Genetic factors contributing to autism spectrum disorder in Williams-Beuren syndrome

Codina‐Solà, Marta; Costa-Roger, Mar; Pérez-García, D.; Flores, Raquel; Palacios-Verdú, Maria Gabriela; Cuscò, Ivon; Pérez-Jurado, Luís A.

doi:10.1136/jmedgenet-2019-106080

Cited by 14 publications

(5 citation statements)

References 52 publications

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“…In Experiment 1, predicted upstream regulators with the largest magnitude of activation or inhibition included Mlxipl, Myc, Kdm5a, and Rest. Variants in Mlxipl are associated with autism in Williams-Beuren syndrome (Codina-Sola et al 2019). Activation z -scores for Mlxipl and Myc were driven by changes in ribosomal and mitochondrial proteins regulated by Myc and Ctnnb1 (Supplementary Table 5).…”

Section: Resultsmentioning

confidence: 99%

Comparing synaptic proteomes across seven mouse models for autism reveals molecular subtypes and deficits in Rho GTPase signaling

Freire-Cobo

Deyneko

et al. 2021

Preprint

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Impaired synaptic function is a common phenotype in animal models for autism spectrum disorder (ASD), and ASD risk genes are enriched for synaptic function. Here we leverage the availability of multiple ASD mouse models exhibiting synaptic deficits and behavioral correlates of ASD and use quantitative mass spectrometry with isobaric tandem mass tagging (TMT) to compare the hippocampal synaptic proteomes from 7 mouse models. We identified common altered cellular and molecular pathways at the synapse, including changes in Rho family small GTPase signaling, suggesting that it may be a point of convergence in ASD. Comparative analyses also revealed clusters of synaptic profiles, with similarities observed among models for Fragile X syndrome (Fmr1 knockout), PTEN hamartoma tumor syndrome (Pten haploinsufficiency), and the BTBR+ model of idiopathic ASD. Opposing changes were found in models for cortical dysplasia focal epilepsy syndrome (Cntnap2 knockout), Phelan McDermid syndrome (Shank3 InsG3680), Timothy syndrome (Cacna1c G406R), and ANKS1B syndrome (Anks1b haploinsufficiency), which were similar to each other. We propose that these clusters of synaptic profiles form the basis for molecular subtypes that explain genetic heterogeneity in ASD despite a common clinical diagnosis. Drawn from an internally controlled survey of the synaptic proteome across animal models, our findings support the notion that synaptic dysfunction in the hippocampus is a shared mechanism of disease in ASD, and that Rho GTPase signaling may be an important pathway leading to disease phenotypes in autism.

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Section: Resultsmentioning

confidence: 99%

Comparing synaptic proteomes across seven mouse models for autism reveals molecular subtypes and deficits in Rho GTPase signaling

Freire-Cobo

Deyneko

et al. 2021

Preprint

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“…This is consistent with observations in humans that neurodevelopmental disorders manifest as a spectrum of conditions, and patients can even exhibit apparently opposite behaviors. For example, excessive social behavior is a characteristic of Williams syndrome, which is often depicted as anti-ASD, even though both disorders share social cues blindness and many brain pathologies [ 57 , 58 ]. Furthermore, ASD phenotypes are, in fact, prevalent in this disorder [ 59 – 61 ].…”

Section: Discussionmentioning

confidence: 99%

Astrocytic β-catenin signaling via TCF7L2 regulates synapse development and social behavior

Szewczyk,

Lipiec,

Liszewska

et al. 2023

Mol Psychiatry

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The Wnt/β-catenin pathway contains multiple high-confidence risk genes that are linked to neurodevelopmental disorders, including autism spectrum disorder. However, its ubiquitous roles across brain cell types and developmental stages have made it challenging to define its impact on neural circuit development and behavior. Here, we show that TCF7L2, which is a key transcriptional effector of the Wnt/β-catenin pathway, plays a cell-autonomous role in postnatal astrocyte maturation and impacts adult social behavior. TCF7L2 was the dominant Wnt effector that was expressed in both mouse and human astrocytes, with a peak during astrocyte maturation. The conditional knockout of Tcf7l2 in postnatal astrocytes led to an enlargement of astrocytes with defective tiling and gap junction coupling. These mice also exhibited an increase in the number of cortical excitatory and inhibitory synapses and a marked increase in social interaction by adulthood. These data reveal an astrocytic role for developmental Wnt/β-catenin signaling in restricting excitatory synapse numbers and regulating adult social behavior.

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“…To date, there has been no analysis of exome or genome data to investigate possible genetic factors in individuals with both Dup7 and ASD, making our study the first to systematically examine the role of rare and low frequency variants in Dup7-ASD. However, exome data have been analyzed for individuals with both ASD and WBS [ 21 , 34 ]. Codina-Sola et al (2019) conducted WES in eight individuals with WBS-ASD, where seven (87.5%) of the 7q11.23 deletions were paternal in origin, and a total of five inherited rare variants were identified in ASD-related or loss-of-function intolerant genes, as well as one de novo LoF variant.…”

Section: Discussionmentioning

confidence: 99%

Rare and low frequency genomic variants impacting neuronal functions modify the Dup7q11.23 phenotype

Qaiser

Yin

Mervis

et al. 2021

Orphanet J Rare Dis

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Background 7q11.23 duplication (Dup7) is one of the most frequent recurrent copy number variants (CNVs) in individuals with autism spectrum disorder (ASD), but based on gold-standard assessments, only 19% of Dup7 carriers have ASD, suggesting that additional genetic factors are necessary to manifest the ASD phenotype. To assess the contribution of additional genetic variants to the Dup7 phenotype, we conducted whole-genome sequencing analysis of 20 Dup7 carriers: nine with ASD (Dup7-ASD) and 11 without ASD (Dup7-non-ASD). Results We identified three rare variants of potential clinical relevance for ASD: a 1q21.1 microdeletion (Dup7-non-ASD) and two deletions which disrupted IMMP2L (one Dup7-ASD, one Dup7-non-ASD). There were no significant differences in gene-set or pathway variant burden between the Dup7-ASD and Dup7-non-ASD groups. However, overall intellectual ability negatively correlated with the number of rare loss-of-function variants present in nervous system development and membrane component pathways, and adaptive behaviour standard scores negatively correlated with the number of low-frequency likely-damaging missense variants found in genes expressed in the prenatal human brain. ASD severity positively correlated with the number of low frequency loss-of-function variants impacting genes expressed at low levels in the brain, and genes with a low level of intolerance. Conclusions Our study suggests that in the presence of the same pathogenic Dup7 variant, rare and low frequency genetic variants act additively to contribute to components of the overall Dup7 phenotype.

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Genetic factors contributing to autism spectrum disorder in Williams-Beuren syndrome

Cited by 14 publications

References 52 publications

Comparing synaptic proteomes across seven mouse models for autism reveals molecular subtypes and deficits in Rho GTPase signaling

Comparing synaptic proteomes across seven mouse models for autism reveals molecular subtypes and deficits in Rho GTPase signaling

Astrocytic β-catenin signaling via TCF7L2 regulates synapse development and social behavior

Rare and low frequency genomic variants impacting neuronal functions modify the Dup7q11.23 phenotype

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