1. Anderson KA, Hemmeter J, Wittenburg D, Baller J, Roux AM, Rast JE, Shattuck PT. National and State Trends in autistic Adult Supplemental Security Income Awardees: 2005-2019. Journal of autism and developmental disorders. 2021.

This paper used Social Security Administration program data from 2005 to 2019 to examine national- and state-level changes in the number of new adult supplemental security income (SSI) awardees on the autism spectrum relative to awardees with intellectual disability and other mental health disorders. We identified three main findings: the number of autistic awards increased between 2005 and 2019 when awards for all other mental health disorders declined; roughly nine out of every 10 autistic adult awardees were between ages 18-25 years; there was variation in the growth of autistic awards across states. These findings support the need to consider geographic and age differences in SSI program participation among autistic adults and determine the underlying causes.

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2. Avni I, Meiri G, Michaelovski A, Menashe I, Shmuelof L, Dinstein I. Basic oculomotor function is similar in young children with ASD and typically developing controls. Autism research : official journal of the International Society for Autism Research. 2021; 14(12): 2580-91.

A variety of eye tracking studies have demonstrated that young children with ASD gaze at images and movies of social interactions differently than typically developing children. These findings have supported the hypothesis that gaze behavior differences are generated by a weaker preference for social stimuli in ASD children. The hypothesis assumes that gaze differences are not caused by abnormalities in oculomotor function including saccade frequency and kinematics. Previous studies of oculomotor function have mostly been performed with school-age children, adolescents, and adults using visual search, anti-saccade, and gap saccade tasks that are less suitable for young pre-school children. Here, we examined oculomotor function in 144 children (90 with ASD and 54 controls), 1-10-years-old, as they watched two animated movies interleaved with the presentation of multiple salient stimuli that elicited saccades-to-targets. The results revealed that the number of fixations, fixation duration, number of saccades, saccade duration, saccade accuracy, and saccade latency did not differ significantly across groups. Minor initial differences in saccade peak velocity were not supported by analysis with a linear mixed model. These findings suggest that most children with ASD exhibit similar oculomotor function to that of controls, when performing saccades-to-targets or freely viewing child-friendly movies. This suggests that previously reported gaze abnormalities in children with ASD are not due to underlying oculomotor deficiencies. LAY SUMMARY: This study demonstrates that children with ASD perform similar eye movements to those of controls when freely observing movies or making eye movements to targets. Similar results were apparent across groups in the number of eye movements, their accuracy, duration, and other measures that assess eye movement control. These findings are important for interpreting previously reported differences in gaze behavior of children with ASD, which are likely due to atypical social preferences rather than impaired control of eye movements.

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3. Bahado-Singh RO, Vishweswaraiah S, Aydas B, Radhakrishna U. Artificial intelligence and placental DNA methylation: newborn prediction and molecular mechanisms of autism in preterm children. The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstet. 2021: 1-10.

BACKGROUND: Autism Spectrum Disorder (ASD) represents a heterogeneous group of disorders with a complex genetic and epigenomic etiology. DNA methylation is the most extensively studied epigenomic mechanism and correlates with altered gene expression. Artificial intelligence (AI) is a powerful tool for group segregation and for handling the large volume of data generated in omics experiments. METHODS: We performed genome-wide methylation analysis for differential methylation of cytosine nucleotide (CpG) was performed in 20 postpartum placental tissue samples from preterm births. Ten newborns went on to develop autism (Autistic Disorder subtype) and there were 10 unaffected controls. AI including Deep Learning (AI-DL) platforms were used to identify and rank cytosine methylation markers for ASD detection. Ingenuity Pathway Analysis (IPA) to identify genes and molecular pathways that were dysregulated in autism. RESULTS: We identified 4870 CpG loci comprising 2868 genes that were significantly differentially methylated in ASD compared to controls. Of these 431 CpGs met the stringent EWAS threshold (p-value <5 × 10(-8)) along with ≥10% methylation difference between CpGs in cases and controls. DL accurately predicted autism with an AUC (95% CI) of 1.00 (1-1) and sensitivity and specificity of 100% using a combination of 5 CpGs [cg13858611 (NRN1), cg09228833 (ZNF217), cg06179765 (GPNMB), cg08814105 (NKX2-5), cg27092191 (ZNF267)] CpG markers. IPA identified five prenatally dysregulated molecular pathways linked to ASD. CONCLUSIONS: The present study provides substantial evidence that epigenetic differences in placental tissue are associated with autism development and raises the prospect of early and accurate detection of the disorder.

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4. Barry L, Holloway J, Gallagher S, McMahon J. Teacher Characteristics, Knowledge and Use of Evidence-Based Practices in Autism Education in Ireland. Journal of autism and developmental disorders. 2021.

Autism evidence-based practices (EBPs) are those with demonstrated improved outcomes for students with autism across a range of skill areas, yet issues persist in adopting these in classroom settings- particularly in general education (GE) settings. This research aimed to identify teacher training, years of experience, access to allied professionals and knowledge and use of autism EBPs in GE settings in Ireland. 369 mainstream primary school teachers reported their characteristics and their knowledge and use of EBPs. Results indicated that the majority of teachers received little initial teacher education training in autism, almost no continuous professional development (CPD) before educating a child with autism, and received little support from allied professionals. Knowledge and use of EBPs differed significantly across teacher characteristics, with findings discussed in relation to teacher training.

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5. Blagojevic C, Heung T, Theriault M, Tomita-Mitchell A, Chakraborty P, Kernohan K, Bulman DE, Bassett AS. Estimate of the contemporary live-birth prevalence of recurrent 22q11.2 deletions: a cross-sectional analysis from population-based newborn screening. CMAJ open. 2021; 9(3): E802-e9.

BACKGROUND: Although pathogenic 22q11.2 deletions are an important cause of developmental delays and lifelong disease burden, their variable and complex clinical expression contributes to under-recognition, delayed molecular diagnosis and uncertainty about prevalence. We sought to estimate the contemporary live-birth prevalence of typical 22q11.2 deletions using a population-based newborn screening sample and to examine data available for associated clinical features. METHODS: Using DNA available from an unbiased sample of about 12% of all dried blood spots collected for newborn screening in Ontario between January 2017 and September 2018, we prospectively screened for 22q11.2 deletions using multiplex quantitative polymerase chain reaction assays and conducted independent confirmatory studies. We used cross-sectional analyses to compare available clinical and T-cell receptor excision circle (TREC, used in newborn screening for severe combined immunodeficiency) data between samples with and without 22q11.2 deletions. RESULTS: The estimated minimum prevalence of 22q11.2 deletions was 1 in 2148 (4.7 per 10 000) live births (95% confidence interval [CI] 2.5 to 7.8 per 10 000), based on a total of 30 074 samples screened, with 14 having confirmed 22q11.2 deletions. Of term singletons, samples with 22q11.2 deletions had significantly younger median maternal age (25.5 v. 32.0 yr, difference -6.5 yr, 95% CI -7 to -2 yr), a greater proportion with small birth weight for gestational age (odds ratio 7.00, 95% CI 2.36 to 23.18) and lower median TREC levels (108.9 v. 602.5 copies/3 μL, p < 0.001). INTERPRETATION: These results indicate that the 22q11.2 deletion syndrome is one of the most common of rare genetic conditions and may be associated with relatively younger maternal ages and with prenatal growth abnormalities. The findings support the public health importance of early - prenatal and neonatal - diagnosis that would enable prompt screening for and management of well-known actionable features associated with 22q11.2 deletions.

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6. Castro MAA, Dos Santos JHV, Honjo RS, Yamamoto GL, Bertola DR, Hurst AC, Chorich LP, Layman LC, Kim CA, Kim HG. Twenty-year follow-up of the facial phenotype of Brazilian patients with Sotos syndrome. American journal of medical genetics Part A. 2021; 185(12): 3916-23.

Sotos syndrome is characterized by overgrowth starting before birth through childhood with intellectual disability and craniofacial anomalies. The majority of patients are large for gestational age with developmental delay or intellectual disability. The majority of cases are caused by pathogenic variants in NSD1. The most consistent physical features in this disorder are facial dysmorphisms including prominent forehead, downslanted palpebral fissures, prognathism with a pointed chin, and a long and narrow face. We present a follow-up to a cohort of 11 individuals found to harbor heterozygous, pathogenic, or likely pathogenic variants in NSD1. We analyzed the facial dysmorphisms and the condition using retrospective over 20 years. Among these patients, followed in our medical genetics outpatient clinic for variable periods of time, all had a phenotype compatible with the characteristic Sotos syndrome facial features, which evolved with time and became superimposed with natural aging modifications. We present here a long-term follow-up of facial features of Brazilian patients with molecularly confirmed Sotos syndrome. In this largest Brazilian cohort of molecularly confirmed patients with Sotos syndrome to date, we provide a careful description of the facial phenotype, which becomes less pronounced with aging and possibly more difficult to recognize in adults. These results may have broad clinical implications for diagnosis and add to the global clinical delineation of this condition.

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7. Farag F, Sims A, Strudwick K, Carrasco J, Waters A, Ford V, Hopkins J, Whitlingum G, Absoud M, Kelly VB. Avoidant/restrictive food intake disorder and autism spectrum disorder: clinical implications for assessment and management. Developmental medicine and child neurology. 2022; 64(2): 176-82.

AIM: We examined clinical and neurodevelopmental presentations of children with avoidant/restrictive food intake disorder (ARFID) to inform clinical assessment and management. METHOD: Five hundred and thirty-six patients (mean age 6y 10mo, SD 3y 5mo, range 10mo-20y; 401 males, 135 females) seen by the tertiary multidisciplinary feeding service at the Evelina London Children’s Hospital between January 2013 and June 2019 were included in this case-control study. These children experienced significant feeding difficulties impacting nutrition, development, and psychosocial functioning requiring tertiary specialized input. Data on ARFID diagnosis, demographics, comorbidity, and nutrition was extracted from electronic patient records. RESULTS: Forty-nine per cent of children met ARFID criteria. The remaining participants had other difficulties including feeding, medical, and/or neurodevelopmental conditions. ARFID is more prevalent among younger patients (4-9 years) and in children with comorbid autism spectrum disorder (ASD). Younger age, comorbid ASD, and male sex significantly predicted ARFID. Diet range and male sex significantly predicted nutritional inadequacy, while comorbid ASD did not. A trend was seen between younger age and nutritional inadequacy. INTERPRETATION: Young children with ARFID should raise suspicion for ASD. Although significant nutritional deficiencies are common in children with comorbid ARFID and ASD, they are correctable with nutritional supplementation. Specialty perspective potentially limits generalizability of findings to community feeding services. We also emphasize the importance of early identification of nutritional deficits and management.

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8. Farini D, Marazziti D, Geloso MC, Sette C. Transcriptome programs involved in the development and structure of the cerebellum. Cellular and molecular life sciences : CMLS. 2021; 78(19-20): 6431-51.

In the past two decades, mounting evidence has modified the classical view of the cerebellum as a brain region specifically involved in the modulation of motor functions. Indeed, clinical studies and engineered mouse models have highlighted cerebellar circuits implicated in cognitive functions and behavior. Furthermore, it is now clear that insults occurring in specific time windows of cerebellar development can affect cognitive performance later in life and are associated with neurological syndromes, such as Autism Spectrum Disorder. Despite its almost homogenous cytoarchitecture, how cerebellar circuits form and function is not completely elucidated yet. Notably, the apparently simple neuronal organization of the cerebellum, in which Purkinje cells represent the only output, hides an elevated functional diversity even within the same neuronal population. Such complexity is the result of the integration of intrinsic morphogenetic programs and extracellular cues from the surrounding environment, which impact on the regulation of the transcriptome of cerebellar neurons. In this review, we briefly summarize key features of the development and structure of the cerebellum before focusing on the pathways involved in the acquisition of the cerebellar neuron identity. We focus on gene expression and mRNA processing programs, including mRNA methylation, trafficking and splicing, that are set in motion during cerebellar development and participate to its physiology. These programs are likely to add new layers of complexity and versatility that are fundamental for the adaptability of cerebellar neurons.

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9. Gutiérrez-Sacristán A, Sáez C, De Niz C, Jalali N, DeSain TN, Kumar R, Zachariasse JM, Fox KP, Palmer N, Kohane I, Avillach P. Multi-PheWAS intersection approach to identify sex differences across comorbidities in 59 140 pediatric patients with autism spectrum disorder. Journal of the American Medical Informatics Association : JAMIA. 2022; 29(2): 230-8.

OBJECTIVE: To identify differences related to sex and define autism spectrum disorder (ASD) comorbidities female-enriched through a comprehensive multi-PheWAS intersection approach on big, real-world data. Although sex difference is a consistent and recognized feature of ASD, additional clinical correlates could help to identify potential disease subgroups, based on sex and age. MATERIALS AND METHODS: We performed a systematic comorbidity analysis on 1860 groups of comorbidities exploring all spectrum of known disease, in 59 140 individuals (11 440 females) with ASD from 4 age groups. We explored ASD sex differences in 2 independent real-world datasets, across all potential comorbidities by comparing (1) females with ASD vs males with ASD and (2) females with ASD vs females without ASD. RESULTS: We identified 27 different comorbidities that appeared significantly more frequently in females with ASD. The comorbidities were mostly neurological (eg, epilepsy, odds ratio [OR] > 1.8, 3-18 years of age), congenital (eg, chromosomal anomalies, OR > 2, 3-18 years of age), and mental disorders (eg, intellectual disability, OR > 1.7, 6-18 years of age). Novel comorbidities included endocrine metabolic diseases (eg, failure to thrive, OR = 2.5, ages 0-2), digestive disorders (gastroesophageal reflux disease: OR = 1.7, 6-11 years of age; and constipation: OR > 1.6, 3-11 years of age), and sense organs (strabismus: OR > 1.8, 3-18 years of age). DISCUSSION: A multi-PheWAS intersection approach on real-world data as presented in this study uniquely contributes to the growing body of research regarding sex-based comorbidity analysis in ASD population. CONCLUSIONS: Our findings provide insights into female-enriched ASD comorbidities that are potentially important in diagnosis, as well as the identification of distinct comorbidity patterns influencing anticipatory treatment or referrals. The code is publicly available (https://github.com/hms-dbmi/sexDifferenceInASD).

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10. Llamosas N, Michaelson SD, Vaissiere T, Rojas C, Miller CA, Rumbaugh G. Syngap1 regulates experience-dependent cortical ensemble plasticity by promoting in vivo excitatory synapse strengthening. Proceedings of the National Academy of Sciences of the United States of America. 2021; 118(34).

A significant proportion of autism risk genes regulate synapse function, including plasticity, which is believed to contribute to behavioral abnormalities. However, it remains unclear how impaired synapse plasticity contributes to network-level processes linked to adaptive behaviors, such as experience-dependent ensemble plasticity. We found that Syngap1, a major autism risk gene, promoted measures of experience-dependent excitatory synapse strengthening in the mouse cortex, including spike-timing-dependent glutamatergic synaptic potentiation and presynaptic bouton formation. Synaptic depression and bouton elimination were normal in Syngap1 mice. Within cortical networks, Syngap1 promoted experience-dependent increases in somatic neural activity in weakly active neurons. In contrast, plastic changes to highly active neurons from the same ensemble that paradoxically weaken with experience were unaffected. Thus, experience-dependent excitatory synapse strengthening mediated by Syngap1 shapes neuron-specific plasticity within cortical ensembles. We propose that other genes regulate neuron-specific weakening within ensembles, and together, these processes function to redistribute activity within cortical networks during experience.

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11. Manzini A, Jones EJH, Charman T, Elsabbagh M, Johnson MH, Singh I. Ethical dimensions of translational developmental neuroscience research in autism. Journal of child psychology and psychiatry, and allied disciplines. 2021; 62(11): 1363-73.

BACKGROUND: Since the 1990s, increasing research has been devoted to the identification of biomarkers for autism to help attain more objective diagnosis; enable early prediction of prognosis; and guide individualized intervention options. Early studies focused on the identification of genetic variants associated with autism, but more recently, research has expanded to investigate neurodevelopmental markers. While ethicists have extensively discussed issues around advances in autism genomics, much less ethical scrutiny has focused on research on early neurodevelopment and on the interventions being developed as a result. OBJECTIVES: We summarize the current state of the science on the identification of early markers for autism and its potential clinical applications, before providing an overview of the ethical issues arising from increasing understanding of children’s neurodevelopment in very early life. RESULTS: Advances in the understanding of brain and behavioral trajectories preceding later autism diagnosis raise ethical concerns around three themes: (a) New models for understanding autism; (b) Risks and benefits of early identification and intervention; and (c) Communication of early concerns to families. These ethical issues should be further investigated in research conducted in partnership with autistic people and their families. CONCLUSIONS: This paper highlights the need for ethical scrutiny of early neurodevelopmental research in autism. Scrutiny requires expertise and methods from the basic sciences and bioethics, as well as constructive collaborations among autistic people, their parents, and autism researchers to anticipate early interventions that serve the community’s interests and accommodate the varied experiences and preferences of people on the spectrum and their families.

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12. Montgomery L, Chondrogianni V, Fletcher-Watson S, Rabagliati H, Sorace A, Davis R. Measuring the Impact of Bilingualism on Executive Functioning Via Inhibitory Control Abilities in Autistic Children. Journal of autism and developmental disorders. 2021.

One factor that may influence how executive functions develop is exposure to more than one language in childhood. This study explored the impact of bilingualism on inhibitory control in autistic (n = 38) and non-autistic children (n = 51). Bilingualism was measured on a continuum of exposure to investigate the effects of language environment on two facets of inhibitory control. Behavioural control of motor impulses was modulated positively through increased bilingual exposure, irrespective of diagnostic status, but bilingual exposure did not significantly affect inhibition involving visual attention. The results partially support the hypothesis that bilingual exposure differentially affects components of inhibitory control and provides important evidence for families that bilingualism is not detrimental to their development.

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13. Paynter J, Sulek R, Trembath D, Keen D. Brief Report: Preliminary Finding for Using Weight-of-Evidence Graphical Information Sheets with Teachers to Correct Misinformation About Autism Practices. Journal of autism and developmental disorders. 2021.

The use of both empirically supported and unsupported practices by teachers is common with autistic students. In this study, strategies were used to reduce use of unsupported practices. First, specially-designed information sheets were shared with teachers about the evidence-base of two practices used in schools: one unsupported (sensory integration therapy [SIT]) and one supported (antecedent-based interventions [ABI]). A professional development program was then implemented to improve knowledge and use of ABI. The information sheets significantly reduced teacher support for SIT, however this was not maintained following professional development. Support for ABI remained unchanged across phases. The need for ongoing teacher professional development in replacing use of unsupported practices with more evidence-based approaches is discussed.

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14. Wittkopf S, Stroth S, Langmann A, Wolff N, Roessner V, Roepke S, Poustka L, Kamp-Becker I. Differentiation of autism spectrum disorder and mood or anxiety disorder. Autism : the international journal of research and practice. 2021: 13623613211039673.

Symptoms of mood and anxiety disorders overlap with symptoms of autism spectrum disorder, making the diagnostic process challenging. This study found that a combination of communicational deficits and unusual and/or inappropriate social overtures facilitates differentiation between autism spectrum disorder and mood and anxiety disorders. Furthermore, the results confirm the essential need of a behavioral observation with the Autism Diagnostic Observation Schedule in combination with a full Autism Diagnostic Interview-Revised to support diagnostic decisions.

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15. Zariffeh A, Youssef AS, Rizvi F, Lew LQ. Post Severe Acute Respiratory Syndrome Coronavirus 2 Infection Tremors in a Nonverbal Autistic Adolescent. Cureus. 2021; 13(7): e16296.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing coronavirus disease 2019 (COVID-19) pandemic in 2020 remains a major public health challenge until mass vaccination. The number of SARS-CoV-2 positive children aged 0-17 years has been increasing as older adults are vaccinated. Infected children tend to have less severe illness compared with adults, have predominantly respiratory or GI symptoms, or no symptoms. Children have an increased risk for multisystem inflammatory syndrome in children (MIS-C), which is unique. Neuropsychological complications of COVID-19 remain uncommon. Case reports and data from series exist. We report a case of tremors as sequelae of SARS-CoV-2 infection in a non-verbal adolescent with autism spectrum disorder (ASD).

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