1. Beck KB, Northrup JB, Breitenfeldt KE, Porton S, Day TN, MacKenzie KT, Conner CM, Mazefsky CA. Stakeholder informed development of the Emotion Awareness and Skills Enhancement team-based program (EASE-Teams). Autism : the international journal of research and practice. 2022; 26(3): 586-600.

Emotion dysregulation (ED) impacts mental health symptoms and well-being in autistic individuals. In prior work, we developed the Emotion Awareness and Skills Enhancement (EASE) to improve emotion dysregulation with autistic adolescents (aged 12-17). The study team partnered with autistic individuals, their caregivers, and expert clinicians to adapt EASE for autistic adolescents and adults with co-occurring intellectual disability and autistic elementary-aged children, groups that often benefit from caregiver support in treatment. In three phases, we (1) gathered caregiver and expert feedback to adapt the original EASE program for autistic adults with intellectual disability, (2) revised the treatment after using it with six autistic adults with intellectual disability, and (3) tested the newly developed caregiver-client team-based treatment, called EASE-Teams, in a small group of 10 autistic individuals with and without intellectual disability (aged 7-25). Families found EASE-Teams to be acceptable and helpful. We found improvements in emotion dysregulation and mental health symptoms for autistic participants. Caregivers reported less stress from their child’s dysregulation after participating. These results show that EASE-Teams can be appropriate for different developmental and cognitive needs. Future studies will need to test the benefits of the treatment in community clinics.

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2. Bilches Medinas D, Malik S, Yıldız-Bölükbaşı E, Borgonovo J, Saaranen MJ, Urra H, Pulgar E, Afzal M, Contreras D, Wright MT, Bodaleo F, Quiroz G, Rozas P, Mumtaz S, Díaz R, Rozas C, Cabral-Miranda F, Piña R, Valenzuela V, Uyan O, Reardon C, Woehlbier U, Brown RH, Sena-Esteves M, Gonzalez-Billault C, Morales B, Plate L, Ruddock LW, Concha ML, Hetz C, Tolun A. Mutation in protein disulfide isomerase A3 causes neurodevelopmental defects by disturbing endoplasmic reticulum proteostasis. The EMBO journal. 2022; 41(2): e105531.

Recessive gene mutations underlie many developmental disorders and often lead to disabling neurological problems. Here, we report identification of a homozygous c.170G>A (p.Cys57Tyr or C57Y) mutation in the gene coding for protein disulfide isomerase A3 (PDIA3, also known as ERp57), an enzyme that catalyzes formation of disulfide bonds in the endoplasmic reticulum, to be associated with syndromic intellectual disability. Experiments in zebrafish embryos show that PDIA3(C57Y) expression is pathogenic and causes developmental defects such as axonal disorganization as well as skeletal abnormalities. Expression of PDIA3(C57Y) in the mouse hippocampus results in impaired synaptic plasticity and memory consolidation. Proteomic and functional analyses reveal that PDIA3(C57Y) expression leads to dysregulation of cell adhesion and actin cytoskeleton dynamics, associated with altered integrin biogenesis and reduced neuritogenesis. Biochemical studies show that PDIA3(C57Y) has decreased catalytic activity and forms disulfide-crosslinked aggregates that abnormally interact with chaperones in the endoplasmic reticulum. Thus, rare disease gene variant can provide insight into how perturbations of neuronal proteostasis can affect the function of the nervous system.

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3. Carthy E, Murphy D. Comorbid Autism Spectrum Disorder and Antisocial Personality Disorder in Forensic Settings. The journal of the American Academy of Psychiatry and the Law. 2021; 49(4): 462-9.

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4. Chandrasekhar T, Hu Q. Meeting the mental health needs of autistic college students: a survey of university and college counseling center clinicians. Journal of American college health : J of ACH. 2021: 1-7.

OBJECTIVE: University and college counseling centers (UCCCs) are a front-line support for the mental health needs of autistic students, though little is known about clinician attitudes, comfort level, and training in autism. PARTICIPANTS: 89 UCCC clinicians were recruited via email listservs. METHODS: The authors developed a survey which assessed attitudes, comfort level, and training in autism. RESULTS: The majority of clinicians (82.0%, n = 73) had interacted with autistic students in the past year, and reported high levels of comfort with treating anxiety and depression. However, a smaller number reported confidence in their ability to diagnose autism. Training on autism emerged as an important deficit, as 31.5% of the clinicians denied receiving training either in their educational program or the UCCC. CONCLUSIONS: In this pilot study, clinicians reported a discrepancy between self-reported levels of comfort with autistic college students and past training, highlighting continuing education as an important area for future intervention.

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5. Holingue C, Poku O, Pfeiffer D, Murray S, Fallin MD. Gastrointestinal concerns in children with autism spectrum disorder: A qualitative study of family experiences. Autism : the international journal of research and practice. 2021: 13623613211062667.

Gastrointestinal problems are common in the autism spectrum disorder community and may affect both the person with autism spectrum disorder and their families. However, little research is available on the experiences of families who have a child with both autism spectrum disorder and gastrointestinal symptoms. We held one-on-one interviews with 12 parents of children who had both autism spectrum disorder and gastrointestinal symptoms. We analyzed the raw text responses from these interviews and identified four main themes. First, parents shared that their children had trouble verbally communicating when they were experiencing gastrointestinal symptoms (Theme 1). This led parents to use bodily signs, such as changes in the stool, and non-verbal behaviors, such as irritability, to recognize when their child was having gastrointestinal symptoms. Next, gastrointestinal issues affected both the child’s well-being and their ability to attend class and extracurricular or social activities (Theme 2). The gastrointestinal issues also affected the family’s routines, overall well-being, and their ability to go out and do activities together as a family (Theme 3). Finally, parents often had challenges receiving accessible and quality healthcare for their child’s gastrointestinal problems (Theme 4). Together, these findings highlight the enormous burden that gastrointestinal symptoms have on the wellness of children with autism spectrum disorder and their families.

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6. Hua J, Barnett AL, Williams GJ, Dai X, Sun Y, Li H, Chen G, Wang L, Feng J, Liu Y, Zhang L, Zhu L, Weng T, Guan H, Gu Y, Zhou Y, Butcher A, Du W. Association of Gestational Age at Birth With Subsequent Suspected Developmental Coordination Disorder in Early Childhood in China. JAMA network open. 2021; 4(12): e2137581.

IMPORTANCE: It remains unknown whether children born at different degrees of prematurity, early term, and post term might have a higher risk of developmental coordination disorder (DCD) compared with completely full-term children (39-40 gestational weeks). OBJECTIVE: To differentiate between suspected DCD in children with different gestational ages based on a national representative sample in China. DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort study was conducted in China from April 1, 2018, to December 31, 2019. A total of 152 433 children aged 3 to 5 years from 2403 public kindergartens in 551 cities of China were included in the final analysis. A multilevel regression model was developed to determine the strength of association for different gestational ages associated with suspected DCD when considering kindergartens as clusters. MAIN OUTCOMES AND MEASURES: Children’s motor performance was assessed using the Little Developmental Coordination Disorder Questionnaire, completed by their parents. Gestational age was determined according to the mother’s medical records and divided into 7 categories: completely full term (39 to 40 weeks’ gestation), very preterm (<32 weeks), moderately preterm (32-33 weeks), late preterm (34-36 weeks), early term (37-38 weeks), late term (41 weeks), and post term (>41 weeks). RESULTS: A total of 152 433 children aged 3 to 5 years (mean [SD] age, 4.5 [0.8] years), including 80 370 boys (52.7%) and 72 063 girls (47.3%), were included in the study. There were 45 052 children (29.6%) aged 3 years, 59 796 (39.2%) aged 4 years, and 47 585 (31.2%) aged 5 years. Children who were born very preterm (odds ratio [OR], 1.35; 95% CI, 1.23-1.48), moderately preterm (OR, 1.18; 95% CI, 1.02-1.36), late preterm (OR, 1.24; 95% CI, 1.16-1.32), early term (OR, 1.11; 95% CI, 1.06-1.16), and post term (OR, 1.17; 95% CI, 1.07-1.27) were more likely to be classified in the suspected DCD category on the Little Developmental Coordination Disorder Questionnaire than completely full-term children after adjusting for the same characteristics. Additionally, there was no association with suspected DCD in younger (aged 3 years) early-term and postterm children by stratified analyses. CONCLUSIONS AND RELEVANCE: In this cohort study, every degree of prematurity at birth, early-term birth, and postterm birth were associated with suspected DCD when compared with full-term birth. These findings have important implications for understanding motor development in children born at different gestational ages. Long-term follow-up and rehabilitation interventions should be considered for children born early and post term.

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7. Johannessen J, Nærland T, Hope S, Torske T, Kaale A, Wirgenes KV, Malt E, Djurovic S, Rietschel M, Andreassen OA. Correction to: Attitudes among parents of persons with autism spectrum disorder towards information about genetic risk and future health. European journal of human genetics : EJHG. 2021.

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8. Lévy J, Cogan G, Maruani A, Maillard A, Dupont C, Drunat S, Rachid M, Atzori P, Delorme R, Jeyarajah S, Isidor B, Pichon O, Moradkhani K, Verloes A, Tabet AC. Rare and de novo duplications containing TCF20 are associated with a neurodevelopmental disorder. Clinical genetics. 2022; 101(3): 364-70.

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.

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9. Major S, Isaev D, Grapel J, Calnan T, Tenenbaum E, Carpenter K, Franz L, Howard J, Vermeer S, Sapiro G, Murias M, Dawson G. Shorter average look durations to dynamic social stimuli are associated with higher levels of autism symptoms in young autistic children. Autism : the international journal of research and practice. 2021: 13623613211056427.

Many studies of autism look at the differences in how autistic research participants look at certain types of images. These studies often focus on where research participants are looking within the image, but that does not tell us everything about how much they are paying attention. It could be useful to know more about how well autistic research participants can focus on an image with people in it, because those who can look at images of people for longer duration without stopping may be able to easily learn other skills that help them to interact with people. We measured how long autistic research participants watched the video without breaking their attention. The video sometimes had a person speaking, and at other times had toys moving and making sounds. We measured the typical amount of time autistic research participants could look at the video before they looked away. We found that research participants with more severe autism tended to look at the video for shorter amounts of time. The ability to focus without stopping may be related to social skills in autistic people.

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10. Rødgaard EM, Jensen K, Miskowiak KW, Mottron L. Childhood diagnoses in individuals identified as autistics in adulthood. Molecular autism. 2021; 12(1): 73.

BACKGROUND: Autism is a developmental condition, where symptoms are expected to occur in childhood, but a significant number of individuals are diagnosed with autism for the first time in adulthood. Here, we examine diagnoses given in childhood among individuals that are diagnosed with autism in adulthood, to investigate whether the late autism diagnosis might be explained by misdiagnosis in childhood or diagnostic overshadowing. METHODS: Through the Danish National Patient Registry, we identified individuals diagnosed with autism in adulthood (N = 2199), as well as a control sample with no records of an autism diagnosis (N = 460,798) and calculated how many had received different psychiatric or neurological diagnoses in childhood. RESULTS: We found that most childhood diagnoses were overrepresented in those with an adult autism diagnosis, and attention-deficit hyperactivity disorder, affective disorders, anxiety, and stress disorders were the most prevalent childhood conditions in this group. However, 69% of males and 61% of females with adult autism diagnoses were not found to have received any of the investigated diagnoses before 18 years of age, and most childhood diagnoses were given after the age of 12. LIMITATIONS: Milder to moderate cases of psychiatric conditions that have been solely treated by family physicians or school psychologists may not be fully included in our dataset. The study is based on data from the Danish health care system, and further research is needed to assess whether the findings can be generalized to other countries. CONCLUSION: A majority of those with an adult autism diagnosis had no records of having received any of the investigated diagnoses in childhood. In these cases, the late autism diagnosis is therefore unlikely to be explained by either misdiagnosis or overshadowing. This result is at odds with the prevailing notion that autistic symptoms tend to diminish with age. Therefore, further research is warranted to examine how and if early signs of autism may have manifested among these individuals, and how similar they are to autistic people diagnosed earlier in their development.

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11. Thorup E, Nyström P, Bölte S, Falck-Ytter T. What are you looking at? Gaze following with and without target objects in ASD and typical development. Autism : the international journal of research and practice. 2021: 13623613211061940.

During the first year of life, infants start to align their attention with that of other people. This ability is called joint attention and facilitates social learning and language development. Although children with autism spectrum disorder (ASD) are known to engage less in joint attention compared to other children, several experimental studies have shown that they follow other’s gaze (a requirement for visual joint attention) to the same extent as other children. In this study, infants’ eye movements were measured at age 10, 14, and 18 months while watching another person look in a certain direction. A target object was either present or absent in the direction of the other person’s gaze. Some of the infants were at elevated likelihood of ASD, due to having an older autistic sibling. At age 3 years, infants were assessed for a diagnosis of ASD. Results showed that infants who met diagnostic criteria at 3 years followed gaze to the same extent as other infants. However, they then looked back at the model faster than typically developing infants when no target object was present. When a target object was present, there was no difference between groups. These results may be in line with the view that directly after gaze following, infants with later ASD are less influenced by other people’s gaze when processing the common attentional focus. The study adds to our understanding of both the similarities and differences in looking behaviors between infants who later receive an ASD diagnosis and other infants.

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12. Viamontes CG, Castillo Gonzalez J, Najjar F, Cook EH. Maternal Duplication 15q11-13 Syndrome with Autism Spectrum Disorder: Mood Stabilization by Carbamazepine. Journal of child and adolescent psychopharmacology. 2022; 32(2): 122-6.

Objectives: Maternal 15q11-13 duplication syndrome (dup15q) is one of the most frequently observed and penetrant genetic abnormalities associated with autism spectrum disorder (ASD), and commonly presents with psychiatric symptoms and seizures. Although carbamazepine has been reported as effective in managing comorbid seizures in dup15q, it has not been reported to be used as a mood stabilizer in this population. Methods: We retrospectively reviewed the charts of five consecutive patients presenting with previously diagnosed dup15q and ASD seeking treatment for psychiatric symptoms and, in four of the patients, seizures. These were the only patients with dup15q treated with carbamazepine in the Neurodevelopmental Psychopharmacology Clinic at the University of Illinois at Chicago during the review period. Results: During treatment, carbamazepine was found to be more effective than other mood stabilizers in all five patients, and in one case a better antiepileptic. Symptoms consistent with bipolar mood disorder such as hyperactivity, impulsivity, irritability, mood lability, intrusiveness, and pressured speech were improved with carbamazepine in combination with other psychotropic medications. This improvement was greater than with other mood stabilizers, including oxcarbazepine, valproate, and lamotrigine. In one case, valproate paradoxically worsened symptoms. In three cases, anxiety was improved with carbamazepine when used in conjunction with other medications targeting anxiety. Conclusions: In treating five patients with dup15q, carbamazepine more effectively stabilized mood-related symptoms than alternative treatments. Prospective randomized controlled trials are necessary to confirm this observation.

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13. Wang X, Choi D, Roeder K. Constructing local cell-specific networks from single-cell data. Proceedings of the National Academy of Sciences of the United States of America. 2021; 118(51).

Gene coexpression networks yield critical insights into biological processes, and single-cell RNA sequencing provides an opportunity to target inquiries at the cellular level. However, due to the sparsity and heterogeneity of transcript counts, it is challenging to construct accurate gene networks. We develop an approach, locCSN, that estimates cell-specific networks (CSNs) for each cell, preserving information about cellular heterogeneity that is lost with other approaches. LocCSN is based on a nonparametric investigation of the joint distribution of gene expression; hence it can readily detect nonlinear correlations, and it is more robust to distributional challenges. Although individual CSNs are estimated with considerable noise, average CSNs provide stable estimates of networks, which reveal gene communities better than traditional measures. Additionally, we propose downstream analysis methods using CSNs to utilize more fully the information contained within them. Repeated estimates of gene networks facilitate testing for differences in network structure between cell groups. Notably, with this approach, we can identify differential network genes, which typically do not differ in gene expression, but do differ in terms of the coexpression networks. These genes might help explain the etiology of disease. Finally, to further our understanding of autism spectrum disorder, we examine the evolution of gene networks in fetal brain cells and compare the CSNs of cells sampled from case and control subjects to reveal intriguing patterns in gene coexpression.

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14. Zoghbi AW, Dhindsa RS, Goldberg TE, Mehralizade A, Motelow JE, Wang X, Alkelai A, Harms MB, Lieberman JA, Markx S, Goldstein DB. High-impact rare genetic variants in severe schizophrenia. Proceedings of the National Academy of Sciences of the United States of America. 2021; 118(51).

Extreme phenotype sequencing has led to the identification of high-impact rare genetic variants for many complex disorders but has not been applied to studies of severe schizophrenia. We sequenced 112 individuals with severe, extremely treatment-resistant schizophrenia, 218 individuals with typical schizophrenia, and 4,929 controls. We compared the burden of rare, damaging missense and loss-of-function variants between severe, extremely treatment-resistant schizophrenia, typical schizophrenia, and controls across mutation intolerant genes. Individuals with severe, extremely treatment-resistant schizophrenia had a high burden of rare loss-of-function (odds ratio, 1.91; 95% CI, 1.39 to 2.63; P = 7.8 × 10(-5)) and damaging missense variants in intolerant genes (odds ratio, 2.90; 95% CI, 2.02 to 4.15; P = 3.2 × 10(-9)). A total of 48.2% of individuals with severe, extremely treatment-resistant schizophrenia carried at least one rare, damaging missense or loss-of-function variant in intolerant genes compared to 29.8% of typical schizophrenia individuals (odds ratio, 2.18; 95% CI, 1.33 to 3.60; P = 1.6 × 10(-3)) and 25.4% of controls (odds ratio, 2.74; 95% CI, 1.85 to 4.06; P = 2.9 × 10(-7)). Restricting to genes previously associated with schizophrenia risk strengthened the enrichment with 8.9% of individuals with severe, extremely treatment-resistant schizophrenia carrying a damaging missense or loss-of-function variant compared to 2.3% of typical schizophrenia (odds ratio, 5.48; 95% CI, 1.52 to 19.74; P = 0.02) and 1.6% of controls (odds ratio, 5.82; 95% CI, 3.00 to 11.28; P = 2.6 × 10(-8)). These results demonstrate the power of extreme phenotype case selection in psychiatric genetics and an approach to augment schizophrenia gene discovery efforts.

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