Prevalence of four Mendelian disorders associated with autism in 2392 affected families

Saskin, Avi; Fulginiti, Vanessa; Birch, Ashley H.; Trakadis, Yannis

doi:10.1038/jhg.2017.16

Cited by 11 publications

(15 citation statements)

References 17 publications

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“…Reduced cholesterol levels occur in Smith-Lemli-Opitz syndrome which is caused by the decreased function of 7-dehydrocholesterol reductase, an enzyme catalyzing the last step of cholesterol synthesis 54 . Out of many symptoms associated with this syndrome, numerous patients present with autistic behavioural characteristics 55 . Interestingly, autism can be associated with NMDAR mutations which decrease NMDAR function 56 .…”

Section: Discussionmentioning

confidence: 99%

Cholesterol modulates presynaptic and postsynaptic properties of excitatory synaptic transmission

Kořı́nek

González‐González

Smejkalová

et al. 2020

Sci Rep

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Cholesterol is a structural component of cellular membranes particularly enriched in synapses but its role in synaptic transmission remains poorly understood. We used rat hippocampal cultures and their acute cholesterol depletion by methyl-β-cyclodextrin as a tool to describe the physiological role of cholesterol in glutamatergic synaptic transmission. Cholesterol proved to be a key molecule for the function of synapses as its depletion resulted in a significant reduction of both NMDA receptor (NMDAR) and AMPA/kainate receptor-mediated evoked excitatory postsynaptic currents (eEPSCs), by 94% and 72%, respectively. We identified two presynaptic and two postsynaptic steps of synaptic transmission which are modulated by cholesterol and explain together the above-mentioned reduction of eEPSCs. In the postsynapse, we show that physiological levels of cholesterol are important for maintaining the normal probability of opening of NMDARs and for keeping NMDARs localized in synapses. In the presynapse, our results favour the hypothesis of a role of cholesterol in the propagation of axonal action potentials. Finally, cholesterol is a negative modulator of spontaneous presynaptic glutamate release. Our study identifies cholesterol as an important endogenous regulator of synaptic transmission and provides insight into molecular mechanisms underlying the neurological manifestation of diseases associated with impaired cholesterol synthesis or decomposition.

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Section: Discussionmentioning

confidence: 99%

Cholesterol modulates presynaptic and postsynaptic properties of excitatory synaptic transmission

Kořı́nek

González‐González

Smejkalová

et al. 2020

Sci Rep

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“…Next-generation sequencing (NGS) methods revolutionized ASD gene discovery and have also substantially contributed to functional genetic data, linking mutations frequently associated with ASD with genes involved in the regulation of brain transcriptional networks during brain development and early synaptogenesis, thus throwing some light on the understanding of the neurobiological consequences of the disruption of these ASD-associated genes [12,15]. Nevertheless, also single-genes syndromes have been associated with ASD, including Fragile-X (FMR1), Tuberous Sclerosis Complex (TSC1-2) and PTEN syndrome [16,17].…”

Section: Introductionmentioning

confidence: 99%

Risk and Protective Environmental Factors Associated with Autism Spectrum Disorder: Evidence-Based Principles and Recommendations

Gialloreti

Mazzone

Benvenuto

et al. 2019

JCM

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Autism Spectrum Disorder (ASD) is a complex condition with early childhood onset, characterized by a set of common behavioral features. The etiology of ASD is not yet fully understood; however, it reflects the interaction between genetics and environment. While genetics is now a well-established risk factor, several data support a contribution of the environment as well. This paper summarizes the conclusions of a consensus conference focused on the potential pathogenetic role of environmental factors and on their interactions with genetics. Several environmental factors have been discussed in terms of ASD risk, namely advanced parental age, assisted reproductive technologies, nutritional factors, maternal infections and diseases, environmental chemicals and toxicants, and medications, as well as some other conditions. The analysis focused on their specific impact on three biologically relevant time windows for brain development: the periconception, prenatal, and early postnatal periods. Possible protective factors that might prevent or modify an ASD trajectory have been explored as well. Recommendations for clinicians to reduce ASD risk or its severity have been proposed. Developments in molecular biology and big data approaches, which are able to assess a large number of coexisting factors, are offering new opportunities to disentangle the gene–environment interplay that can lead to the development of ASD.

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“…Probes used to target 44 ASD candidate genes 3 (2495) 2 (M) Unknown Unknown N/A ASD Non-verbal IQ = 50, 33, 77 0.56 *Orrico et al (2009), Italy [ 56 ] Patients referred for genetic counselling due to macrocephaly associated with cognitive and behavioural impairment with or without features of ASD. 3 (40) 2 (M) 5–9 years Vineland Adaptive Behaviour Scales and Childhood Autism Rating Scale (CARS) Classification of ASD based on CARS Moderately impaired communication, daily living skills, social interaction and motor skills ( n = 1), severe ASD ( n = 1), overall low adaptive behaviour and communication, daily living skills, socialisation and motor skills ( n = 1) 0.78 *Saskin et al (2017), USA [ 57 ] Analysis of whole-exome data from National Database for Autism Research. 6 (2392 families) Unknown Unknown Unknown ASD classification (further details unknown) ASD ( n = 2) and developmental delay ( n = 1) 0.56 *Varga et al (2009), USA [ 58 ] Search of medical records of a list of patients who had clinical PTEN gene sequencing ordered between January 1, 2005, and December 31, 2007, at a children’s hospital.…”

Section: Resultsmentioning

confidence: 99%

“…Group B papers ( N = 12) reported on a total of 5353 participants, including data from two large prevalence studies: O’Roak et al and Saskin et al [ 55 , 57 ]. A total of 56 participants in these papers (1.0%) had a confirmed PTEN mutation or diagnosis of PHTS (confirmed number of cases ranged from three to 11 per paper), with age ranging from 1.6 to 35 years.…”

Section: Resultsmentioning

confidence: 99%

Behavioural and psychological features of PTEN mutations: a systematic review of the literature and meta-analysis of the prevalence of autism spectrum disorder characteristics

Cummings

Watkins

Jones

et al. 2022

J Neurodevelop Disord

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Background Phosphatase and tensin homologue (PTEN) is a cancer suppressor gene. Constitutional mutations affecting this gene are associated with several conditions, collectively termed PTEN hamartoma tumour syndromes (PHTS). In addition to hamartomas, PTEN aberrations have been associated with a range of non-tumoural phenotypes such as macrocephaly, and research indicates possibly increased rates of developmental delay and autism spectrum disorder (ASD) for people with germline mutations affecting PTEN. Method A systematic review of literature reporting behavioural and psychological variables for people with constitutional PTEN mutations/PHTS was conducted using four databases. Following in-depth screening, 25 articles met the inclusion criteria and were used in the review. Fourteen papers reported the proportion of people with PTEN mutations/PTHS meeting criteria for or having characteristics of ASD and were thus used in a pooled prevalence meta-analysis. Results Meta-analysis using a random effects model estimated pooled prevalence of ASD characteristics at 25% (95% CI 16–33%), although this should be interpreted cautiously due to possible biases in existing literature. Intellectual disability and developmental delay (global, motor and speech and language) were also reported frequently. Emotional difficulties and impaired cognitive functioning in specific domains were noted but assessed/reported less frequently. Methods of assessment of psychological/behavioural factors varied widely (with retrospective examination of medical records common). Conclusions Existing research suggests approximately 25% of people with constitutional PTEN mutations may meet criteria for or have characteristics of ASD. Studies have also begun to establish a range of possible cognitive impairments in affected individuals, especially when ASD is also reported. However, further large-scale studies are needed to elucidate psychological/behavioural corollaries of this mutation, and how they may relate to physiological/physical characteristics.

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Prevalence of four Mendelian disorders associated with autism in 2392 affected families

Cited by 11 publications

References 17 publications

Cholesterol modulates presynaptic and postsynaptic properties of excitatory synaptic transmission

Cholesterol modulates presynaptic and postsynaptic properties of excitatory synaptic transmission

Risk and Protective Environmental Factors Associated with Autism Spectrum Disorder: Evidence-Based Principles and Recommendations

Behavioural and psychological features of PTEN mutations: a systematic review of the literature and meta-analysis of the prevalence of autism spectrum disorder characteristics

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