Gene Disrupting Mutations Associated with Regression in Autism Spectrum Disorder

Goin‐Kochel, Robin P.; Trinh, Sandy; Barber, Shelley; Bernier, Raphael

doi:10.1007/s10803-017-3256-4

Cited by 21 publications

(15 citation statements)

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“…Others have reported reduced social engagement and non‐verbal communication between 6 and 12 months [Bryson et al, ] and atypical language trajectories with declining expressive and/or receptive skills in the second year of life [Landa, Gross, Stuart, & Faherty, ]. Such trajectories that include loss of these and other skills are sometimes reported in some children with genetic disorders [see Table for details and see Goin‐Kochel, Trinh, Barber, & Bernier, ], specific language impairment, and even occasionally in typical development [Brignell et al, ; Thurm, Manwaring, Luckenbaugh, Lord, & Swedo, ]. However, results of other studies lead to the conclusion that regression is largely specific to ASD [Baird, Charman, et al, ; Pickles et al, ].…”

Section: Onset Of Autism Revisited: Findings From Prospective Researchmentioning

confidence: 99%

Loss of skills and onset patterns in neurodevelopmental disorders: Understanding the neurobiological mechanisms

et al. 2017

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Loss of previously acquired skills, or regression, has been reported in Autism Spectrum Disorder since Kanner's reports in the 1950's. The current report reflects discussion from an NIMH convened meeting in 2016 with the purpose of bridging clinical autism research with basic and translational work in this area. This summary describes the state of the field regarding clinical studies and suggests use of model systems during the developmental period and cutting-edge methods, for a better understanding of the neurobiological pathways that result in loss of previously-attained skills.

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Section: Onset Of Autism Revisited: Findings From Prospective Researchmentioning

confidence: 99%

Loss of skills and onset patterns in neurodevelopmental disorders: Understanding the neurobiological mechanisms

et al. 2017

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“…Developmental regression is present in approximately one‐third of children with ASD [Barger, Campbell, & McDonough, ] and is believed to have a greater‐than‐chance association with epilepsy. Developmental regression in idiopathic ASD tends to occur around 18–24 months of age [Barger et al, ; El Achkar & Spence, ; Goin‐Kochel, Trinh, Barber, & Bernier, ; Spence & Schneider, ; Thurm, Manwaring, Luckenbaugh, Lord, & Swedo, ; Tuchman & Rapin, ; Viscidi et al, ]. The epilepsy syndrome of Landau–Kleffner (LKS) similarly involves regression of developmental abilities followed by the presence of an autistic‐like social‐communicative phenotype, though in LKS, regression most often occurs around 5 years of age, and most but not all affected children also have convulsive seizures [Shao & Stafstrom, ].…”

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confidence: 99%

Epilepsy and Autism Severity: A Study of 6,975 Children

Ewen

Marvin²,

Law

et al. 2019

Autism Research

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Epilepsy is known to occur in a higher-than-expected proportion of individuals with autism spectrum disorders (ASDs). Prior studies of this heterogeneous disorder have suggested that intelligence quotient (IQ) may drive this relationship. Because intellectual disability (ID) is, independently of ASD, a risk factor for epilepsy, current literature calls into question the long-understood unique relationship between ASD and epilepsy. Second, data have been unclear about whether developmental regression in ASD is associated with epilepsy. Using two cohorts from an online research registry, totaling 6,975 children with ASD, we examined the independent role of four ASD severity measures in driving the relationship with epilepsy: ID, language impairment, core ASD symptom severity, and motor dysfunction, controlling for two known relevant factors: age and sex. We also examined whether developmental regression and epilepsy have an independent statistical link. All four ASD severity factors showed independent statistical associations with epilepsy in one cohort, and three in the other. ID showed the largest relative risk (RR) in both cohorts. Effect sizes were modest. Regression similarly showed an independent statistical association with epilepsy, but with small effect size. Similar to previous work, ID showed the greatest contribution to RR for epilepsy among children with ASD. However, other ASD severity markers showed statistical associations, demonstrating that the ASD-epilepsy association is not reducible to the effect of ID. Inconsistencies in the literature may be due to underpowered studies, yet moving forward with larger-n studies, clinical significance and scientific relevance may be dictated by effect size and not merely statistical significance.Lay Summary: Epilepsy is known to occur more often in individuals with autism spectrum disorders (ASDs) than is the case in the general population. The association between ASD and epilepsy is of interest because studying the two disorders in combination may help advance our understanding of genetic, molecular, and cellular mechanisms-as well as therapies-for both. Recent studies have suggested that intelligence quotient (IQ) alone in individuals with ASD may account for the increased prevalence of epilepsy. However, our approach was to look at a range of severity factors relevant to ASD and to look for correlations between each severity factor and epilepsy, within two large samples of children with ASD. In summary, we found that each severity factor-presence of intellectual disability, presence of language atypicalities, ASD-specific symptoms severity, and presence of motor issues-independently predicted a small increased risk for epilepsy, countering the argument that IQ alone is a risk factor. We also examined whether epilepsy is associated with developmental regression. Although severe epilepsy syndromes such as Landau-Kleffner syndrome are known to cause autistic-like symptoms following developmental regression, there is controversy about whether other forms of epil...

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“…This indicates that disturbances to synaptic proteins in autism could be related to symptoms of NLF, an idea that may be worthy of further exploration in relation to autistic regression given the role of synaptic impairment in the etiologies of many neurodegenerative disorders ( 26 ). Interestingly, recent research indicates that autistic individuals with gene disrupting mutations in postsynaptic density genes are more likely to experience autistic regression than individuals with mutations in genes of other functional classes ( 27 ) (see Additional File 4, “Table _ 19 ” tab for more extensive enrichment results by subgroup).…”

Section: Resultsmentioning

confidence: 99%

Widespread Genotype-Phenotype Correlations in Intellectual Disability

et al. 2018

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Background: Linking genotype to phenotype is a major aim of genetics research, yet the underlying biochemical mechanisms of many complex conditions continue to remain elusive. Recent research provides evidence that relevant gene-phenotype associations are discoverable in the study of intellectual disability (ID). Here we expand on that work, identifying distinctive gene interaction modules with unique enrichment patterns reflective of associated clinical features in ID.Methods: Two hundred twelve forms of monogenic ID were curated according to comorbidities with autism and epilepsy. These groups were further subdivided according to secondary clinical manifestations of complex vs. simple facial dysmorphia and neurodegenerative-like features due to their clinical prominence, modest symptom overlap, and probable etiological divergence. An aggregate gene interaction ID network for these phenotype subgroups was discovered via a public database of known gene interactions: protein-protein, genetic, and mRNA coexpression. Additional annotation resources (Gene Ontology, Human Phenotype Ontology, TRANSFAC/JASPAR, and KEGG/WikiPathways) were utilized to assess functional and phenotypic enrichment patterns within subgroups.Results: Phenotypic analysis revealed high rates of complex facial dysmorphia in ID with comorbid autism. In contrast, neurodegenerative-like features were overrepresented in ID with epilepsy. Network analysis subsequently showed that gene groups divided according to clinical features of interest resulted in distinctive interaction clusters, with unique functional enrichments according to gene set.Conclusions: These data suggest that specific comorbid and secondary clinical features in ID are predictive of underlying genotype. In summary, ID form unique clusters, which are comprised of individual conditions with remarkable genotypic and phenotypic overlap.

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Gene Disrupting Mutations Associated with Regression in Autism Spectrum Disorder

Cited by 21 publications

References 73 publications

Loss of skills and onset patterns in neurodevelopmental disorders: Understanding the neurobiological mechanisms

Loss of skills and onset patterns in neurodevelopmental disorders: Understanding the neurobiological mechanisms

Epilepsy and Autism Severity: A Study of 6,975 Children

Widespread Genotype-Phenotype Correlations in Intellectual Disability

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