure to thrive with normal birth weights. Patients had a profound intellectual disability and cognitive impairment with almost no acquired developmental milestones by 12 months. Early-onset axial hypotonia evolved with progressive muscle weakness, reduced muscle tone, and hyporeflexia. Craniofacial dysmorphism consisted of a triangular face with a prominent forehead and midface hypoplasia. Magnetic resonance imaging (MRI) demonstrated thinning of the corpus callosum and paucity of white matter. Genome-wide linkage analysis identified a single ~4 Mbp disease-associated locus on chromosome 7q21.13-q21.3 (LOD score>5). Whole-exome and genome sequencing identified no nonsynonymous pathogenic biallelic variants in any of the genes within this locus. Following the exclusion of partially resembling syndromes, we now describe a novel autosomal recessive syndrome mapped to a ~4Mbp locus on chromosome 7.

Association between ultrasonography foetal anomalies and autism spectrum disorder.

Multiple pieces of evidence support the prenatal predisposition of autism spectrum disorder (ASD). Nevertheless, robust data about abnormalities in foetuses later developing into children diagnosed with ASD are lacking. Prenatal ultrasound is an excellent tool to study abnormal foetal development as it is frequently used to monitor foetal growth and identify foetal anomalies throughout pregnancy. We conducted a retrospective case-sibling-control study of children diagnosed with ASD (cases); their own typically developing, closest-in-age siblings (TDS); and typically developing children from the general population (TDP), matched by year of birth, sex and ethnicity to investigate the association between ultrasonography foetal anomalies and ASD. The case group was drawn from all children diagnosed with ASD enrolled at the National Autism Research Center of Israel. Foetal ultrasound data from the foetal anatomy survey were obtained from prenatal ultrasound clinics of Clalit Health Services in southern Israel. The study comprised 659 children: 229 ASD, 201 TDS and 229 TDP. Ultrasonography foetal anomalies were found in 29.3% of ASD cases versus only 15.9% and 9.6% in the TDS and TDP groups [adjusted odds ratio (aOR) = 2.23, 95% confidence interval (CI) = 1.32-3.78, and aOR = 3.50, 95%CI = 2.07-5.91, respectively]. Multiple co-occurring ultrasonography foetal anomalies were significantly more prevalent among ASD cases. Ultrasonography foetal anomalies in the urinary system, heart, and head and brain were the most significantly associated with ASD diagnosis (aORUrinary = 2.08, 95%CI = 0.96-4.50 and aORUrinary = 2.90, 95%CI = 1.41-5.95; aORHeart = 3.72, 95%CI = 1.50-9.24 and aORHeart = 8.67, 95%CI = 2.62-28.63; and aORHead&Brain = 1.96, 95%CI = 0.72-5.30 and aORHead&Brain = 4.67, 95%CI = 1.34-16.24; versus TDS and TDP, respectively). ASD females had significantly more ultrasonography foetal anomalies than ASD males (43.1% versus 25.3%, P = 0.013) and a higher prevalence of multiple co-occurring ultrasonography foetal anomalies (15.7% versus 4.5%, P = 0.011). No sex differences were seen among TDS and TDP controls. ASD foetuses were characterized by a narrower head and a relatively wider ocular-distance versus TDP foetuses (ORBPD = 0.81, 95%CI = 0.70-0.94, and aOROcular distance = 1.29, 95%CI = 1.06-1.57). Ultrasonography foetal anomalies were associated with more severe ASD symptoms. Our findings shed important light on the multiorgan foetal anomalies associated with ASD.

Sleep Disturbances and Sensory Sensitivities Co-Vary in a Longitudinal Manner in Pre-School Children with Autism Spectrum Disorders.

Previous research has demonstrated that sleep disturbances are positively correlated with sensory sensitivities in children with ASD. Most of these studies, however, were based on cross-sectional analyses, where the relationship across symptom domains was examined at a single time-point. Here, we examined the development of 103 pre-school children with ASD over a 1-3-year period. The results revealed that spontaneous longitudinal changes in sleep disturbances were specifically correlated with changes in sensory sensitivities and not with changes in other sensory processing domains nor with changes in core ASD symptoms. These finding demonstrate a consistent longitudinal relationship between sleep disturbances and sensory sensitivities, which suggests that these symptoms may be generated by common or interacting underlying physiological mechanisms.

Early diagnosis of autism in the community is associated with marked improvement in social symptoms within 1-2 years.

LAY ABSTRACT: It is widely believed that early diagnosis and treatment of autism spectrum disorder is essential for better outcome. This is demonstrated by the American Academy of Pediatrics recommendation to screen all 1.5-2.5-year-old toddlers for autism spectrum disorder. However, multiple longitudinal studies of children diagnosed with autism spectrum disorder at 1.5-6 years of age and treated in community settings have not reported any associations between earlier diagnosis and improved outcome in core autism spectrum disorder symptoms. In this study, we measured changes in core autism spectrum disorder symptoms over a 1-2-year period in 131 children diagnosed with autism spectrum disorder at 1.2-5 years of age, and treated in the community. The results revealed that children who were diagnosed before 2.5 years of age were three times more likely to exhibit considerable improvements in social autism spectrum disorder symptoms in comparison to children diagnosed at later ages. These results highlight the importance of early diagnosis and treatment of autism spectrum disorder even in community settings with heterogeneous services. In addition, these results motivate further prioritization of universal screening for autism spectrum disorder before 2.5 years of age.

Association Between Antenatal Antimicrobial Therapy and Autism Spectrum Disorder-A Nested Case-Control Study.

Background: Multiple prenatal factors have been associated with autism spectrum disorder (ASD) risk. However, current data about the association between antimicrobial use during pregnancy and ASD is limited. Methods: A nested matched case-control study of children with ASD (cases), and children without ASD or other psychiatric or genetic disorders (controls). We compared the use of antimicrobial therapy during the 3 months before conception or during pregnancy between mothers of cases and controls and used multivariate conditional logistic regression models to assess the independent association between maternal use of antimicrobials during pregnancy and the risk of ASD in their offspring. Results: More than half of the mothers in the study (54.1%) used antimicrobial drugs during the 3 months before conception or during pregnancy. Rates of antimicrobial use were lower for mothers of children with ASD compared to mothers of controls (49.0 vs. 55.1%, respectively; p = 0.02), especially during the third trimester of pregnancy (18.8 vs. 22.9%, respectively; p = 0.03), and for the use of penicillins (15.7 vs. 19.7%, respectively; p = 0.06). These case-control differences suggest that antimicrobial administration during pregnancy was associated with a reduced risk of ASD in the offspring (aOR = 0.75, 95% CI = 0.61-0.92). Interestingly, this association was seen only among Jewish but not for the Bedouin mothers (aOR = 0.62, 95% CI = 0.48-0.79 and aOR = 1.21, 95% CI = 0.82-1.79). Conclusions: The reduced risk of ASD associated with prenatal antimicrobials use only in the Jewish population suggest the involvement of other ethnic differences in healthcare services utilization in this association.

Phenotypic variability in patients with unique double homozygous mutations causing variant ataxia telangiectasia.

Ataxia-Telangiectasia (A-T) is a neurodegenerative disease caused by bi-allelic mutations in the Ataxia-Telangiectasia-Mutated (ATM) gene. Complete lack of ATM activity leads to severe A-T and mutations allowing for residual activity cause a milder phenotype, termed variant A-T. There are only sparse data on the variability in phenotypes of variant A-T patients carrying the same mutations. A retrospective study of 15 patients with variant A-T, all double homozygous for the same mutations was conducted. The age of first symptom ranged from 4-180 months, including: truncal ataxia at <18 months of age in 9 patients, ataxia and instability only during fever in one patient, dystonia in one patient and malignancy in 4 patients. Global developmental delay and occulo-motor apraxia were recorded in 4/14 patients. Variant A-T patients with the same mutations in ATM, have variable phenotypes. Environmental, epigenetic, and post translational factors are likely to play a role in creation of the phenotype in variant A-T patients.

Distorted Optic Nerve Portends Neurological Complications in Infants With External Hydrocephalus.

Background: Benign external hydrocephalus (BEH) is defined by rapid increase in head circumference in infancy, with neuroimaging evidence of enlarged cerebrospinal fluid (CSF) spaces. BEH was postulated to predispose to subdural hematoma, neurocognitive impairments, and autism. There is currently no consensus on BEH diagnostic criteria and no biomarkers to predict neurological sequalae. Methods: MRI-based quantitative approach was used for measurement of potential imaging markers related to external hydrocephalus and their association with neurological outcomes. We scanned 23 infants diagnosed with BEH and 11 age-similar controls. Using anatomical measurements from a large sample of healthy infants (n = 150), Z-scores were calculated to classify subject's CSF spaces as enlarged (≥1.96SD of mean values) or normal. Results: Subjects with abnormally enlarged CSF spaces had a significantly wider and longer ON (p = 0.017 and p = 0.020, respectively), and a significantly less tortuous ON (p = 0.006). ON deformity demonstrated a high diagnostic accuracy for abnormally enlarged frontal subarachnoid space (AUC = 0.826) and interhemispheric fissure (AUC = 0.833). No significant association found between enlarged CSF spaces and neurological complications (OR = 0.330, 95%CI 0.070-1.553, p = 0.161). However, cluster analysis identified a distinct subgroup of children (23/34, 67.6%) with enlarged CSF spaces and a wider, longer and less tortuous ON, to have an increased risk for neurological complications (RR = 7.28, 95%CI 1.07-49.40). Discussion: This is the first report on the association between external hydrocephalus, ON deformity and neurological complications. Our findings challenge the current view of external hydrocephalus as a benign condition. ON deformity is a potential auxiliary marker for risk stratification in patients with enlarged CSF spaces.

Association Between Abnormal Fetal Head Growth and Autism Spectrum Disorder.

OBJECTIVE: Despite evidence for the prenatal onset of abnormal head growth in children with autism spectrum disorder (ASD), studies on fetal ultrasound data in ASD are limited and controversial. METHOD: We conducted a longitudinal matched case-sibling-control study on prenatal ultrasound biometric measures of children with ASD, and 2 control groups: (1) their own typically developed sibling (TDS) and (2) typically developed population (TDP). The cohort comprised 528 children (72.7% male), 174 with ASD, 178 TDS, and 176 TDP. RESULTS: During the second trimester, ASD and TDS fetuses had significantly smaller biparietal diameter (BPD) than TDP fetuses (adjusted odds ratio for the z score of BPD [aORzBPD] = 0.685, 95% CI = 0.527-0.890, and aORzBPD = 0.587, 95% CI = 0.459-0.751, respectively). However, these differences became statistically indistinguishable in the third trimester. Interestingly, head biometric measures varied by sex, with male fetuses having larger heads than female fetuses within and across groups. A linear mixed-effect model assessing the effects of sex and group assignment on fetal longitudinal head growth indicated faster BPD growth in TDS versus both ASD and TDP in male fetuses (ß = 0.084 and ß = 0.100 respectively; p < .001) but not in female fetuses, suggesting an ASD-sex interaction in head growth during gestation. Finally, fetal head growth showed conflicting correlations with ASD severity in male and female children across different gestation periods, thus further supporting the sex effect on the association between fetal head growth and ASD. CONCLUSION: Our findings suggest that abnormal fetal head growth is a familial trait of ASD, which is modulated by sex and is associated with the severity of the disorder. Thus, it could serve as an early biomarker for ASD.

Young Autism Spectrum Disorder Children in Special and Mainstream Education Settings Have Similar Behavioral Characteristics.

In many countries, parents can place autism spectrum disorder (ASD) children in either mainstream or special education settings, which differ in their ability to provide structured early intervention programs. There are no clear guidelines for how to make initial placement decisions and ongoing debate about the benefits and drawbacks of each educational setting. Previous studies have mostly examined placement of school-age children and reported that those with poorer cognitive abilities and more severe ASD symptoms tend to be placed in special education. The placement of younger children has rarely been studied. Here, we utilized the database at the National Autism Research Center of Israel to examine whether ASD severity, cognitive abilities, and parent education influenced the placement of 242 children. We performed the analyses separately for 1-3-year-old children who were placed in daycare centers and 3-5-year-old children who were placed in pre-school kindergartens. Our analyses revealed surprisingly small differences across special and mainstream education settings, particularly in daycare centers. Cognitive scores and parent education were significantly higher in ASD children placed in mainstream education, but these differences were of moderate effect size and explained a relatively small percentage of the variability in placement choices (<15%). Indeed, we found considerable overlap in the characteristics of ASD children across educational settings, which suggests that initial placement decisions are performed with little regard to the children's abilities. Given the importance of optimal early intervention, further studies are warranted to determine whether children with specific abilities and needs benefit more from placement in either educational setting. LAY SUMMARY: Currently, there are no clear recommendations for placing young children with ASD in special versus mainstream education settings. We examined the influence of ASD severity, cognitive abilities, and parent education on the initial placement of 242 children. While we found significantly higher cognitive scores and parental education in children placed in mainstream education, there was a remarkable overlap in the characteristics of children across both settings, suggesting that initial placement is performed with limited regard to the children's abilities. Autism Res 2021, 14: 699-708. © 2020 International Society for Autism Research and Wiley Periodicals LLC.

Diagnostic Yield and Economic Implications of Whole-Exome Sequencing for ASD Diagnosis in Israel.

Whole-exome sequencing (WES) is an effective approach to identify the susceptibility of genetic variants of autism spectrum disorder (ASD). The Israel Ministry of Health supports WES as an adjunct tool for ASD diagnosis, despite its unclear diagnostic yield and cost effectiveness. To address this knowledge gap, we applied WES to a population-based sample of 182 Bedouin and Jewish children with ASD from southern Israel, and assessed its yield in a gene panel of 205 genes robustly associated with ASD. We then compared the incremental cost-effectiveness ratios (ICERs) for an ASD diagnosis by WES, chromosomal microarray analysis (CMA), and CMA + WES. Overall, 32 ASD candidate variants were detected in 28 children, corresponding to an overall WES diagnostic yield of 15.4%. Interestingly, the diagnostic yield was significantly higher for the Bedouin children than for the Jewish children, i.e., 27.6% vs. 11.1% (p = 0.036). The most cost-effective means for genetic testing was the CMA alone, followed closely by the CMA + WES strategy (ICER = USD 117 and USD 124.8 per child). Yet, WES alone could become more cost effective than the other two approaches if there was to be a 25% increase in its yield or a 50% decrease in its cost. These findings suggest that WES should be recommended to facilitate ASD diagnosis in Israel, especially for highly consanguineous populations, such as the Bedouin.

Factors Affecting Family Compliance with Genetic Testing of Children Diagnosed with Autism Spectrum Disorder.

There is broad consensus about the importance of post-diagnostic genetic testing for children with ASD. However, the extent of compliance with these tests and the factors affecting compliance have rarely been examined. We surveyed a sample of 114 families with a child with ASD in Israel, where such genetic testing is funded by the government. We found that only one-third of these families completed post-diagnosis genetic testing for their child. The main factor influencing compliance was the doctor's recommendation (OR 11.6; 95% CI 3.2-42.4; p < 0.001). Furthermore, > 50% of the non-compliant families reported that genetic testing was irrelevant to them. Our findings highlight the importance of providing clear recommendations and explanations regarding the benefits and relevance of post-diagnosis genetic testing for children with ASD.

Ethnic Disparities in the Diagnosis of Autism in Southern Israel.

The prevalence of autism spectrum disorder (ASD) is continuously rising worldwide, with remarkable differences in ASD rates being reported across ethnic and socioeconomic groups. We conducted a prospective cohort study to identify the reasons for differences in ASD rates between the Bedouin and Jewish populations in southern Israel. Screening, referral, and diagnosis of toddlers aged 16-36 months were compared between Bedouin and Jewish populations. ASD screening was conducted at 35 randomly selected mother and child health centers (MCHCs) by trained nurses using the Modified Checklist for Autism in Toddlers with follow-up (M-CHAT/F) instrument. Toddlers screened positive at the MCHCs were monitored throughout the referral and diagnosis process at a single medical center until a diagnosis was determined by a physician specialist using DSM-5 criteria. The study cohort comprised 3,343 toddlers (996 Jewish and 2,347 Bedouin). Bedouin toddlers, compared to Jewish toddlers, were less likely to screen positive with M-CHAT/F (3.0% vs. 3.9%; P = 0.165), were significantly less likely to begin the hospital diagnosis process (HR = 0.38, 95% CI: 0.14-1.08; P = 0.068), and had a higher rates of loss-to-follow-up during the hospital diagnosis process (42.9% vs. 15.6%, respectively; P = 0.001). The results suggest that ethnic-specific barriers in the diagnosis process of ASD contribute to under-diagnosis of ASD in the Bedouin population. Facilitating the diagnosis process for Bedouin families will help to identify more children with ASD at earlier ages and consequently close the ethnic gap in ASD rates. LAY SUMMARY: We followed Bedouin and Jewish toddlers aged 16-36 months from southern Israel through their autism spectrum disorder (ASD) screening referral and diagnosis to identify the reasons for the differences in ASD prevalence between these ethnic groups. Jewish and Bedouin toddlers were equally identified in the ASD screening. However, Bedouin toddlers were less likely to complete the diagnosis process due to higher rates of loss-to-follow-up and slower diagnosis process. Facilitating ASD diagnosis for the Bedouin population will help identifying more toddlers with ASD.

Novel MTMR2 mutation causing severe Charcot-Marie-Tooth type 4B1 disease: a case report.

Mutations in myotubularin-related protein 2 (MTMR2) were shown to underlie Charcot-Marie-Tooth type 4B1 (CMT4B1) disease, a rare autosomal recessive demyelinating neuropathy, characterized by severe early-onset motor and sensory neuropathy. We describe three siblings of consanguineous kindred presenting with hypotonia, reduced muscle tone, action tremor, dysmetria, areflexia, and skeletal deformities, consistent with a diagnosis of CMT. Whole-exome sequencing identified a novel homozygous c.336_337 insertion mutation in MTMR2, resulting in a frameshift and putative truncated protein. In this concise report, we discuss the clinical presentation of this rare disease and support the limited number of observations regarding the pathogenesis of MTMR2-related neuropathies.

Phenotypic variability and mutation hotspot in COX15-related Leigh syndrome.

COX15 mutations were shown to underlie Leigh syndrome (LS), a progressive subacute necrotizing encephalopathy caused by defects in the mitochondrial respiratory chain. Here, two siblings of consanguineous kindred presented in infancy with a syndrome of hypotonia, nystagmus, psychomotor retardation, and pyramidal signs. Toward the end of their second year, both patients developed progressive quadriparesis, convulsions, and pseudobulbar palsy. Similar to two previously reported cases, one of the two affected siblings had severe hypertrophic obstructive cardiomyopathy, hearing loss, and no visual response. Through linkage analysis and whole-exome sequencing, we identified a homozygous p.R217W mutation in Cytochrome C oxidase assembly protein COX15 homolog. Consistent with the known heterogeneity of mitochondrial diseases in general and that of LS in particular, several phenotypic features were markedly distinguished between the affected siblings and in relation to previous reports of COX15 mutations. Interestingly, of the previously reported five cases of COX15-mutated patients, all of different ethnic origins, three had a p.R217W mutation. We highlight p.R217W as a hotspot mutation in COX15 and delineate the phenotypic variability, both between the patients we describe and in all cases reported to date.

Comorbidity and health services' usage in children with autism spectrum disorder: a nested case-control study.

AIMS: Children with autism spectrum disorder (ASD) tend to suffer from various medical comorbidities. We studied the comorbidity burden and health services' utilisation of children with ASD to highlight potential aetiologies and to better understand the medical needs of these children. METHODS: In this nested case-control study, ASD cases and controls - matched by age, sex and ethnicity in a 1:5 ratio - were sampled from all children born between 2009 and 2016 at a tertiary medical centre. Data were obtained from the hospital's electronic database. Comorbid diagnoses were classified according to pathophysiological aetiology and anatomical/systemic classification of disease. Standard univariate and multivariate statistics were used to demonstrate comorbidities and health services' utilisation patterns that are significantly associated with ASD. RESULTS: ASD children had higher rates of comorbidities according to both pathophysiological and anatomical/systemic classifications (p < 0.001). The most marked significant differences were observed for: hearing impairments (OR = 4.728; 95% CI 2.207-10.127) and other auricular conditions (OR = 5.040; 95% CI 1.759-14.438); neurological (OR = 8.198; 95% CI 5.690-11.813) and ophthalmological (OR = 3.381; 95% CI 1.617-7.068) conditions; and ADD/ADHD (OR = 3.246; 95% CI 1.811-5.818). A subgroup analysis revealed a more profound case-control difference in anaemia rates among girls than in boys (OR = 3.25; 95% CI 1.04-10.19 v. OR = 0.74; 95% CI 0.33-1.64 respectively) and an opposite trend (larger differences in males than in females in cardiovascular diseases (OR = 1.99; 95% CI 1.23-3.23 v. OR = 0.76; 95% CI 0.17-3.45, respectively)). In addition, larger case-control differences were seen among Bedouin children than in Jewish children in a number of medical comorbidities (Breslow-Day test for homogeneity of odds ratio p-value <0.05). Finally, we found that children with ASD tended to be referred to the emergency department and to be admitted to the hospital more frequently than children without ASD, even after adjusting for their comorbidity burden (aOR = 1.28; 95% CI 1.08-1.50 and aOR = 1.28; 95% CI 1.11-1.47 for >1 referrals and admissions per year, respectively). CONCLUSIONS: The findings of this study contribute to the overall understanding of comorbid conditions and health services' utilisation for children with ASD. The higher prevalences of comorbidities and healthcare services' utilisation for children with ASD highlight the additional medical burden associated with this condition.

Language regression is associated with faster early motor development in children with autism spectrum disorder.

Language regression (LR) is a consistent and reproducible phenomenon that is reported by ~25% of parents who have children with autism spectrum disorder (ASD). However, there is controversy regarding the etiological and clinical significance of this phenomenon. Here, we examined data from a cohort of 218 children with ASD from the Negev Autism Center in Israel. We identified 36 children with ASD who were reported to exhibit clear LR by their parent on three independent occasions and compared them to 104 children whose parents did not report any concern of regression (NR). We compared a variety of key developmental characteristics across these two groups. We found that the age at which children with ASD in the LR group achieve key developmental milestones of crawling, walking, and use of first words is significantly younger than the age of children in the NR group, and comparable to the age of typically developing children. In contrast, no differences were observed in physical growth characteristics such as head circumference, weight, or height between the groups. Furthermore, almost all children with LR were born close to full term (>35 weeks) and none had a history of hypotonia. Notably, despite their apparently typical early development, children with LR were diagnosed with more severe symptoms of ASD than children with NR. These results strengthen the motivation to continue and study LR among children with ASD and suggest that early detection and intervention studies of ASD may benefit from stratifying children into LR and NR groups. Autism Res 2020, 13: 145-156. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: The presence of language regression (LR) among children with autism is still a matter of scientific debate. Here, we show that children with autism and reported LR start to crawl, talk, and walk at the same age as other typically developing children and significantly earlier than other children with autism. These findings, along with other medical differences between these groups, suggest that children who experienced LR comprise a distinct subgroup within the autism spectrum.

Reduced sleep pressure in young children with autism.

STUDY OBJECTIVES: Sleep disturbances and insomnia are highly prevalent in children with Autism Spectrum Disorder (ASD). Sleep homeostasis, a fundamental mechanism of sleep regulation that generates pressure to sleep as a function of wakefulness, has not been studied in children with ASD so far, and its potential contribution to their sleep disturbances remains unknown. Here, we examined whether slow-wave activity (SWA), a measure that is indicative of sleep pressure, differs in children with ASD. METHODS: In this case-control study, we compared overnight electroencephalogram (EEG) recordings that were performed during Polysomnography (PSG) evaluations of 29 children with ASD and 23 typically developing children. RESULTS: Children with ASD exhibited significantly weaker SWA power, shallower SWA slopes, and a decreased proportion of slow-wave sleep in comparison to controls. This difference was largest during the first 2 hours following sleep onset and decreased gradually thereafter. Furthermore, SWA power of children with ASD was significantly negatively correlated with the time of their sleep onset in the lab and at home, as reported by parents. CONCLUSIONS: These results suggest that children with ASD may have a dysregulation of sleep homeostasis that is manifested in reduced sleep pressure. The extent of this dysregulation in individual children was apparent in the amplitude of their SWA power, which was indicative of the severity of their individual sleep disturbances. We, therefore, suggest that disrupted homeostatic sleep regulation may contribute to sleep disturbances in children with ASD.

Children with autism observe social interactions in an idiosyncratic manner.

Previous eye-tracking studies have reported that children with autism spectrum disorders (ASD) fixate less on faces in comparison to controls. To properly understand social interactions, however, children must gaze not only at faces but also at actions, gestures, body movements, contextual details, and objects, thereby creating specific gaze patterns when observing specific social interactions. We presented three different movies with social interactions to 111 children (71 with ASD) who watched each of the movies twice. Typically developing children viewed the movies in a remarkably predictable and reproducible manner, exhibiting gaze patterns that were similar to the mean gaze pattern of other controls, with strong correlations across individuals (intersubject correlations) and across movie presentations (intra-subject correlations). In contrast, children with ASD exhibited significantly more variable/idiosyncratic gaze patterns that differed from the mean gaze pattern of controls and were weakly correlated across individuals and presentations. Most importantly, quantification of gaze idiosyncrasy in individual children enabled separation of ASD and control children with higher sensitivity and specificity than traditional measures such as time gazing at faces. Individual magnitudes of gaze idiosyncrasy were also significantly correlated with ASD severity and cognitive scores and were significantly correlated across movies and movie presentations, demonstrating clinical sensitivity and reliability. These results suggest that gaze idiosyncrasy is a potent behavioral abnormality that characterizes a considerable number of children with ASD and may contribute to their impaired development. Quantification of gaze idiosyncrasy in individual children may aid in assessing symptom severity and their change in response to treatments. Autism Res 2020, 13: 935-946. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Typically, developing children watch movies of social interactions in a reliable and predictable manner, attending faces, gestures, actions, body movements, and objects that are relevant to the social interaction and its narrative. Here, we demonstrate that children with ASD watch such movies with significantly more variable/idiosyncratic gaze patterns that differ across individuals and across movie presentations. We demonstrate that quantifying this gaze variability may aid in identifying children with ASD and in determining the severity of their symptoms.