Exonic Mosaic Mutations Contribute Risk for Autism Spectrum Disorder

Krupp, Deidre R.; Barnard, Rebecca; Duffourd, Yannis; Evans, Sara A.; Bernier, Raphael; Rivière, Jean‐Baptiste; Fombonne, Éric; O’Roak, Brian J.

doi:10.1101/083428

Cited by 19 publications

(25 citation statements)

References 78 publications

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“…A similar finding was reported in a cancer study . In addition, a recent study analyzing postzygotic mosaic mutations in ASD (2264 families: 1698 quads and 566 trios) reported enrichment of near‐splice site synonymous mosaic mutations in ASD . In this study, the authors also reanalyzed high‐confidence germline synonymous DNM and confirmed that these DNM in ASD are significantly closer to splice sites than in controls, indicating that both germline and postzygotic mosaic synonymous mutations are enriched in near‐splice site regions in ASD.…”

Section: Rapidly Expanding Knowledge On Functional Non‐coding Elementssupporting

confidence: 87%

Estimating contribution of rare non‐coding variants to neuropsychiatric disorders

Takata

2018

Psychiatry Clin Neurosci

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Owing to recent advances in DNA sequencing technology, a number of large‐scale comprehensive analyses of genetic variations in protein‐coding regions (i.e., whole‐exome sequencing studies), have been conducted for neuropsychiatric and neurodevelopmental disorders, such as autism spectrum disorders, intellectual disability, and schizophrenia. These studies, especially those focusing on de novo (newly arising) mutations and extremely rare variants, have successfully identified previously unrecognized disease genes/mutations with a large effect size and deepen our understanding of the biology of neuropsychiatric diseases. Along with the continuously dropping sequencing cost, now the target of sequencing studies is expanding from the exome to the whole human genome. Several pioneering works have provided important insights into the contribution of rare non‐coding variants to neuropsychiatric diseases. At the same time, these studies highlight need for further larger sample sizes and improvement in annotation of non‐coding regulatory variants. In this review, key findings from recent studies as well as likely future directions are overviewed.

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Section: Rapidly Expanding Knowledge On Functional Non‐coding Elementssupporting

confidence: 87%

Estimating contribution of rare non‐coding variants to neuropsychiatric disorders

Takata

2018

Psychiatry Clin Neurosci

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“…Both representations describe the same resulting genotype. The other three papers report just one of the contiguous SNVs each [Krupp et al, ]: C‐ > A; [Ji et al, ]; and [Satterstrom et al, ]: C‐>G). This complex variant can also be viewed directly in VariCarta at varicarta.msl.ubc.ca/variant?chr=5&start=134059281&stop=134059281.…”

Section: Resultsmentioning

confidence: 99%

VariCarta: A Comprehensive Database of Harmonized Genomic Variants Found in Autism Spectrum Disorder Sequencing Studies

et al. 2019

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Recent years have seen a boom in the application of the next‐generation sequencing technology to the study of human disorders, including Autism Spectrum Disorder (ASD), where the focus has been on identifying rare, possibly causative genomic variants in ASD individuals. Because of the high genetic heterogeneity of ASD, a large number of subjects is needed to establish evidence for a variant or gene ASD‐association, thus aggregating data across cohorts and studies is necessary. However, methodological inconsistencies and subject overlap across studies complicate data aggregation. Here we present VariCarta, a web‐based database developed to address these challenges by collecting, reconciling, and consistently cataloging literature‐derived genomic variants found in ASD subjects using ongoing semi‐manual curation. The careful manual curation combined with a robust data import pipeline rectifies errors, converts variants into a standardized format, identifies and harmonizes cohort overlaps, and documents data provenance. The harmonization aspect is especially important since it prevents the potential double counting of variants, which can lead to inflation of gene‐based evidence for ASD‐association. The database currently contains 170,416 variant events from 10,893 subjects, collected across 61 publications, and reconciles 16,202 variants that have been reported in literature multiple times. VariCarta is freely accessible at http://varicarta.msl.ubc.ca. Autism Res 2019, 12: 1728–1736. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. Lay Summary The search for genetic factors underlying Autism Spectrum Disorder (ASD) yielded numerous studies reporting potentially causative genomic variants found in ASD individuals. However, methodological differences and subject overlap across studies complicate the assembly of these data, diminishing its utility and accessibility. We developed VariCarta, a web‐based database that aggregates carefully curated, annotated, and harmonized literature‐derived variants identified in individuals with ASD using ongoing semi‐manual curation.

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“…Pathogenic variants in CHD2 have been identified in patient cohorts diagnosed with other neurodevelopmental disorders, including autism spectrum disorder, 1,4,6,13,14 intellectual disability, 15 developmental delay, 16,17 microcephalus, 6 developmental malformation, 18,19 and facial abnormalities. 1,10,18,20 Not all patients have seizures.…”

Section: Discussionmentioning

confidence: 99%

CHD2‐related epilepsy: novel mutations and new phenotypes

Chen

Zhang

Liu

et al. 2019

Develop Med Child Neuro

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The aim of this report was to refine the genotypes and phenotypes of chromodomain helicase DNA‐binding protein 2 (CHD2)‐related epilepsy. Seventeen patients with CHD2 mutations were enrolled. CHD2 mutations were identified by application of next‐generation sequencing of epilepsy or whole exome sequencing. Sixteen mutations were identified, among which 15 have not yet been reported. Thirteen mutations were de novo. Age at seizure onset ranged from 3 months to 10 years 5 months. Seizures observed were generalized tonic–clonic, myoclonic, atonic, atypical absence, focal, and myoclonic–atonic. Epileptic spasms occurred in two patients. Developmental disability was present in 14 patients. Autism features were observed in seven patients. Video electroencephalogram was abnormal in 15 patients. Five patients were diagnosed with non‐specific epileptic encephalopathy, two with epilepsy with myoclonic–atonic seizures, two with Lennox–Gastaut syndrome, two with febrile seizures plus, and one with West syndrome. Seizures were controlled in nine patients. Q1392TfsX17 may be a hot‐spot mutation of CHD2. West syndrome was observed as a new phenotype of CHD2 mutation. The severity of the phenotypes of CHD2 mutations ranged from mild febrile seizures to severe epileptic encephalopathy. What this paper adds Q1392TfsX17 maybe the hot‐spot mutation of CHD2. West syndrome could be a new phenotype of CHD2 mutation.

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Exonic Mosaic Mutations Contribute Risk for Autism Spectrum Disorder

Cited by 19 publications

References 78 publications

Estimating contribution of rare non‐coding variants to neuropsychiatric disorders

Estimating contribution of rare non‐coding variants to neuropsychiatric disorders

VariCarta: A Comprehensive Database of Harmonized Genomic Variants Found in Autism Spectrum Disorder Sequencing Studies

CHD2‐related epilepsy: novel mutations and new phenotypes

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