25. Identification of De novo, Deleterious Mutations through Exome Sequencing of Sporadic Autism Spectrum Disorder Trios

2018 ◽  
Author(s):  
Shalandra Wood
Keyword(s):  
Autism Spectrum Disorder ◽  
Exome Sequencing ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
De Novo Mutations ◽  
Genetic Etiology ◽  
Affected Child ◽  
Biological Relevance

  Autism Spectrum Disorder (ASD) is a prevalent neurodevelopmental disorder that has a strong genetic component consisting of many genes contributing to its cause. To help understand this complex genetic etiology, we are looking for novel genes that may be involved in the reason individuals develop ASD. We are doing this by using 5 sporadic ASD cases to determine de novo mutations (mutations new to the affected child that are not previously found in the family). These sporadic cases ensure that the disorder is not likely to arise through any inherited mutations, but through a new mutation found solely in the affected child. We use a trio analysis in which the genes of the affected child are compared to those of their mother and father, so pure de novo single nucleotide polymorphisms (SNPs) can be determined. These SNPs are then filtered based on predicted deleterious effect, quality and biological relevance. Using whole-exome sequencing on these 5 sporadic trios numerous deleterious, de novo mutations have been determined. These are being reviewed for biological relevance, and will be validated using Sanger Sequencing. Of these proposed SNPs being validated a few, such as SHANK3 and DVL1, have previously been linked to ASD. Whereas others, such as C11orf31, are novel candidate genes for the disorder. Through this experiment our understanding of the genetic etiology of ASD continues to grow and evolve, leading to greater insight into this disorder and new directions for possible treatments

scholarly journals Intranasal oxytocin administration ameliorates social behavioral deficits in a POGZWT/Q1038R mouse model of autism spectrum disorder

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Kohei Kitagawa ◽  
Kensuke Matsumura ◽  
Masayuki Baba ◽  
Momoka Kondo ◽  
Tomoya Takemoto ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Social Behavior ◽  
Mouse Model ◽  
Mouse Models ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
De Novo Mutation ◽  
Behavioral Deficits

AbstractAutism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder characterized by core symptoms of impaired social behavior and communication. Recent studies have suggested that the oxytocin system, which regulates social behavior in mammals, is potentially involved in ASD. Mouse models of ASD provide a useful system for understanding the associations between an impaired oxytocin system and social behavior deficits. However, limited studies have shown the involvement of the oxytocin system in the behavioral phenotypes in mouse models of ASD. We have previously demonstrated that a mouse model that carries the ASD patient-derived de novo mutation in the pogo transposable element derived with zinc finger domain (POGZWT/Q1038R mice), showed ASD-like social behavioral deficits. Here, we have explored whether oxytocin (OXT) administration improves impaired social behavior in POGZWT/Q1038R mice and found that intranasal oxytocin administration effectively restored the impaired social behavior in POGZWT/Q1038R mice. We also found that the expression level of the oxytocin receptor gene (OXTR) was low in POGZWT/Q1038R mice. However, we did not detect significant changes in the number of OXT-expressing neurons between the paraventricular nucleus of POGZWT/Q1038R mice and that of WT mice. A chromatin immunoprecipitation assay revealed that POGZ binds to the promoter region of OXTR and is involved in the transcriptional regulation of OXTR. In summary, our study demonstrate that the pathogenic mutation in the POGZ, a high-confidence ASD gene, impairs the oxytocin system and social behavior in mice, providing insights into the development of oxytocin-based therapeutics for ASD.

scholarly journals De novo Mutations (DNMs) in Autism Spectrum Disorder (ASD): Pathway and Network Analysis

2018 ◽  
Vol 9 ◽  
Author(s):  
Aitana Alonso-Gonzalez ◽  
Cristina Rodriguez-Fontenla ◽  
Angel Carracedo
Keyword(s):  
Autism Spectrum Disorder ◽  
Network Analysis ◽  
De Novo ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
De Novo Mutations

scholarly journals Noncoding de novo mutations contribute to autism spectrum disorder via chromatin interactions

2019 ◽  
Author(s):  
Il Bin Kim ◽  
Taeyeop Lee ◽  
Junehawk Lee ◽  
Jonghun Kim ◽  
Hyunseong Lee ◽  
...  
Keyword(s):  
Gene Expression ◽  
Autism Spectrum Disorder ◽  
Stem Cells ◽  
Target Genes ◽  
De Novo ◽  
Regulatory Elements ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
De Novo Mutations ◽  
Chromatin Interactions

Three-dimensional chromatin structures regulate gene expression across genome. The significance of de novo mutations (DNMs) affecting chromatin interactions in autism spectrum disorder (ASD) remains poorly understood. We generated 931 whole-genome sequences for Korean simplex families to detect DNMs and identified target genes dysregulated by noncoding DNMs via long-range chromatin interactions between regulatory elements. Notably, noncoding DNMs that affect chromatin interactions exhibited transcriptional dysregulation implicated in ASD risks. Correspondingly, target genes were significantly involved in histone modification, prenatal brain development, and pregnancy. Both noncoding and coding DNMs collectively contributed to low IQ in ASD. Indeed, noncoding DNMs resulted in alterations, via chromatin interactions, in target gene expression in primitive neural stem cells derived from human induced pluripotent stem cells from an ASD subject. The emerging neurodevelopmental genes, not previously implicated in ASD, include CTNNA2, GRB10, IKZF1, PDE3B, and BACE1. Our results were reproducible in 517 probands from MSSNG cohort. This work demonstrates that noncoding DNMs contribute to ASD via chromatin interactions.

scholarly journals Increased cortical volume without increased neuron number in heterozygous Chd8 mutant mouse cortex

2021 ◽  
Author(s):  
Cesar P. Canales ◽  
Samuel Frank ◽  
Jeffrey Bennett ◽  
Paris Beauregard ◽  
Pierre Lavenex ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
De Novo ◽  
Brain Size ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Cognitive Disability ◽  
De Novo Mutations ◽  
Neuron Number ◽  
Cortical Volume ◽  
Soma Size

AbstractDe novo mutations in the chromatin-remodeling factor CHD8 (Chromodomain-Helicase DNA-binding protein 8) have emerged as a key genetic risk factor for Autism Spectrum Disorder (ASD) and, more generally, neurodevelopmental disorders. Individuals with heterozygous mutations in CHD8 typically present hallmarks of ASD with comorbid cognitive disability and macrocephaly. Knockdown or haploinsufficiency of Chd8 in animal models has recapitulated phenotypes observed in patients, including increased head circumference and brain size. Here, we aimed to determine whether increased neuron numbers or soma size drives increased cortical volume. We performed design-based stereological analyses of cortical structure in adult male and female heterozygous Chd8 mice and wild-type littermate controls. Chd8 haploinsufficient male mice displayed a ~8-12% increase in cortical volume, no differences in cortical neuron number and comparable neuronal soma size. Our study reproduced previous reports of increased brain size associated with CHD8 mutation in humans and mice and are consistent with reported sex-specific impacts of Chd8 mutations in mice and increased burden of CHD8 mutations in human males with ASD. These findings suggest that the nature of the cortical enlargement due to Chd8 haploinsufficiency is complex and appears to be due to a factor other than an increased neuron number or soma size.Lay SummaryWe measured the size and neuron number in the neocortex in mice with heterozygous Chd8 mutation, a model relevant to Autism Spectrum Disorder. We found an increased cortical volume in male mutants, which was not accompanied by increased neuron number or soma size. Our results indicate that the enlarged brain in Chd8 mutant mice is complex, more evident here in males, and is due to factors other than increased neuron number.

Brain-expressed exons under purifying selection are enriched for de novo mutations in autism spectrum disorder

2014 ◽  
Vol 46 (7) ◽  
pp. 742-747 ◽  
Author(s):  
Mohammed Uddin ◽  
Kristiina Tammimies ◽  
Giovanna Pellecchia ◽  
Babak Alipanahi ◽  
Pingzhao Hu ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
De Novo ◽  
Purifying Selection ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
De Novo Mutations

scholarly journals Environmental exposures associated with elevated risk for autism spectrum disorder may augment the burden of deleterious de novo mutations among probands

2021 ◽  
Author(s):  
Kealan Pugsley ◽  
Stephen W. Scherer ◽  
Mark A. Bellgrove ◽  
Ziarih Hawi
Keyword(s):  
Autism Spectrum Disorder ◽  
Oxidative Dna Damage ◽  
De Novo ◽  
Genetic Material ◽  
Environmental Exposures ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Individual Risk ◽  
De Novo Mutations ◽  
Birth Cohorts

AbstractAlthough the full aetiology of autism spectrum disorder (ASD) is unknown, familial and twin studies demonstrate high heritability of 60–90%, indicating a predominant role of genetics in the development of the disorder. The genetic architecture of ASD consists of a complex array of rare and common variants of all classes of genetic variation usually acting additively to augment individual risk. The relative contribution of heredity in ASD persists despite selective pressures against the classic autistic phenotype; a phenomenon thought to be explained, in part, by the incidence of spontaneous (or de novo) mutations. Notably, environmental exposures attributed as salient risk factors for ASD may play a causal role in the emergence of deleterious de novo variations, with several ASD-associated agents having significant mutagenic potential. To explore this hypothesis, this review article assesses published epidemiological data with evidence derived from assays of mutagenicity, both in vivo and in vitro, to determine the likely role such agents may play in augmenting the genetic liability in ASD. Broadly, these exposures were observed to elicit genomic alterations through one or a combination of: (1) direct interaction with genetic material; (2) impaired DNA repair; or (3) oxidative DNA damage. However, the direct contribution of these factors to the ASD phenotype cannot be determined without further analysis. The development of comprehensive prospective birth cohorts in combination with genome sequencing is essential to forming a causal, mechanistic account of de novo mutations in ASD that links exposure, genotypic alterations, and phenotypic consequences.

scholarly journals Variants in PRKAR1B cause a neurodevelopmental disorder with autism spectrum disorder, apraxia, and insensitivity to pain

2021 ◽  
Author(s):  
Felix Marbach ◽  
◽  
Georgi Stoyanov ◽  
Florian Erger ◽  
Constantine A. Stratakis ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Global Developmental Delay ◽  
Missense Variants ◽  
Large Patient ◽  
Significant Enrichment

Abstract Purpose We characterize the clinical and molecular phenotypes of six unrelated individuals with intellectual disability and autism spectrum disorder who carry heterozygous missense variants of the PRKAR1B gene, which encodes the R1β subunit of the cyclic AMP-dependent protein kinase A (PKA). Methods Variants of PRKAR1B were identified by single- or trio-exome analysis. We contacted the families and physicians of the six individuals to collect phenotypic information, performed in vitro analyses of the identified PRKAR1B-variants, and investigated PRKAR1B expression during embryonic development. Results Recent studies of large patient cohorts with neurodevelopmental disorders found significant enrichment of de novo missense variants in PRKAR1B. In our cohort, de novo origin of the PRKAR1B variants could be confirmed in five of six individuals, and four carried the same heterozygous de novo variant c.1003C>T (p.Arg335Trp; NM_001164760). Global developmental delay, autism spectrum disorder, and apraxia/dyspraxia have been reported in all six, and reduced pain sensitivity was found in three individuals carrying the c.1003C>T variant. PRKAR1B expression in the brain was demonstrated during human embryonal development. Additionally, in vitro analyses revealed altered basal PKA activity in cells transfected with variant-harboring PRKAR1B expression constructs. Conclusion Our study provides strong evidence for a PRKAR1B-related neurodevelopmental disorder.

scholarly journals Whole exome sequencing reveals inherited and de novo variants in autism spectrum disorder: a trio study from Saudi families

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Bashayer Al-Mubarak ◽  
Mohamed Abouelhoda ◽  
Aisha Omar ◽  
Hesham AlDhalaan ◽  
Mohammed Aldosari ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
De Novo ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Whole Exome

scholarly journals Genome-wide de novo risk score implicates promoter variation in autism spectrum disorder

Science ◽  
2018 ◽  
Vol 362 (6420) ◽  
pp. eaat6576 ◽  
Author(s):  
Joon-Yong An ◽  
Kevin Lin ◽  
Lingxue Zhu ◽  
Donna M. Werling ◽  
Shan Dong ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Risk Score ◽  
De Novo ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
De Novo Mutations ◽  
Promoter Regions ◽  
Complex Disorders ◽  
Genome Wide ◽  
Evolutionarily Conserved

Whole-genome sequencing (WGS) has facilitated the first genome-wide evaluations of the contribution of de novo noncoding mutations to complex disorders. Using WGS, we identified 255,106 de novo mutations among sample genomes from members of 1902 quartet families in which one child, but not a sibling or their parents, was affected by autism spectrum disorder (ASD). In contrast to coding mutations, no noncoding functional annotation category, analyzed in isolation, was significantly associated with ASD. Casting noncoding variation in the context of a de novo risk score across multiple annotation categories, however, did demonstrate association with mutations localized to promoter regions. We found that the strongest driver of this promoter signal emanates from evolutionarily conserved transcription factor binding sites distal to the transcription start site. These data suggest that de novo mutations in promoter regions, characterized by evolutionary and functional signatures, contribute to ASD.

Sign in / Sign up

Export Citation Format

Share Document