Frequency and Complexity of De Novo Structural Mutation in Autism

Brandler, William M.; Antaki, Danny; Gujral, Madhusudan; Noor, Amina; Rosanio, Gabriel; Chapman, Timothy R.; Barrera, Daniel J.; Lin, Guan Ning; Malhotra, Dheeraj; Watts, Amanda C.; Wong, Lawrence C.; Estabillo, Jasper A.; Gadomski, Therese; Hong, Oanh; Fajardo, Karin V. Fuentes; Bhandari, Abhishek; Owen, Renius; Baughn, Michael; Yuan, Jeffrey; Solomon, Terry; Moyzis, Alexandra G; Maile, Michelle S.; Sanders, Stephan; Reiner, Gail; Vaux, Keith K.; Strom, Charles M.; Zhang, Kang; Muotri, Alysson R.; Akshoomoff, Natacha; Leal, Suzanne M.; Pierce, Karen; Courchesne, Eric; Iakoucheva, Lilia M.; Corsello, Christina; Sebat, Jonathan

doi:10.1016/j.ajhg.2016.02.018

Cited by 88 publications

(68 citation statements)

References 45 publications

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“…Lastly, we recognize that a majority of structural variants (SVs) are not detectable with current genotyping platforms 32 . New technologies for whole genome sequencing will ultimately provide an assessment of the contribution of a wider array of rare variants including balanced rearrangements, small CNVs 33 and short tandem repeats 34 .…”

Section: Discussionmentioning

confidence: 99%

Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects

Marshall¹,

Howrigan²,

Merico³

et al. 2016

Nat Genet

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862

826

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Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden was observed in cases (OR=1.11, P=5.7×10−15), which persisted after excluding loci implicated in previous studies (OR=1.07, P=1.7 ×10−6). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 ×10−11) and neurobehavioral phenotypes in mouse (OR = 1.18, P= 7.3 ×10−5). Genome-wide significant evidence was obtained for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by non-allelic homologous recombination.

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Section: Discussionmentioning

confidence: 99%

Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects

Marshall¹,

Howrigan²,

Merico³

et al. 2016

Nat Genet

Self Cite

862

826

View full text Add to dashboard Cite

show abstract

“…More generally, balanced chromosomal abnormalities have been shown to underlie congenital abnormalities by disrupting topologically associating domains (TADs) in loci that are known to cause developmental disorders 100 . Long-read sequencing technologies were recently used to implicate a deletion of the first exon of protein kinase cAMP-dependent type I regulatory subunit-a ( PRKAR1A ) in autosomal dominant Carney complex 101 , and WGS studies of autism spectrum disorder estimated that between 1 in 5 and 1 in 20 individuals harbour a de novo structural mutation, further strengthening the argument for comprehensive WGS-based structural variant analysis in Mendelian disorders 102 .…”

Section: Current Challenges and Emerging Solutionsmentioning

confidence: 99%

Settling the score: variant prioritization and Mendelian disease

2017

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When investigating Mendelian disease using exome or genome sequencing, distinguishing disease-causing genetic variants from the multitude of candidate variants is a complex, multidimensional task. Many prioritization tools and online interpretation resources exist, and professional organizations have offered clinical guidelines for review and return of prioritization results. In this Review, we describe the strengths and weaknesses of widely used computational approaches, explain their roles in the diagnostic and discovery process and discuss how they can inform (and misinform) expert reviewers. We place variant prioritization in the wider context of gene prioritization, burden testing and genotype–phenotype association, and we discuss opportunities and challenges introduced by whole-genome sequencing.

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“…However, while large indels and small CNVs may have a greater impact on noncoding function, there are considerably fewer such variants compared to SNVs 18 . The utility of this strategy will depend on the balance between these two opposing effects.…”

Section: Identifying Functional Variantsmentioning

confidence: 99%

“…7, 2017; might have substantially higher effect sizes 1 , increasing tractability for biological experimentation. WGS also enables detection of most structural variation including translocations, inversions, and copy number variants (CNVs) 18,19 . Furthermore, WGS can improve detection of common variants in existing GWAS by statistically inferring SNPs not directly genotyped (imputation) and identifying the specific risk variants within a risk region (fine mapping).…”

Section: Studymentioning

confidence: 99%

Whole Genome Sequencing in Psychiatric Disorders: the WGSPD Consortium

Sanders

Neale

Huang

et al. 2017

Preprint

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As technology advances, whole genome sequencing (WGS) is likely to supersede other genotyping technologies. The rate of this change depends on its relative cost and utility. Variants identified uniquely through WGS may reveal novel biological pathways underlying complex disorders and provide high-resolution insight into when, where, and in which cell type these pathways are affected. Alternatively, cheaper and less computationally intensive approaches may yield equivalent insights. Understanding the role of rare variants in the noncoding gene-regulating genome, through pilot WGS projects, will be critical to determine which of these two extremes best represents reality. With large cohorts, well-defined risk loci, and a compelling need to understand the underlying biology, psychiatric disorders have a role to play in this preliminary WGS assessment. The WGSPD consortium will integrate data for 18,000 individuals with psychiatric disorders, beginning with autism spectrum disorder, schizophrenia, bipolar disorder, and major depressive disorder, along with over 150,000 controls.

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Frequency and Complexity of De Novo Structural Mutation in Autism

Cited by 88 publications

References 45 publications

Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects

Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects

Settling the score: variant prioritization and Mendelian disease

Whole Genome Sequencing in Psychiatric Disorders: the WGSPD Consortium

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