Neural Activity of 16p11.2 CNV Human and Mouse

Although rare in the population, individuals affected by deletions or duplications of DNA material at 16p11.2 chromosomal region (within the region ’11.2’ in the short arm of chromosome 16) are at higher risk of myriad clinical features and neurodevelopmental disorders including intellectual disability, developmental delays, and autism spectrum disorder. Whether inherited or appearing for the first time in the family, this 16p11.2 copy number variation (CNV) seems to impact on brain structure and function that may, in turn, drive the profile and severity of 16p11.2 associated phenotypes. As studies of 16p11.2 CNV brain function are scarce, the aim of this thesis is to investigate EEG activity in (human) 16p11.2 CNV carriers and parallel in-vivo electrophysiological activity in 16p11.2 deletion mouse model. Data-sharing platforms and collaborative efforts made it possible to access datasets of this rare population and analyse it for the purpose of this thesis. The thesis is comprised of three studies: 1) an investigation of visual-evoked neural variability, as measured by variability of intra-participant ERP and spectral power, and signal-to-noise ratio, in 16p11.2 CNV carriers; 2) a study of spontaneous neural activity, as measured by multi-scale entropy and conventional spectral power, in 16p11.2 deletion carriers; and 3) a study of spontaneous neural activity in 16p11.2 deletion mouse model. Neural variability was mostly higher in 16p11.2 deletion carriers relative to typical controls and 16p11.2 duplication carriers. Compared to typical controls, higher entropy was found in 16p11.2 deletion carriers and this was associated with certain psychiatric and behavioural traits, e.g., anxiety problems. The 16p11.2 deletion mice showed no group differences in neural activity compared to wild-type control mice. In conclusion, despite the lack of converging evidence from the mouse model, the collective 16p11.2 CNV human findings indicated that neural activity in 16p11.2 deletion carriers, especially, was altered and related to psychiatric traits found in 16p11.2 deletion carriers

Resources available for autism research in the big data era: a systematic review

Recently, there has been a move encouraged by many stakeholders towards generating big, open data in many areas of research. One area where big, open data is particularly valuable is in research relating to complex heterogeneous disorders such as Autism Spectrum Disorder (ASD). The inconsistencies of findings and the great heterogeneity of ASD necessitate the use of big and open data to tackle important challenges such as understanding and defining the heterogeneity and potential subtypes of ASD. To this end, a number of initiatives have been established that aim to develop big and/or open data resources for autism research. In order to provide a useful data reference for autism researchers, a systematic search for ASD data resources was conducted using the Scopus database, the Google search engine, and the pages on ‘recommended repositories’ by key journals, and the findings were translated into a comprehensive list focused on ASD data. The aim of this review is to systematically search for all available ASD data resources providing the following data types: phenotypic, neuroimaging, human brain connectivity matrices, human brain statistical maps, biospecimens, and ASD participant recruitment. A total of 33 resources were found containing different types of data from varying numbers of participants. Description of the data available from each data resource, and links to each resource is provided. Moreover, key implications are addressed and underrepresented areas of data are identified

Sensory Processing in Sotos Syndrome and Tatton-Brown Rahman Syndrome

Sotos syndrome (Sotos) and Tatton-Brown Rahman Syndrome (TBRS) are two of the most common overgrowth disorders associated with intellectual disability. Individuals with these syndromes tend to have similar cognitive profiles and high likelihood of autism symptomatology. However, whether and how sensory processing is affected is currently unknown. Parents/caregivers of 36 children with Sotos and 20 children with TBRS completed the Child Sensory Profile 2 (CSP-2) and the Sensory Behaviour Questionnaire (SBQ) along with other standardised questionnaires assessing autistic traits (SRS-2), ADHD traits (Conners 3), anxiety (SCAS-P) and adaptive behaviour (VABS-3). Sensory processing differences were clearly evident in both syndromes, though there was significant variation in both cohorts. SBQ data indicated that both the frequency and impact of sensory behaviour were more severe when compared to neurotypicals, with levels of sensory behaviour impact and frequency being similar to autistic children. CSP-2 data indicated 77% of children with Sotos and 85% children with TBRS displayed clear differences in sensory Registration (missing sensory input). Clear differences relating to Body Position (proprioceptive response to joint and muscle position; 79% Sotos; 90% TBRS) and Touch (somatosensory response to touch on skin; 56% Sotos; 60% TBRS) were also particularly prevalent. Correlation analyses demonstrated that in both syndromes sensory processing differences tend to be associated with difficulties relating to autistic traits, anxiety and some domains of ADHD. In Sotos, sensory processing differences were also associated with lower adaptive behaviour skills. This first detailed assessment of sensory processing, alongside other clinical features, in relatively large cohorts of children with Sotos and TBRS, demonstrates that sensory processing differences have a profound impact on everyday life

Reduced visual evoked potential amplitude in autism spectrum disorder, a variability effect?

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SOX11 variants cause a neurodevelopmental disorder with infrequent ocular malformations and hypogonadotropic hypogonadism and with distinct DNA methylation profile.

PURPOSE This study aimed to undertake a multidisciplinary characterization of the phenotype associated with SOX11 variants. METHODS Individuals with protein altering variants in SOX11 were identified through exome and genome sequencing and international data sharing. Deep clinical phenotyping was undertaken by referring clinicians. Blood DNA methylation was assessed using Infinium MethylationEPIC array. The expression pattern of SOX11 in developing human brain was defined using RNAscope. RESULTS We reported 38 new patients with SOX11 variants. Idiopathic hypogonadotropic hypogonadism was confirmed as a feature of SOX11 syndrome. A distinctive pattern of blood DNA methylation was identified in SOX11 syndrome, separating SOX11 syndrome from other BAFopathies. CONCLUSION SOX11 syndrome is a distinct clinical entity with characteristic clinical features and episignature differentiating it from BAFopathies

SOX11 variants cause a neurodevelopmental disorder with infrequent ocular malformations and hypogonadotropic hypogonadism and with distinct DNA methylation profile

PURPOSE: This study aimed to undertake a multidisciplinary characterization of the phenotype associated with SOX11 variants. METHODS: Individuals with protein altering variants in SOX11 were identified through exome and genome sequencing and international data sharing. Deep clinical phenotyping was undertaken by referring clinicians. Blood DNA methylation was assessed using Infinium MethylationEPIC array. The expression pattern of SOX11 in developing human brain was defined using RNAscope. RESULTS: We reported 38 new patients with SOX11 variants. Idiopathic hypogonadotropic hypogonadism was confirmed as a feature of SOX11 syndrome. A distinctive pattern of blood DNA methylation was identified in SOX11 syndrome, separating SOX11 syndrome from other BAFopathies. CONCLUSION: SOX11 syndrome is a distinct clinical entity with characteristic clinical features and episignature differentiating it from BAFopathies.RD&E staff can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted.Accepted version (6 month embargo), submitted versio