Autism Research Foundation

Caregivers and families of autistic people have experienced stress and increase in demands due to the COVID‐19 pandemic that may have long‐term negative consequences for both their own and their children's mental health. A scoping review was conducted to identify pandemic related demands experienced by caregivers and families of autistic children and youth. The review also consolidated information on coping strategies and parenting‐related guidelines that have emerged to help parents meet these demands. Search strategies were approved by a research librarian and were conducted in peer‐reviewed and gray literature databases between May 2020 and February 2021. Additional resources were solicited through author networks and social media. All articles were published between December 2019 and February 2021. Article summaries were charted, and a thematic analysis was conducted with confirmation of findings with our knowledge users. Twenty‐three published articles and 14 pieces of gray literature were included in the review. The majority of articles characterized and highlighted the increase in demands on caregivers of autistic children and youth during the pandemic globally. Both quantitative and qualitative studies suggest that parents have experienced an increase in stress and mental health‐related symptoms during lockdown measures. Findings suggest that families are employing coping strategies, but there no evidence‐based supports were identified. The review highlighted the potential long‐term impact of prolonged exposure to increasing demands on the mental health and wellbeing of caregivers and families of autistic people, and pointed to a need for the rapid development and evaluation of flexible and timely support programs.Lay SummaryCaregivers and families of autistic children and youth have faced increased demands due to pandemic‐related lockdown measures. We reviewed the literature to outline sources of stress, links to their influence on caregiver mental health, and if support programs have emerged to help them. Our findings suggest a number of demands have increased caregivers' risk to mental health challenges, and their potential impact on family wellbeing. Ongoing development of evidence‐based supports of all families of autistic children and youth are needed.

SHANK genes code for scaffold proteins located at the post-synaptic density of glutamatergic synapses. In neurons, SHANK2 and SHANK3 have a positive effect on the induction and maturation of dendritic spines, whereas SHANK1 induces the enlargement of spine heads. Mutations in SHANK genes have been associated with autism spectrum disorders (ASD), but their prevalence and clinical relevance remain to be determined. Here, we performed a new screen and a meta-analysis of SHANK copy-number and coding-sequence variants in ASD. Copy-number variants were analyzed in 5,657 patients and 19,163 controls, coding-sequence variants were ascertained in 760 to 2,147 patients and 492 to 1,090 controls (depending on the gene), and, individuals carrying de novo or truncating SHANK mutations underwent an extensive clinical investigation. Copy-number variants and truncating mutations in SHANK genes were present in ∼1% of patients with ASD: mutations in SHANK1 were rare (0.04%) and present in males with normal IQ and autism; mutations in SHANK2 were present in 0.17% of patients with ASD and mild intellectual disability; mutations in SHANK3 were present in 0.69% of patients with ASD and up to 2.12% of the cases with moderate to profound intellectual disability. In summary, mutations of the SHANK genes were detected in the whole spectrum of autism with a gradient of severity in cognitive impairment. Given the rare frequency of SHANK1 and SHANK2 deleterious mutations, the clinical relevance of these genes remains to be ascertained. In contrast, the frequency and the penetrance of SHANK3 mutations in individuals with ASD and intellectual disability—more than 1 in 50—warrant its consideration for mutation screening in clinical practice.

Reports of unrelated individuals with autism spectrum disorder (ASD) and similar clinical features having overlapping de novo interstitial deletions at 2p15-p16.1 suggest that this region harbors a gene(s) important to the development of autism. We molecularly characterized two such deletions, selecting two genes in this region, exportin 1 (XPO1) and orthodenticle homolog 1 (OTX1) for association studies in three North American cohorts (Autism Spectrum Disorder - Canadian American Research Consortium (ASD-CARC), New York, and Autism Genetic Resource Exchange (AGRE)) and one Italian cohort (Società Italiana per la Ricerca e la Formazione sull'Autismo (SIRFA)) of families with ASD. In XPO1, rs6735330 was associated with autism in all four cohorts (P<0.05), being significant in ASD-CARC cohorts (P-value following false discovery rate correction for multiple testing (P(FDR))=1.29 × 10(-5)), the AGRE cohort (P(FDR)=0.0011) and the combined families (P(FDR)=2.34 × 10(-9)). Similarly, in OTX1, rs2018650 and rs13000344 were associated with autism in ASD-CARC cohorts (P(FDR)=8.65 × 10(-7) and 6.07 × 10(5), respectively), AGRE cohort (P(FDR)=0.0034 and 0.015, respectively) and the combined families (P(FDR)=2.34 × 10(-9) and 0.00017, respectively); associations were marginal or insignificant in the New York and SIRFA cohorts. A significant association (P(FDR)=2.63 × 10(-11)) was found for the rs2018650G-rs13000344C haplotype. The above three SNPs were associated with severity of social interaction and verbal communication deficits and repetitive behaviors (P-values <0.01). No additional deletions were identified following screening of 798 ASD individuals. Our results indicate that deletion 2p15-p16.1 is not commonly associated with idiopathic ASD, but represents a novel contiguous gene syndrome associated with a constellation of phenotypic features (autism, intellectual disability, craniofacial/CNS dysmorphology), and that XPO1 and OXT1 may contribute to ASD in 2p15-p16.1 deletion cases and non-deletion cases of ASD mapping to this chromosome region.

Putatively benign copy number variants (bCNVs) can be broadly defined as DNA copy number gains or losses that do not lead to a recognizable clinical phenotype. Detection of bCNVs in genomes of clinically healthy individuals is increasing with the widespread use of whole genome arrays of different resolutions and the use of sequence comparison methods. However, the role of bCNVs in human disease susceptibility and phenotype diversity is mostly unknown. In order to explore a potential role of bCNVs in the susceptibility to and/or pathogenesis of human neurodevelopmental disorders we examined the frequency and type of common bCNVs (detected in ≥2 independent control studies) amongst 221 subjects with an autism spectrum disorder (ASD) and/or intellectual disability (ID) in comparison to 40 controls using three array platforms of increasing resolution (Spectral Genomics (1 Mb), Agilent (0.03 Mb) and NimbleGen (0.01 Mb)). We determined that the number of bCNVs/subject, type and frequency of most common bCNVs were similar for both the test and control cohorts when the same array platform was used. The comparison of the ‘load’ of bCNVs (i.e. number/subject) to a standardized metric of phenotypic features (see de Vries et al., 2001) in 91 ASD subjects revealed that a phenotype score ≥4 is significantly more common (P < 0.05) in persons with an ASD having one or more bCNVs via 1 Mb array-CGH, whereas individuals without any recognizable bCNVs are significantly more likely to have a less complex phenotype and a score ≤3. Finally, we report 14 CNVs found amongst our ASD and ID cohorts that are infrequent in neurodevelopmentally normal controls and are of familial origin, thus comprising rare CNVs of unknown significance. Two of these rare familial bCNVs revealed variation in size when transmitted from parent to child, indicating genomic instability. The ongoing discovery and correlation of the pathogenic versus putatively benign underpinnings of the human genome, its inherent variability and potential gene, positional and epigenetic influences will continue to improve our understanding of genome plasticity and its influences on human neurodevelopmental disorders.