Rare<i>RELN</i>variants affect Reelin-DAB1 signal transduction in autism spectrum disorder

Sánchez-Sánchez, Sandra M; Magdalon, Juliana; Griesi-Oliveira, Karina; Yamamoto, Guilherme Lopes; Santacruz-Pérez, Carolina; Fogo, Mariana Soares; Passos‐Bueno, Maria Rita; Sertié, Andréa L.

doi:10.1002/humu.23584

Cited by 32 publications

(41 citation statements)

References 49 publications

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“…Our patient (F2688-1) presents no HALD4 features, and besides ASD features shows macrocrania and ADHD. Another study from our research group identified in this patient two inherited missense pathogenic variants in RELN, altering reelin secretion and signal transduction in neuronal cells from this patient [Sánchez-Sánchez et al, 2018]. These results suggest that despite CACNA1H is considered an ASD gene, the de novo LoF variant identified is not the only cause of ASD in our patient and may contribute to the phenotype in an oligogenic model.…”

Section: Discussionmentioning

confidence: 57%

Meta‐Analyses Support Previous and Novel Autism Candidate Genes: Outcomes of an Unexplored Brazilian Cohort

et al. 2019

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Large genomic databases of neurodevelopmental disorders (NDD) are helpful resources of genomic variations in complex and heterogeneous conditions, as Autism Spectrum Disorder (ASD). We evaluated the role of rare copy number variations (CNVs) and exonic de novo variants, in a molecularly unexplored Brazilian cohort of 30 ASD trios (n = 90), by performing a meta‐analysis of our findings in more than 20,000 patients from NDD cohorts. We identified three pathogenic CNVs: two duplications on 1q21 and 17p13, and one deletion on 4q35. CNVs meta‐analysis (n = 8,688 cases and n = 3,591 controls) confirmed 1q21 relevance by identifying duplications in other 16 ASD patients. Exome analysis led the identification of seven de novo variants in ASD genes (SFARI list): three loss‐of‐function pathogenic variants in CUL3, CACNA1H, and SHANK3; one missense pathogenic variant in KCNB1; and three deleterious missense variants in ATP10A, ANKS1B, and DOCK1. From the remaining 12 de novo variants in non‐previous ASD genes, we prioritized PRPF8 and RBM14. Meta‐analysis (n = 13,754 probands; n = 2,299 controls) identified six and two additional patients with validated de novo variants in PRPF8 and RBM14, respectively. By comparing the de novo variants with a previously established mutational rate model, PRPF8 showed nominal significance before multiple test correction (P = 0.039, P‐value adjusted = 0.079, binomial test), suggesting its relevance to ASD. Approximately 60% of our patients presented comorbidities, and the diagnostic yield was estimated in 23% (7/30: three pathogenic CNVs and four pathogenic de novo variants). Our uncharacterized Brazilian cohort with tetra‐hybrid ethnic composition was a valuable resource to validate and identify possible novel candidate loci. Autism Res 2020, 13: 199–206. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. Lay Summary We believed that to study an unexplored autistic population, such as the Brazilian, could help to find novel genes for autism. In order to test this idea, with our limited budget, we compared candidate genes obtained from genomic analyses of 30 children and their parents, with those of more than 20,000 individuals from international studies. Happily, we identified a genetic cause in 23% of our patients and suggest a possible novel candidate gene for autism (PRPF8).

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Section: Discussionmentioning

confidence: 57%

Meta‐Analyses Support Previous and Novel Autism Candidate Genes: Outcomes of an Unexplored Brazilian Cohort

et al. 2019

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“…The variations in DAB1 function might contribute to make one genetically susceptible to autism, supporting the view that a defect in the Reelin signaling pathway might be a predisposing factor for ASD. 10,11 More recently, Sánchez-Sánchez et al, using iPSC-derived neural progenitor cells (NPCs) from one patient with nonsyndromic ASD, suggested an abnormal interplay between Reelin-DAB1 and mTORC1 signaling pathways and further support a multihit model of nonsyndromic ASD risk, in which a coincidental occurrence of disrupting variants in convergent molecular pathways may contribute to ASD. 10 To evaluate the inheritance of this CNV, biological parents were studied by quantitative polymerase chain reaction (qPCR) and the technique showed that the father is a carrier of the same microdeletion.…”

Section: Casementioning

confidence: 97%

“…10,11 More recently, Sánchez-Sánchez et al, using iPSC-derived neural progenitor cells (NPCs) from one patient with nonsyndromic ASD, suggested an abnormal interplay between Reelin-DAB1 and mTORC1 signaling pathways and further support a multihit model of nonsyndromic ASD risk, in which a coincidental occurrence of disrupting variants in convergent molecular pathways may contribute to ASD. 10 To evaluate the inheritance of this CNV, biological parents were studied by quantitative polymerase chain reaction (qPCR) and the technique showed that the father is a carrier of the same microdeletion. However, it is not clear if haploinsufficiency of DAB1 gene may have an isolated role in the pathophysiology of autism, making it difficult to advise parents on this matter.…”

Section: Casementioning

confidence: 97%

Identification of Copy Number Variation by Array-CGH in Portuguese Children and Adolescents Diagnosed with Autism Spectrum Disorders

et al. 2019

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Background Autism spectrum disorders (ASD) affect many children with an estimated prevalence of 1%. Array-comparative genomic hybridization (CGH) offers significant sensitivity for the identification of submicroscopic chromosomal abnormalities and it is one of the most used techniques in daily practice. The main objective of this study was to describe the usefulness of array-CGH in the etiologic diagnosis of ASD. Methods Two-hundred fifty-three patients admitted to a neurogenetic outpatient clinic and diagnosed with ASD were selected for array-CGH (4 × 180K microarrays). Public databases were used for classification in accordance with the American College of Medical Genetics Standards and Guidelines. Results About 3.56% (9/253) of copy number variations (CNVs) were classified as pathogenic. When likely pathogenic CNVs were considered, the rate increased to 11.46% (29/253). Some CNVs apparently not correlated to the ASD were also found. Considering a phenotype–genotype correlation, the patients were divided in two groups. One group according to previous literature includes all the CNVs related to ASDs (23 CNVs present in 22 children) and another with those apparently not related to ASD (10 CNVs present in 7 children). In 18 patients, a next-generation sequencing (NGS) panel were performed. From these, one pathogenic and 16 uncertain significance variants were identified. Conclusion The results of our study are in accordance with the literature, highlighting the relevance of array-CGH in the genetic of diagnosis of ASD population, namely when associated with other features. Our study also reinforces the need for complementarity between array-CGH and NGS panels or whole exome sequencing in the etiological diagnosis of ASD.

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“…Deletion of one copy of these genes should result in a 1.5 to 2-fold Fig. 3 Examples of studies utilizing iPSC models to study nonsyndromic idiopathic ASD [18,34,[49][50][51][52][53][54][55][56]. Studies are ordered by year with the most recent at the top and include the total number of XX and XY patient iPSCs used in the bar chart reduction in gene expression.…”

Section: An Ideal Scenariomentioning

confidence: 99%

Using human pluripotent stem cell models to study autism in the era of big data

Nehme

Barrett

2020

Molecular Autism

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Advances in human pluripotent stem cell (hPSC) biology coupled with protocols to generate diverse brain cell types in vitro have provided neuroscientists with opportunities to dissect basic and disease mechanisms in increasingly relevant cellular substrates. At the same time, large data collections and analyses have facilitated unprecedented insights into autism genetics, normal human genetic variation, and the molecular landscape of the developing human brain. While such insights have enabled the investigation of key mechanistic questions in autism, they also highlight important limitations associated with the use of existing hPSC models. In this review, we discuss four such issues which influence the efficacy of hPSC models for studying autism, including (i) sources of variance, (ii) scale and format of study design, (iii) divergence from the human brain in vivo, and (iv) regulatory policies and compliance governing the use of hPSCs. Moreover, we advocate for a set of immediate and long-term priorities to address these issues and to accelerate the generation and reproducibility of data in order to facilitate future fundamental as well as therapeutic discoveries.

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RareRELNvariants affect Reelin-DAB1 signal transduction in autism spectrum disorder

Cited by 32 publications

References 49 publications

Meta‐Analyses Support Previous and Novel Autism Candidate Genes: Outcomes of an Unexplored Brazilian Cohort

Meta‐Analyses Support Previous and Novel Autism Candidate Genes: Outcomes of an Unexplored Brazilian Cohort

Identification of Copy Number Variation by Array-CGH in Portuguese Children and Adolescents Diagnosed with Autism Spectrum Disorders

Using human pluripotent stem cell models to study autism in the era of big data

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