Autism Spectrum Disorder Associated with Germline Heterozygous <i>PTEN</i> Mutations

Frazier, Thomas

doi:10.1101/cshperspect.a037002

Cited by 28 publications

(25 citation statements)

References 114 publications

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“…We found duplications at 16p13.3 in two female children with ASD. PTEN loss involved in white matter pathology in human with ASD is consistent with in mouse models of Pten loss [62]. We revealed that deletions at 10q23.2-q23.31 overlapping PTEN in 13 male children with ASD, rather than 3 female children with ASD.…”

Section: Discussionsupporting

confidence: 81%

Nexus Between Genome-Wide Copy Number Variations and Autism Spectrum Disorder in Northeast Han Chinese Population

Qiu

Cong

et al. 2021

Preprint

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Background: Autism spectrum disorder (ASD) is a common neurodevelopmental condition, with an increasing prevalence worldwide. Copy number variation (CNV), as one of genetic factors, is involved in ASD etiology. However, there exist substantial differences in terms of location and frequency of some CNVs in the general Asian population. Whole-genome studies of CNVs in Northeast Han Chinese samples are still lacking, necessitating our ongoing work to investigate the characteristics of CNVs in a Northeast Han Chinese population with clinically diagnosed ASD.Methods: We performed a genome-wide CNVs screening in Northeast Han Chinese individuals with ASD using array-based comparative genomic hybridization.Results: We found 22 kinds of CNVs (six deletions and 16 duplications) were potential pathogenic. These CNVs were distributed in chromosome 1p36.33, 1p36.31, 1q42.13, 2p23.1-p22.3, 5p15.33, 5p15.33-p15.2, 7p22.3, 7p22.3-p22.2, 7q22.1-q22.2, 10q23.2-q23.31, 10q26.2-q26.3, 11p15.5, 11q25, 12p12.1-p11.23, 14q11.2, 15q13.3, 16p13.3, 16q21, 22q13.31-q13.33, and Xq12-q13.1. Additionally, we found 20 potential pathogenic genes of ASD in our population, including eight protein coding genes (six duplications [DRD4, HRAS, OPHN1, SHANK3, SLC6A3, and TSC2] and two deletions [CHRNA7 and PTEN]) and 12 microRNAs genes (ten duplications [MIR202, MIR210, MIR3178, MIR339, MIR4516, MIR4717, MIR483, MIR675, MIR6821, and MIR940] and two deletions [MIR107 and MIR558]).Limitations: The sample size in our study may confer limited statistical power to discover significant findings. De novo or inherited of the CNVs were not be classified because of the lack of data from parents.Conclusions: We identified CNVs and genes implicated in ASD risks, conferring perception to further reveal ASD etiology.

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Section: Discussionsupporting

confidence: 81%

Nexus Between Genome-Wide Copy Number Variations and Autism Spectrum Disorder in Northeast Han Chinese Population

Qiu

Cong

et al. 2021

Preprint

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“…PTEN mutations were associated with autism spectrum disorder (ASD) 65 , 66 and found in about 2% of total ASD patients 67 . A current model suggests PTEN mutation-induced increase of dendritic branching in PFC may disrupt the brain connectivity and then cause ASD-related neurobehavioral deficits 68 . We showed that knockout of PTEN in individual neurons led to hypertrophy (Fig.…”

Section: Discussionmentioning

confidence: 99%

PTEN in prefrontal cortex is essential in regulating depression-like behaviors in mice

et al. 2021

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Chronic stress is an environmental risk factor for depression and causes neuronal atrophy in the prefrontal cortex (PFC) and other brain regions. It is still unclear about the molecular mechanism underlying the behavioral alterations and neuronal atrophy induced by chronic stress. We here report that phosphatase and tensin homolog deleted on chromosome ten (PTEN) is a mediator for chronic stress-induced depression-like behaviors and neuronal atrophy in mice. One-month chronic restraint stress (CRS) up-regulated PTEN signaling pathway in the PFC of mice as indicated by increasing levels of PTEN, p-MEK, and p-ERK but decreasing levels of p-AKT. Over-expression of Pten in the PFC led to an increase of depression-like behaviors, whereas genetic inactivation or knockdown of Pten in the PFC prevented the CRS-induced depression-like behaviors. In addition, systemic administration of PTEN inhibitor was also able to prevent these behaviors. Cellular examination showed that Pten over-expression or the CRS treatment resulted in PFC neuron atrophy, and this atrophy was blocked by genetic inactivation of Pten or systemic administration of PTEN inhibitor. Furthermore, possible causal link between Pten and glucocorticoids was examined. In chronic dexamethasone (Dex, a glucocorticoid agonist) treatment-induced depression model, increased PTEN levels were observed, and depression-like behaviors and PFC neuron atrophy were attenuated by the administration of PTEN inhibitor. Our results indicate that PTEN serves as a key mediator in chronic stress-induced neuron atrophy as well as depression-like behaviors, providing molecular evidence supporting the synaptic plasticity theory of depression.

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“…103 Similarly, several genetic syndromes associated with ASD have specific cooccurring medical conditions with treatment implications 104 or that require ongoing surveillance, 105 such as cancer surveillance in individuals with ASD who have germline heterozygous PTEN mutations. 106 This points to an opportunity to continue to identify and characterize underlying genomic profiles of ASD (and associated comorbidities) with the potential to personalize ongoing treatment plans.…”

Section: The Future Of Asd Screening Diagnosis and Treatmentmentioning

confidence: 99%

Tackling healthcare access barriers for individuals with autism from diagnosis to adulthood

Malik-Soni¹,

Shaker²,

Luck³

et al. 2021

Pediatr Res

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148

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Most individuals with autism spectrum disorder (ASD)-a complex, life-long developmental disorder-do not have access to the care required to address their diverse health needs. Here, we review: (1) common barriers to healthcare access (shortage/cost of services; physician awareness; stigma); (2) barriers encountered primarily during childhood (limited screening/diagnosis; unclear referral pathways), transition to adulthood (insufficient healthcare transition services; suboptimal physician awareness of healthcare needs) and adulthood (shortage of services/limited insurance; communication difficulties with physicians; limited awareness of healthcare needs of aging adults); and (3) advances in research/program development for better healthcare access. A robust understanding of barriers to accessing healthcare across the lifespan of autistic individuals is critical to ensuring the best use of healthcare resources to improve social, physical, and mental health outcomes. Stakeholders must strengthen healthcare service provision by coming together to: better understand healthcare needs of underserved populations; strengthen medical training on care of autistic individuals; increase public awareness of ASD; promote research into/uptake of tools for ASD screening, diagnosis, and treatment; understand specific healthcare needs of autistic individuals in lower resource countries; and conduct longitudinal studies to understand the lifetime health, social, and economic impacts of ASD and enable the evaluation of novel approaches to increasing healthcare access.

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Autism Spectrum Disorder Associated with Germline Heterozygous PTEN Mutations

Cited by 28 publications

References 114 publications

Nexus Between Genome-Wide Copy Number Variations and Autism Spectrum Disorder in Northeast Han Chinese Population

Nexus Between Genome-Wide Copy Number Variations and Autism Spectrum Disorder in Northeast Han Chinese Population

PTEN in prefrontal cortex is essential in regulating depression-like behaviors in mice

Tackling healthcare access barriers for individuals with autism from diagnosis to adulthood

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