Copy number variations in a Brazilian cohort with autism spectrum disorders highlight the contribution of cell adhesion genes

Costa, Claudia Ismania Samogy; Montenegro, Eduarda Morgana da Silva; Zarrei, Mehdi; Moreira, Eloisa De Sá; Silva, Isabela Maya Wahys; Scliar, Marília de Oliveira; Wang, Jaqueline Yu Ting; Zachi, Elaine Cristina; Branco, Elisa Varella; Costa, Silvia Souza da; Lourenço, Naila Cristina Vilaça; Vianna‐Morgante, Angela Maria; Rosenberg, Carla; Krepischi, Ana Cristina Victorino; Scherer, Stephen W.; Passos‐Bueno, Maria Rita

doi:10.1111/cge.14072

Cited by 14 publications

(11 citation statements)

References 18 publications

(14 reference statements)

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“…10 Costa et al very recently highlighted the role of copy number variations in cell adhesion genes, specifically FAT1 deletion, in the development of ASD. 2 This deletion is comparable to ours in terms of size and contains both the MTNR1A and FAT1 genes. We recommend considering FAT1 duplication also as a potential cause of ASD.…”

supporting

confidence: 77%

“…There has been one reported clinical case of 4q35.2 duplication, but it is not comparable to our patient due to its size, although it includes the FAT1 gene 10 . Costa et al very recently highlighted the role of copy number variations in cell adhesion genes, specifically FAT1 deletion, in the development of ASD 2 . This deletion is comparable to ours in terms of size and contains both the MTNR1A and FAT1 genes.…”

Section: Figurecontrasting

confidence: 59%

“…FAT1 (FAT atypical cadherin 1, OMIM*600976) is a gene that encodes a member of a small family of cadherin‐like proteins that are involved in cell–cell adhesion as well as polarity, including the development of epithelial structures, neuronal migration, and cellular proliferation. FAT1 variants have been linked with autism spectrum disorder (ASD), 1,2 bipolar affective disorder, 3 and other clinical manifestations 4 . In this study, we report a 7‐year‐old girl who presented to a neurology consultation for an ASD evaluation and was found to have a de novo 4q35.2 duplication containing the FAT1 gene.…”

Section: Figurementioning

confidence: 95%

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De novo 4q35.2 duplication containing FAT1 is associated with autism spectrum disorder

et al. 2022

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supporting

confidence: 77%

Section: Figurecontrasting

confidence: 59%

Section: Figurementioning

confidence: 95%

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De novo 4q35.2 duplication containing FAT1 is associated with autism spectrum disorder

et al. 2022

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“…Therefore, our study raises the need to evaluate the impact of Cntnap2 heterozygosity on the functions of Caspr2 in these processes as well, to further assess the possible consequences of CNTNAP2 alterations in neurodevelopmental disorders. It would also be of great interest to conduct similar studies for other members of the Contactin Associated Protein family, which have also been associated with neurodevelopmental disorders such as ASD, especially Caspr3/ CNTNAP3 ( Vaags et al, 2012 ; Turner et al, 2017 ), Caspr4/ CNTNAP4 ( Wang et al, 2010 ; O’Roak et al, 2012 ; Costa et al, 2022 ), and Caspr5/ CNTNAP5 ( Pagnamenta et al, 2010 ; Aleo et al, 2020 ; Ludington et al, 2020 ). Little is known about the functions of these three proteins compared to Caspr2.…”

Section: Discussionmentioning

confidence: 99%

Differential impacts of Cntnap2 heterozygosity and Cntnap2 null homozygosity on axon and myelinated fiber development in mouse

et al. 2023

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Over the last decade, a large variety of alterations of the Contactin Associated Protein 2 (CNTNAP2) gene, encoding Caspr2, have been identified in several neuronal disorders, including neurodevelopmental disorders and peripheral neuropathies. Some of these alterations are homozygous but most are heterozygous, and one of the current challenges is to estimate to what extent they could affect the functions of Caspr2 and contribute to the development of these pathologies. Notably, it is not known whether the disruption of a single CNTNAP2 allele could be sufficient to perturb the functions of Caspr2. To get insights into this issue, we questioned whether Cntnap2 heterozygosity and Cntnap2 null homozygosity in mice could both impact, either similarly or differentially, some specific functions of Caspr2 during development and in adulthood. We focused on yet poorly explored functions of Caspr2 in axon development and myelination, and performed a morphological study from embryonic day E17.5 to adulthood of two major brain interhemispheric myelinated tracts, the anterior commissure (AC) and the corpus callosum (CC), comparing wild-type (WT), Cntnap2–/– and Cntnap2+/– mice. We also looked for myelinated fiber abnormalities in the sciatic nerves of mutant mice. Our work revealed that Caspr2 controls the morphology of the CC and AC throughout development, axon diameter at early developmental stages, cortical neuron intrinsic excitability at the onset of myelination, and axon diameter and myelin thickness at later developmental stages. Changes in axon diameter, myelin thickness and node of Ranvier morphology were also detected in the sciatic nerves of the mutant mice. Importantly, most of the parameters analyzed were affected in Cntnap2+/– mice, either specifically, more severely, or oppositely as compared to Cntnap2–/– mice. In addition, Cntnap2+/– mice, but not Cntnap2–/– mice, showed motor/coordination deficits in the grid-walking test. Thus, our observations show that both Cntnap2 heterozygosity and Cntnap2 null homozygosity impact axon and central and peripheral myelinated fiber development, but in a differential manner. This is a first step indicating that CNTNAP2 alterations could lead to a multiplicity of phenotypes in humans, and raising the need to evaluate the impact of Cntnap2 heterozygosity on the other neurodevelopmental functions of Caspr2.

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“…In vertebrates, FAT1 homologues are highly expressed in various fetal epithelia, yet lack of expression in mice was lethal and associated with brain and kidney defects 4 , 5 . In human, mutations or structural aberrations of the FAT1 gene are associated with numerous developmental disorders like 4q-syndrome, nephropathy and syndactyly 1 , 6 , 7 , mental diseases such as bipolar or autism spectrum disorder 8 – 10 or kidney diseases such as glomerulotubular nephropathy 11 .…”

Section: Introductionmentioning

confidence: 99%

FAT1 expression in T-cell acute lymphoblastic leukemia (T-ALL) modulates proliferation and WNT signaling

Liebig

Neumann

Silva

et al. 2023

Sci Rep

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FAT atypical cadherin 1 (FAT1), a transmembrane protein, is frequently mutated in various cancer types and has been described as context-dependent tumor suppressor or oncogene. The FAT1 gene is mutated in 12–16% of T-cell acute leukemia (T-ALL) and aberrantly expressed in about 54% of T-ALL cases contrasted with absent expression in normal T-cells. Here, we characterized FAT1 expression and profiled the methylation status from T-ALL patients. In our T-ALL cohort, 53% of patient samples were FAT1 positive (FAT1pos) compared to only 16% FAT1 positivity in early T-ALL patient samples. Aberrant expression of FAT1 was strongly associated with FAT1 promotor hypomethylation, yet a subset, mainly consisting of TLX1-driven T-ALL patient samples showed methylation-independent high FAT1 expression. Genes correlating with FAT1 expression revealed enrichment in WNT signaling genes representing the most enriched single pathway. FAT1 knockdown or knockout led to impaired proliferation and downregulation of WNT pathway target genes (CCND1, MYC, LEF1), while FAT1 overexpressing conveyed a proliferative advantage. To conclude, we characterized a subtype pattern of FAT1 gene expression in adult T-ALL patients correlating with promotor methylation status. FAT1 dependent proliferation and WNT signaling discloses an impact on deeper understanding of T-ALL leukemogenesis as a fundament for prospective therapeutic strategies.

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Copy number variations in a Brazilian cohort with autism spectrum disorders highlight the contribution of cell adhesion genes

Cited by 14 publications

References 18 publications

De novo 4q35.2 duplication containing FAT1 is associated with autism spectrum disorder

De novo 4q35.2 duplication containing FAT1 is associated with autism spectrum disorder

Differential impacts of Cntnap2 heterozygosity and Cntnap2 null homozygosity on axon and myelinated fiber development in mouse

FAT1 expression in T-cell acute lymphoblastic leukemia (T-ALL) modulates proliferation and WNT signaling

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