Autism Spectrum Disorder Profile in Neurofibromatosis Type I

Garg, Shruti; Plasschaert, Ellen; Descheemaeker, Mie-Jef; Huson, Susan M.; Borghgraef, Martine; Vogels, Annick; Evans, D. Gareth; Legius, Eric; Green, Jonathan

doi:10.1007/s10803-014-2321-5

Cited by 64 publications

(65 citation statements)

References 40 publications

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“…Our phenotype analyses suggested additional similarities with idiopathic ASDs, such as a male-biased sex ratio. Other groups have performed independent studies with highly consistent findings[57–62]. Studying multiple disorders in the same biological pathway could therefore both increase the power of our study and increase the likelihood of results translating to an even broader diagnostic category, idiopathic ASDs.…”

Section: Introductionsupporting

confidence: 53%

Reverse Pathway Genetic Approach Identifies Epistasis in Autism Spectrum Disorders

et al. 2017

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Although gene-gene interaction, or epistasis, plays a large role in complex traits in model organisms, genome-wide by genome-wide searches for two-way interaction have limited power in human studies. We thus used knowledge of a biological pathway in order to identify a contribution of epistasis to autism spectrum disorders (ASDs) in humans, a reverse-pathway genetic approach. Based on previous observation of increased ASD symptoms in Mendelian disorders of the Ras/MAPK pathway (RASopathies), we showed that common SNPs in RASopathy genes show enrichment for association signal in GWAS (P = 0.02). We then screened genome-wide for interactors with RASopathy gene SNPs and showed strong enrichment in ASD-affected individuals (P < 2.2 x 10−16), with a number of pairwise interactions meeting genome-wide criteria for significance. Finally, we utilized quantitative measures of ASD symptoms in RASopathy-affected individuals to perform modifier mapping via GWAS. One top region overlapped between these independent approaches, and we showed dysregulation of a gene in this region, GPR141, in a RASopathy neural cell line. We thus used orthogonal approaches to provide strong evidence for a contribution of epistasis to ASDs, confirm a role for the Ras/MAPK pathway in idiopathic ASDs, and to identify a convergent candidate gene that may interact with the Ras/MAPK pathway.

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Section: Introductionsupporting

confidence: 53%

Reverse Pathway Genetic Approach Identifies Epistasis in Autism Spectrum Disorders

et al. 2017

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“…Indeed, in recently published pathway network analyses and sequencing studies, overlap was found for several ASD candidate genes and cancer [30, 112]. Correspondingly, germline mutations in NF1, which cause neurofibromatosis type I, often display autistic-like behaviors [113, 114]. The molecular genetic overlap suggests that some novel cancer therapies currently being developed, especially those that target the epigenome might be beneficial in treating subgroups of individuals with neurodevelopmental disorders [112, 115].…”

Section: Discussionmentioning

confidence: 99%

CRISPR/Cas9-mediated heterozygous knockout of the autism gene CHD8 and characterization of its transcriptional networks in cerebral organoids derived from iPS cells

et al. 2017

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Background CHD8 (chromodomain helicase DNA-binding protein 8), which codes for a member of the CHD family of ATP-dependent chromatin-remodeling factors, is one of the most commonly mutated genes in autism spectrum disorders (ASD) identified in exome-sequencing studies. Loss of function mutations in the gene have also been found in schizophrenia (SZ) and intellectual disabilities and influence cancer cell proliferation. We previously reported an RNA-seq analysis carried out on neural progenitor cells (NPCs) and monolayer neurons derived from induced pluripotent stem (iPS) cells that were heterozygous for CHD8 knockout (KO) alleles generated using CRISPR-Cas9 gene editing. A significant number of ASD and SZ candidate genes were among those that were differentially expressed in a comparison of heterozygous KO lines (CHD8 +/−) vs isogenic controls (CHD8 +/−), including the SZ and bipolar disorder (BD) candidate gene TCF4, which was markedly upregulated in CHD8 +/− neuronal cells.MethodsIn the current study, RNA-seq was carried out on CHD8 +/− and isogenic control (CHD8 +/+) cerebral organoids, which are 3-dimensional structures derived from iPS cells that model the developing human telencephalon.Results TCF4 expression was, again, significantly upregulated. Pathway analysis carried out on differentially expressed genes (DEGs) revealed an enrichment of genes involved in neurogenesis, neuronal differentiation, forebrain development, Wnt/β-catenin signaling, and axonal guidance, similar to our previous study on NPCs and monolayer neurons. There was also significant overlap in our CHD8 +/− DEGs with those found in a transcriptome analysis carried out by another group using cerebral organoids derived from a family with idiopathic ASD. Remarkably, the top DEG in our respective studies was the non-coding RNA DLX6-AS1, which was markedly upregulated in both studies; DLX6-AS1 regulates the expression of members of the DLX (distal-less homeobox) gene family. DLX1 was also upregulated in both studies. DLX genes code for transcription factors that play a key role in GABAergic interneuron differentiation. Significant overlap was also found in a transcriptome study carried out by another group using iPS cell-derived neurons from patients with BD, a condition characterized by dysregulated WNT/β-catenin signaling in a subgroup of affected individuals.ConclusionsOverall, the findings show that distinct ASD, SZ, and BD candidate genes converge on common molecular targets—an important consideration for developing novel therapeutics in genetically heterogeneous complex traits.Electronic supplementary materialThe online version of this article (doi:10.1186/s13229-017-0124-1) contains supplementary material, which is available to authorized users.

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“…However, earlier reports 8,13 on subsets of this cohort demonstrated no association between QAT burden and NF1 severity, and we recapitulate the independence of QAT ratings from measurement of IQ as similarly seen in idiopathic ASD. 38–40 Although deficits in reciprocal social behavior have been demonstrated 41,42 to be genetically independent from non-ADHD domains of psychopathology, significant elevations have been observed in patients with anxiety disorder. To this end, the lack of general psychopathology data in this cohort limits a comprehensive characterization of the NF1-ASD phenotype and should be a focus of future research.…”

Section: Discussionmentioning

confidence: 99%

Disease Burden and Symptom Structure of Autism in Neurofibromatosis Type 1

et al. 2016

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IMPORTANCE Recent reports have demonstrated a higher incidence of autism spectrum disorder (ASD) and substantially elevated autistic trait burden in individuals with neurofibromatosis type 1 (NF1). However, important discrepancies regarding the distribution of autistic traits, sex predominance, and association between ASD symptoms and attentional problems have emerged, and critical features of the ASD phenotype within NF1 have never been adequately explored. Establishing NF1 as a monogenic cause for ASD has important implications for affected patients and for future research focused on establishing convergent pathogenic mechanisms relevant to the potential treatment targets for ASD. OBJECTIVE To characterize the quantitative autistic trait (QAT) burden in a pooled NF1 data set. DESIGN, SETTING, AND PARTICIPANTS Anonymized, individual-level primary data were accumulated from 6 tertiary referral centers in the United States, Belgium, United Kingdom, and Australia. A total of 531 individuals recruited from NF1 clinical centers were included in the study. MAIN OUTCOMES AND MEASURES Distribution of ASD traits (Social Responsiveness Scale, second edition [SRS-2], with T scores of ≥75 associated with a categorical ASD diagnosis); attention-deficit/hyperactivity disorder (ADHD) traits (4 versions of Conners Rating Scale, with T scores of ≥65 indicating clinically significant ADHD symptoms); ASD symptom structure, latent structure, base rate derived from mixture modeling; and familiality. RESULTS Of the 531 patients included in the analysis, 247 were male (46.5%); median age was 11 years (range, 2.5–83.9 years). QAT scores were continuously distributed and pathologically shifted; 13.2%(95%CI, 10.3%–16.1%) of individuals scored within the most severe range (ie, above the first percentile of the general population distribution) in which the male to female ratio was markedly attenuated (1.6:1) relative to idiopathic ASD. Autistic symptoms in this NF1 cohort demonstrated a robust unitary factor structure, with the first principal component explaining 30.9%of the variance in SRS-2 scores, and a strong association with ADHD symptoms (r = 0.61). Within-family correlation for QAT burden (intraclass correlation coefficient, 0.73 in NF1-affected first-degree relatives) exceeded that observed in the general population and ASD family samples. CONCLUSIONS AND RELEVANCE This study provides confirmation that the diversity of mutations that give rise to NF1 function as quantitative trait loci for ASD. Moreover, the within-family correlation implicates a high degree of mutational specificity for this associated phenotype. Clinicians should be alerted to the increased frequency of this disabling comorbidity, and the scientific community should be aware of the potential for this monogenic disorder to help elucidate the biological features of idiopathic autism.

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Autism Spectrum Disorder Profile in Neurofibromatosis Type I

Cited by 64 publications

References 40 publications

Reverse Pathway Genetic Approach Identifies Epistasis in Autism Spectrum Disorders

Reverse Pathway Genetic Approach Identifies Epistasis in Autism Spectrum Disorders

CRISPR/Cas9-mediated heterozygous knockout of the autism gene CHD8 and characterization of its transcriptional networks in cerebral organoids derived from iPS cells

Disease Burden and Symptom Structure of Autism in Neurofibromatosis Type 1

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