Search

Fully understanding autism spectrum disorder (ASD) genetics requires whole-genome sequencing (WGS). We present the latest release of the Autism Speaks MSSNG resource, which includes WGS data from 5,100 individuals with ASD and 6,212 non-ASD parents and siblings (total n = 11,312). Examining a wide variety of genetic variants in MSSNG and the Simons Simplex Collection (SSC; n = 9,205), we identified ASD-associated rare variants in 718/5,100 individuals with ASD from MSSNG (14.1%) and 350/2,419 from SSC (14.5%). Considering genomic architecture, 52% were nuclear sequence-level variants, 46% were nuclear structural variants (including copy-number variants, inversions, large insertions, uniparental isodisomies, and tandem repeat expansions), and 2% were mitochondrial variants. Our study provides a guidebook for exploring genotype-phenotype correlations in families who carry ASD-associated rare variants and serves as an entry point to the expanded studies required to dissect the etiology in the ∼85% of the ASD population that remain idiopathic.

Truncating variants in exons 33 and 34 of the SNF2-related CREBBP activator protein (SRCAP) gene cause the neurodevelopmental disorder (NDD) Floating-Harbor syndrome (FLHS), characterized by short stature, speech delay, and facial dysmorphism. Here, we present a cohort of 33 individuals with clinical features distinct from FLHS and truncating (mostly de novo) SRCAP variants either proximal (n = 28) or distal (n = 5) to the FLHS locus. Detailed clinical characterization of the proximal SRCAP individuals identified shared characteristics: developmental delay with or without intellectual disability, behavioral and psychiatric problems, non-specific facial features, musculoskeletal issues, and hypotonia. Because FLHS is known to be associated with a unique set of DNA methylation (DNAm) changes in blood, a DNAm signature, we investigated whether there was a distinct signature associated with our affected individuals. A machine-learning model, based on the FLHS DNAm signature, negatively classified all our tested subjects. Comparing proximal variants with typically developing controls, we identified a DNAm signature distinct from the FLHS signature. Based on the DNAm and clinical data, we refer to the condition as "non-FLHS SRCAP-related NDD." All five distal variants classified negatively using the FLHS DNAm model while two classified positively using the proximal model. This suggests divergent pathogenicity of these variants, though clinically the distal group presented with NDD, similar to the proximal SRCAP group. In summary, for SRCAP, there is a clear relationship between variant location, DNAm profile, and clinical phenotype. These results highlight the power of combined epigenetic, molecular, and clinical studies to identify and characterize genotype-epigenotype-phenotype correlations.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

PURPOSE: For neurodevelopmental disorders (NDDs), etiological evaluation can be a diagnostic odyssey involving numerous genetic tests, underscoring the need to develop a streamlined algorithm maximizing molecular diagnostic yield for this clinical indication. Our objective was to compare the yield of exome sequencing (ES) with that of chromosomal microarray (CMA), the current first-tier test for NDDs. METHODS: We performed a PubMed scoping review and meta-analysis investigating the diagnostic yield of ES for NDDs as the basis of a consensus development conference. We defined NDD as global developmental delay, intellectual disability, and/or autism spectrum disorder. The consensus development conference included input from genetics professionals, pediatric neurologists, and developmental behavioral pediatricians. RESULTS: After applying strict inclusion/exclusion criteria, we identified 30 articles with data on molecular diagnostic yield in individuals with isolated NDD, or NDD plus associated conditions (such as Rett-like features). Yield of ES was 36% overall, 31% for isolated NDD, and 53% for the NDD plus associated conditions. ES yield for NDDs is markedly greater than previous studies of CMA (15-20%). CONCLUSION: Our review demonstrates that ES consistently outperforms CMA for evaluation of unexplained NDDs. We propose a diagnostic algorithm placing ES at the beginning of the evaluation of unexplained NDDs.

Autism spectrum disorder (ASD) is genetically heterogeneous, with evidence for hundreds of susceptibility loci. Previous microarray and exome-sequencing studies have examined portions of the genome in simplex families (parents and one ASD-affected child) having presumed sporadic forms of the disorder. We used whole-genome sequencing (WGS) of 85 quartet families (parents and two ASD-affected siblings), consisting of 170 individuals with ASD, to generate a comprehensive data resource encompassing all classes of genetic variation (including noncoding variants) and accompanying phenotypes, in apparently familial forms of ASD. By examining de novo and rare inherited single-nucleotide and structural variations in genes previously reported to be associated with ASD or other neurodevelopmental disorders, we found that some (69.4%) of the affected siblings carried different ASD-relevant mutations. These siblings with discordant mutations tended to demonstrate more clinical variability than those who shared a risk variant. Our study emphasizes that substantial genetic heterogeneity exists in ASD, necessitating the use of WGS to delineate all genic and non-genic susceptibility variants in research and in clinical diagnostics., Evidence from twin and family studies suggests substantial heritability in ASD (1). Risk of recurrence in families is high, ranging from 12.9 (ref. 2) to 18.7% (ref. 3), suggesting that [...]

The Per family of genes functions as a primary circadian rhythm maintenance in the brain. Mutations in PER2 are associated with familial advanced sleep‐phase syndrome 1 (FASPS1), and recently suggested in delayed sleep phase syndrome and idiopathic hypersomnia. The detection of PER2 variants in individuals with autism spectrum disorder (ASD) and without reported sleep disorders, has suggested a role of circadian‐relevant genes in the pathophysiology of ASD. It remains unclear whether these individuals may have, in addition to ASD, an undiagnosed circadian rhythm sleep disorder. The MSSNG database was used to screen whole genome sequencing data of 5,102 individuals with ASD for putative mutations in PER2. Families identified were invited to complete sleep phenotyping consisting of a structured interview and two standardized sleep questionnaires: the Pittsburgh Sleep Quality Index and the Morningness‐Eveningness Questionnaire. From 5,102 individuals with ASD, two nonsense, one frameshift, and one de novo missense PER2 variants were identified (0.08%). Of these four, none had a diagnosed sleep disorder. Three reported either a history of, or ongoing sleep disturbances, and one had symptoms highly suggestive of FASPS1 (as did a mutation carrier father without ASD). The individual with the missense variant did not report sleep concerns. The ASD and cognitive profiles of these individuals varied in severity and symptoms. The results support a possible role of PER2‐related circadian rhythm disturbances in the dysregulation of sleep overall and sometimes FASPS1. The relationship between dysregulated sleep and the pathophysiology of ASD require further exploration. [ABSTRACT FROM AUTHOR]

Interpretation of pediatric chromosome microarray (CMA) results presents diagnostic and medical management challenges. Understanding management practices triggered by CMA will inform clinical utility and resource planning. Using a retrospective cohort design, we extracted clinical and management-related data from the records of 752 children with congenital anomalies and/or developmental delay who underwent CMA in an academic pediatric genetics clinic (2009-2011). Frequency distributions and relative rates (RR) of post-CMA medical recommendations in children with reportable and benign CMA results were calculated. Medical recommendations were provided for 79.6% of children with reportable results and 62.0% of children with benign results. Overall, recommendations included specialist consultation (40.8%), imaging (32.5%), laboratory investigations (17.2%), surveillance (4.6%), and family investigations (4.9%). Clinically significant variants and variants of uncertain clinical significance were associated with higher and slightly higher rates of management recommendations, respectively, compared with benign/no variants (RR=1.34; 95% CI (1.22-1.47); RR=1.23; 95% CI (1.09-1.38)). Recommendation rates for clinically significant versus uncertain results depended upon how uncertainty was classified (RRbroad=1.09; 95% CI (0.99-1.2); RRnarrow=1.12; 95% CI (1.02-1.24)). Recommendation rates also varied by the child's age and provider type. In conclusion, medical recommendations follow CMA for the majority of children. Compared with benign CMA results, clinically significant CMA variants are a significant driver of pediatric medical recommendations. Variants of uncertain clinical significance drive recommendations, but to a lesser extent. As a broadening range of specialists will need to respond to CMA results, targeted capacity building is warranted. [ABSTRACT FROM AUTHOR]

Background: Digital health literacy (DHL) enables healthy decisions, improves protective behaviors and adherence to COVID-19 measures, especially during the era of the "infodemic", and enhances psychological well-being., Objective: We aimed to explore the mediating roles of fear of COVID-19, information satisfaction, and the importance of online information searching on the association between DHL and well-being., Methods: A cross-sectional web-based survey was conducted among 1631 Taiwanese university students, aged 18 years and above, from June 2021 to March 2022. The collected data include sociodemographic characteristics (sex, age, social status, and financial satisfaction), the importance of online information searching, information satisfaction, fear of COVID-19, DHL, and well-being. A linear regression model was utilized to investigate factors associated with well-being, followed by a pathway analysis to assess the direct and indirect relationship between DHL and well-being., Results: The scores of DHL and overall well-being were 3.1 ±   0.4 and 74.4 ± 19.7, respectively. Social status (B = 2.40, 95% confidence interval (CI) 1.73-3.07, p  < 0.001), DHL (B 0.29, 95% CI 0.10-0.49, p  < 0.001), importance of online information searching (B = 0.78, 95% CI 0.38-1.17, p  < 0.001), and information satisfaction (B = 3.59, 95% CI 2.22-4.94, p  < 0.001) were positively associated with well-being, whereas higher fear of COVID-19 scores (B = -0.38, 95% CI -0.55-(-0.21), p  < 0.001) and female (B = -2.99, 95% CI -5.02-0.6, p  = 0.004) were associated with lower well-being, when compared with lower fear scores and male, respectively. Fear of COVID-19 (B = 0.03, 95% CI 0.016-0.04, p  < 0.001), importance of online information searching (B = 0.03, 95% CI 0.01-0.05, p  = 0.005), and information satisfaction (B = 0.05, 95% CI 0.023-0.067, p  < 0.001) were significantly mediated the relationship between DHL and well-being., Conclusion: Higher DHL scores show direct and indirect associations with higher well-being scores. Fear, importance of online information searching, and information satisfaction significantly contributed to the association., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Background: Health literacy (HL) has shown its important role on reducing the burden of heart diseases. However, no study has provided a comprehensive worldwide view of the data regarding HL and heart diseases. The study aimed to provide insight into: (1) the intellectual structure, (2) research trends, and (3) research gaps on HL and heart diseases; and (4) to explore HL scales commonly utilized in heart studies., Materials and Methods: Studies related to HL and heart diseases were retrieved from Web of Science, Scopus, and PubMed. All publications published between 2000 and 2021 were included after conducting keyword searches on "heart diseases" in general or on specific types of heart diseases (e.g., "heart failure") and "health literacy". Bibliometric analyses were carried out using the Bibliometrix R package and VOSviewer 1.6.14., Findings: A total of 388 original research articles and reviews on HL and heart diseases were included in our study. The studies were primarily conducted in the United States and developed countries. A total of 337 studies (86.9%) focused on heart failure (200 studies, 51.5%) and ischemic heart diseases (137 studies, 35.3%). Sixty-two studies (16.0%) focused on other heart diseases (e.g., valvular diseases and rheumatic heart diseases). The number of interventional studies was limited (52 studies, 13.4%) and fluctuated from 2000 to 2021. The most common questionnaires measuring health literacy among patients with heart diseases were the Test of Functional Health Literacy in Adults (TOFHLA), Short Test of Functional Health Literacy in Adults (STOFHLA), and Brief Health Literacy Screen (BHLS). Use of the eHealth Literacy Scale (eHEALS) has become the latest trend among patients with heart diseases., Conclusion: Health literacy and heart diseases were most often studied in the United States and developed countries. Several HL tools were used; eHEALS has been lately used in this field. These findings suggest the need to conduct more empirical studies on HL and heart diseases in different settings (e.g., developing or poor countries) and with different types of heart diseases (e.g., valvular and rheumatic disorders). Additionally, it is necessary to develop heart disease-specified HL scales for research and practice., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Huy, Truong, Hoang, Nguyen, Nguyen, Dang, Hsu, Huang, Chang, Shih, Carbone, Yang and Duong.)

Digital Health Literacy (DHL) helps online users with navigating the infodemic and co-existing conspiracy beliefs to avoid mental distress and maintain well-being. We aimed to investigate the association between DHL and future anxiety (FA); and examine the potential mediation roles of information satisfaction and fear of COVID-19 (F-CoV). A web-based cross-sectional survey was carried out among 1631 Taiwanese university students aged 18 years and above from June 2021 to March 2022. Data collected were socio-demographic characteristics (sex, age, social status, university location), information satisfaction, F-CoV, DHL and FA (using Future Dark scale). The linear regression model was used to explore factors associated with FA. The pathway analysis was further used to evaluate the direct and indirect relationship between DHL and FA. A higher score of DHL (B = -0.21; 95% CI, -0.37, -0.06; p = 0.006), and information satisfaction (B = -0.16; 95% CI, -0.24, -0.08; p < 0.001) were associated with a lower FA score, whereas a higher F-CoV score was associated with a higher FA score (B = 0.43; 95% CI, 0.36, 0.50; p < 0.001). DHL showed the direct impact (B = -0.1; 95% CI, -0.17, -0.04; p = 0.002) and indirect impact on FA as mediated by information satisfaction (B = -0.04; 95% CI, -0.06, -0.01; p = 0.002) and F-CoV (B = -0.06, 95% CI, -0.08, -0.04; p < 0.001). Strategic approaches to promote DHL, information satisfaction, lower F-CoV are suggested to reduce FA among students.