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"Bernier, Raphael"
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A quarter century of progress on the early detection and treatment of autism spectrum disorder
The last 25 years have witnessed tremendous changes in our ability to detect autism very early in life and provide interventions that can significantly influence children's outcomes. It was once questioned whether autism could be recognized before children had developed language and symbolic play skills; now changes in early behaviors, as well as structural brain changes, have been documented in infants 6–12 months of age who later develop autism. Advances in brain imaging and genetics offer the possibility of detecting autism before the syndrome is fully manifest, thereby reducing or preventing symptoms from developing. Whereas the primary mode of behavioral intervention a few decades ago relied on operant conditioning, recent approaches integrate the methods of applied behavioral analysis within a developmental, relationship-focused intervention model that are implemented by both parents and clinicians. These interventions have been found to have positive effects on children's developmental trajectory, as measured by both behavioral and neurophysiological assessments. Future approaches will likely combine both behavioral and pharmacological treatments for children who have less robust responses to behavioral interventions. There has been a paradigm shift in the way that autism is viewed, evolving from a lifelong condition with a very poor prognosis to one in which significant gains and neuroplasticity is expected, especially when the condition is detected early and appropriate interventions are provided. The grand challenge for the future is to bridge the tremendous gap between research and the implementation of evidence-based practices in the broader community, both in the United States and worldwide. Significant disparities in access to appropriate health care for children with autism exist that urgently require advocacy and more resources.
Journal Article
Neurodevelopmental disease genes implicated by de novo mutation and copy number variation morbidity
We combined de novo mutation (DNM) data from 10,927 individuals with developmental delay and autism to identify 253 candidate neurodevelopmental disease genes with an excess of missense and/or likely gene-disruptive (LGD) mutations. Of these genes, 124 reach exome-wide significance (
P
< 5 × 10
−7
) for DNM. Intersecting these results with copy number variation (CNV) morbidity data shows an enrichment for genomic disorder regions (30/253, likelihood ratio (LR) +1.85,
P
= 0.0017). We identify genes with an excess of missense DNMs overlapping deletion syndromes (for example,
KIF1A
and the 2q37 deletion) as well as duplication syndromes, such as recurrent
MAPK3
missense mutations within the chromosome 16p11.2 duplication, recurrent
CHD4
missense DNMs in the 12p13 duplication region, and recurrent
WDFY4
missense DNMs in the 10q11.23 duplication region. Network analyses of genes showing an excess of DNMs highlights functional networks, including cell-specific enrichments in the D1
+
and D2
+
spiny neurons of the striatum.
Analysis of ~10,000 cases of developmental delay and autism identifies 253 candidate neurodevelopmental disease genes. Network analysis highlights cell-specific enrichments of disease-related genes in the D1
+
and D2
+
spiny neurons of the striatum.
Journal Article
Linking social motivation with social skill: The role of emotion dysregulation in autism spectrum disorder
Autism spectrum disorder (ASD) is associated with pervasive social deficits as well as marked emotion dysregulation across the life span. Decreased social motivation accounts in part for social difficulties, but factors moderating its influence are not fully understood. In this paper, we (a) characterize social and emotional functioning among children and adolescents with ASD, (b) explore contributions of social motivation and emotion dysregulation to social skill, and (c) consider biological sex and intellectual functioning as moderators of these associations. In a sample of 2,079 children and adolescents with ASD from the Simons Simplex Collection, we document direct effects of social motivation, internalizing symptoms, aggression, attention problems, irritability, and self-injurious behavior on children's social skills. Furthermore, dysregulation in several domains moderated the association between social motivation and social skill, suggesting a blunting effect on social motivation in the context of emotional difficulties. Moreover, when considering only individuals with intellectual skills in the average range or higher, biological sex further moderated these associations. Findings add to our understanding of social–emotional processes in ASD, suggest emotion dysregulation as a target of intervention in the service of social skill improvements, and build on efforts to understand sources of individual difference that contribute to heterogeneity among individuals with ASD.
Journal Article
A framework for an evidence-based gene list relevant to autism spectrum disorder
Autism spectrum disorder (ASD) is often grouped with other brain-related phenotypes into a broader category of neurodevelopmental disorders (NDDs). In clinical practice, providers need to decide which genes to test in individuals with ASD phenotypes, which requires an understanding of the level of evidence for individual NDD genes that supports an association with ASD. Consensus is currently lacking about which NDD genes have sufficient evidence to support a relationship to ASD. Estimates of the number of genes relevant to ASD differ greatly among research groups and clinical sequencing panels, varying from a few to several hundred. This Roadmap discusses important considerations necessary to provide an evidence-based framework for the curation of NDD genes based on the level of information supporting a clinically relevant relationship between a given gene and ASD.A curated list of genes that are relevant to autism spectrum disorder (ASD) would greatly benefit clinical genetic testing. This Roadmap discusses the need for an evidence-based framework for gene curation that is based on the level of information supporting a clinically relevant relationship between a given gene and ASD.
Journal Article
Excess of rare, inherited truncating mutations in autism
Evan Eichler and colleagues analyze the relative impact of
de novo
and rare, inherited variants on autism risk. They show a statistically independent role for rare, inherited mutations and implicate several new candidate genes likely contributing to autism risk.
To assess the relative impact of inherited and
de novo
variants on autism risk, we generated a comprehensive set of exonic single-nucleotide variants (SNVs) and copy number variants (CNVs) from 2,377 families with autism. We find that private, inherited truncating SNVs in conserved genes are enriched in probands (odds ratio = 1.14,
P
= 0.0002) in comparison to unaffected siblings, an effect involving significant maternal transmission bias to sons. We also observe a bias for inherited CNVs, specifically for small (<100 kb), maternally inherited events (
P
= 0.01) that are enriched in CHD8 target genes (
P
= 7.4 × 10
−3
). Using a logistic regression model, we show that private truncating SNVs and rare, inherited CNVs are statistically independent risk factors for autism, with odds ratios of 1.11 (
P
= 0.0002) and 1.23 (
P
= 0.01), respectively. This analysis identifies a second class of candidate genes (for example,
RIMS1
,
CUL7
and
LZTR1
) where transmitted mutations may create a sensitized background but are unlikely to be completely penetrant.
Journal Article
Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases
Evan Eichler and colleagues use single-molecule molecular-inversion probes to sequence the coding and splicing regions of 208 candidate genes in more than 11,730 individuals with neurodevelopmental disorders. They report 91 genes with an excess of
de novo
or private disruptive mutations, identify 25 genes showing a bias for autism versus intellectual disability, and highlight a network associated with high-functioning autism.
Gene-disruptive mutations contribute to the biology of neurodevelopmental disorders (NDDs), but most of the related pathogenic genes are not known. We sequenced 208 candidate genes from >11,730 cases and >2,867 controls. We identified 91 genes, including 38 new NDD genes, with an excess of
de novo
mutations or private disruptive mutations in 5.7% of cases.
Drosophila
functional assays revealed a subset with increased involvement in NDDs. We identified 25 genes showing a bias for autism versus intellectual disability and highlighted a network associated with high-functioning autism (full-scale IQ >100). Clinical follow-up for
NAA15
,
KMT5B
, and
ASH1L
highlighted new syndromic and nonsyndromic forms of disease.
Journal Article
The Autism Biomarkers Consortium for Clinical Trials (ABC-CT): Scientific Context, Study Design, and Progress Toward Biomarker Qualification
Clinical research in neurodevelopmental disorders remains reliant upon clinician and caregiver measures. Limitations of these approaches indicate a need for objective, quantitative, and reliable biomarkers to advance clinical research. Extant research suggests the potential utility of multiple candidate biomarkers; however, effective application of these markers in trials requires additional understanding of replicability, individual differences, and intra-individual stability over time. The Autism Biomarkers Consortium for Clinical Trials (ABC-CT) is a multi-site study designed to investigate a battery of electrophysiological (EEG) and eye-tracking (ET) indices as candidate biomarkers for autism spectrum disorder (ASD). The study complements published biomarker research through: inclusion of large, deeply phenotyped cohorts of children with ASD and typical development; a longitudinal design; a focus on well-evidenced candidate biomarkers harmonized with an independent sample; high levels of clinical, regulatory, technical, and statistical rigor; adoption of a governance structure incorporating diverse expertise in the ASD biomarker discovery and qualification process; prioritization of open science, including creation of a repository containing biomarker, clinical, and genetic data; and use of economical and scalable technologies that are applicable in developmental populations and those with special needs. The ABC-CT approach has yielded encouraging results, with one measure accepted into the FDA's Biomarker Qualification Program to date. Through these advances, the ABC-CT and other biomarker studies in progress hold promise to deliver novel tools to improve clinical trials research in ASD.
Journal Article
Weaker neural suppression in autism
Abnormal sensory processing has been observed in autism, including superior visual motion discrimination, but the neural basis for these sensory changes remains unknown. Leveraging well-characterized suppressive neural circuits in the visual system, we used behavioral and fMRI tasks to demonstrate a significant reduction in neural suppression in young adults with autism spectrum disorder (ASD) compared to neurotypical controls. MR spectroscopy measurements revealed no group differences in neurotransmitter signals. We show how a computational model that incorporates divisive normalization, as well as narrower top-down gain (that could result, for example, from a narrower window of attention), can explain our observations and divergent previous findings. Thus, weaker neural suppression is reflected in visual task performance and fMRI measures in ASD, and may be attributable to differences in top-down processing.
Sensory hypersensitivity is common in autism spectrum disorders. Using functional MRI, psychophysics, and computational modeling, Schallmo et al. show that differences in visual motion perception in ASD are accompanied by weaker neural suppression in visual cortex.
Journal Article
Recent ultra-rare inherited variants implicate new autism candidate risk genes
Autism is a highly heritable complex disorder in which de novo mutation (DNM) variation contributes significantly to risk. Using whole-genome sequencing data from 3,474 families, we investigate another source of large-effect risk variation, ultra-rare variants. We report and replicate a transmission disequilibrium of private, likely gene-disruptive (LGD) variants in probands but find that 95% of this burden resides outside of known DNM-enriched genes. This variant class more strongly affects multiplex family probands and supports a multi-hit model for autism. Candidate genes with private LGD variants preferentially transmitted to probands converge on the E3 ubiquitin–protein ligase complex, intracellular transport and Erb signaling protein networks. We estimate that these variants are approximately 2.5 generations old and significantly younger than other variants of similar type and frequency in siblings. Overall, private LGD variants are under strong purifying selection and appear to act on a distinct set of genes not yet associated with autism.
Analysis of whole-genome sequence data from 3,474 families finds an excess of private, likely gene-disrupting variants in individuals with autism. These variants are under purifying selection and suggest candidate genes not previously associated with autism.
Journal Article