GABA/Glutamate synaptic pathways targeted by integrative genomic and electrophysiological explorations distinguish autism from intellectual disability

Bonnet‐Brilhault, Frédérique; Alirol, Servane; Blanc, R.; Bazaud, S; Marouillat, Sylviane; Thépault, R-A; Andres, Christian R.; Lemonnier, Éric; Barthélémy, Catherine; Raynaud, Martine; Toutain, Annick; Gomot, Marie; Laumonnier, Frédéric

doi:10.1038/mp.2015.75

Cited by 31 publications

(20 citation statements)

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“…42,43 The 800 kb deletion at Xp22.32 (containing NLGN4X) in the male subject 19303-30889 is supported by multiple reports of damaging variants in NLGN4X in ASD probands. 44,45 Literature reports and/or other ASD sequencing efforts, in combination with our confirmation of concordance to published phenotype, supported the potential pathogenic relevance of several of the highranking variants in probands for whom we did not have both parental DNA samples available ( Table 2 and File S8). All the variants in Table 2 are predicted to be damaging and have an ExAC frequency of zero.…”

Section: Discussionsupporting

confidence: 81%

“…The involvement of a 627 kb de novo 16p11.2 duplication in the ASD etiology of the female subject 15554‐26282 is supported by the multiple 16p11.2 duplications and deletions that have been previously found in ASD probands . The 800 kb deletion at Xp22.32 (containing NLGN4X ) in the male subject 19303‐30889 is supported by multiple reports of damaging variants in NLGN4X in ASD probands …”

Section: Discussionmentioning

confidence: 75%

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Whole genome sequencing and variant discovery in the ASPIRE autism spectrum disorder cohort

et al. 2019

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Autism spectrum disorder (ASD) is a highly heterogeneous genetic disorder with strong evidence of ASD‐association currently available only for a small number of genes. This makes it challenging to identify the underlying genetic cause in many cases of ASD, and there is a continuing need for further discovery efforts. We sequenced whole genomes of 119 deeply phenotyped ASD probands in order to identify likely pathogenic variants. We prioritized variants found in each subject by predicted damage, population frequency, literature evidence, and phenotype concordance. We used Sanger sequencing to determine the inheritance status of high‐priority variants where possible. We report five novel de novo damaging variants as well as several likely damaging variants of unknown inheritance; these include two novel de novo variants in the well‐established ASD gene SCN2A. The availability of rich phenotypic information and its concordance with the literature allowed us to increase our confidence in pathogenicity of discovered variants, especially in probands without parental DNA. Our results contribute to the documentation of potential pathogenic variants and their associated phenotypes in individuals with ASD.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 75%

Whole genome sequencing and variant discovery in the ASPIRE autism spectrum disorder cohort

et al. 2019

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“…Neurophysiological endophenotypes are known to be relevant for genotype/phenotype correlation studies. Regarding ASD research, atypical mismatch negativity of auditory evoked potential (MMN) has been proposed as a candidate endophenotype 11 , distinguishing autism from intellectual disablity 12 . Another component of auditory evoked potential (i.e., N250 amplitude component) has been reported to be correlated with language abilities 13 .…”

Section: Introductionmentioning

confidence: 99%

22q13 deletion syndrome: communication disorder or autism? Evidence from a specific clinical and neurophysiological phenotype

et al. 2018

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Phelan–McDermid syndrome is related to terminal 22q13 deletions of various sizes affecting the SHANK3 gene. In this neurodevelopmental disorder, behavioural symptoms of autism spectrum disorder (ASD) are reported in half of cases. Extensive clinical and neurophysiological characterization is lacking to understand the genotype–phenotype correlation. Eighteen patients (8 males, mean age 12.7 years, SD = 9.2) with known 22q13 deletions were fully explored with determination of deletion size, along with behavioural, language and cognitive standardized assessments. Neurophysiological indices previously reported to be altered in autism (i.e., eye tracking in a social/non-social task and auditory evoked potential mismatch) were also recorded. Thirty-nine percent met ASD clinical criteria, exceeding cut-off scores on both ADI-R (Autism Diagnosis Interview based on the period spanning 4–5 years of age) and ADOS-2 (Autism Diagnosis Observation Schedule for the current period). All patients had intellectual disability and language disability. Deletion size was significantly correlated with expressive and receptive language disability but not with ASD standardized assessment scores. Developmental Quotient tended to be lower in patients with the largest deletions. Using Eye Tracking, smaller pupil size, which is typically described in ASD, was not observed in these patients. Furthermore, atypical shortened latency of mismatch negativity response previously reported in ASD was not observed, whereas the N250 pattern, related to language, was affected. Language disability combined with cognitive deficits may lead to autistic behavioural symptoms, but with different neurophysiological networks compared to typical autism. These results highlight the indication for early speech therapy rather than intensive autism programme to treat these patients.

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“…Individuals with mutations of NLGN4X-coding genes, expressed in inhibitory and excitatory synapses(84), were more likely to exhibit ASD and showed abnormal ERP to auditory deviance detection. In Fragile X syndrome, both auditory and visual ERP amplitudes were increased(85).…”

Section: Electrophysiology and Magnetoencephalographymentioning

confidence: 99%

Searching for Cross-Diagnostic Convergence: Neural Mechanisms Governing Excitation and Inhibition Balance in Schizophrenia and Autism Spectrum Disorders

Foss‐Feig

Adkinson

et al. 2017

Biological Psychiatry

247

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Recent theoretical accounts have proposed excitation (E) and inhibition (I) imbalance as a possible mechanistic, network-level hypothesis underlying neural and behavioral dysfunction across neurodevelopmental disorders, particularly autism spectrum disorder (ASD) and schizophrenia (SCZ). These two disorders share some overlap in their clinical presentation as well as convergence in their underlying genes and neurobiology. However, there are also clear points of dissociation in terms of phenotypes and putatively affected neural circuitry. Here we highlight emerging work from the clinical neuroscience literature examining neural correlates of E/I imbalance across children and adults with ASD and adults with both chronic and early-course SCZ. We discuss findings from diverse neuroimaging studies across distinct modalities, conducted with EEG, MEG, 1H-MRS, and fMRI, including effects observed both during task and at rest. Throughout this review we discuss points of convergence and divergence in the ASD and SCZ literature, with a focus on disruptions in neural E/I balance. We also consider these findings in relation to predictions generated by theoretical neuroscience, particularly computational models predicting E/I imbalance across disorders. Finally, we discuss how human non-invasive neuroimaging can benefit from pharmacological challenge studies to reveal mechanisms in ASD and SCZ. Collectively, we attempt to shed light on shared and divergent neuroimaging effects across disorders with the goal of informing future research examining the mechanisms underlying the E/I imbalance hypothesis across neurodevelopmental disorders. We posit that such translational efforts are vital to facilitate development of neurobiologically informed treatment strategies across neuropsychiatric conditions.

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GABA/Glutamate synaptic pathways targeted by integrative genomic and electrophysiological explorations distinguish autism from intellectual disability

Cited by 31 publications

References 50 publications

Whole genome sequencing and variant discovery in the ASPIRE autism spectrum disorder cohort

Whole genome sequencing and variant discovery in the ASPIRE autism spectrum disorder cohort

22q13 deletion syndrome: communication disorder or autism? Evidence from a specific clinical and neurophysiological phenotype

Searching for Cross-Diagnostic Convergence: Neural Mechanisms Governing Excitation and Inhibition Balance in Schizophrenia and Autism Spectrum Disorders

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