Paternally inherited cis-regulatory structural variants are associated with autism

Brandler, William M.; Antaki, Danny; Gujral, Madhusudan; Kleiber, Morgan L.; Whitney, J. Andrew; Maile, Michelle S.; Hong, Oanh; Chapman, Timothy R.; Tan, Shirley; Tandon, Prateek; Pang, Tao; Tang, Shih C.; Vaux, Keith K.; Yang, Yan; Harrington, Eoghan; Juul, Sissel; Turner, Daniel J.; Thiruvahindrapuram, Bhooma; Kaur, Gaganjot; Wang, Zhuozhi; Kingsmore, Stephen F.; Gleeson, Joseph G.; Bisson, Denis; Kakaradov, Boyko; Telenti, Amalio; Venter, J. Craig; Corominas, Roser; Toma, Claudio; Cormand, Bru; Rueda, Isabel; Guijarro, Silvina; Messer, Karen; Nievergelt, Caroline M.; Arranz, Maria; Courchesne, Eric; Pierce, Karen; Muotri, Alysson R.; Iakoucheva, Lilia M.; Hervás, Amaia; Scherer, Stephen W.; Corsello, Christina; Sebat, Jonathan

doi:10.1126/science.aan2261

Cited by 172 publications

(174 citation statements)

References 33 publications

(35 reference statements)

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“…62 Indeed, early efforts to deploy WGS in cardiovascular disease, autism, and type 2 diabetes were largely consistent in their analyses of SNVs using GATK, but all studies have differed in their analyses of SVs. 25,37,50,[57][58][59]63,64 Thus, while ExAC and gno-mAD have catalyzed remarkable advances in medical and population genetics, the same opportunities for new discovery and translational impact have not yet been realized for SVs. Although gnomAD-SV is by no means comprehensive, the nearly half-million SVs it contains were derived from WGS methods and a reference genome that match those currently used in many research and clinical settings.…”

Section: Discussionmentioning

confidence: 99%

“…These scores have become core resources in human genetics. [21][22][23] Existing metrics like pLI are reliant on SNVs, and while previous studies have attempted to compute similar scores using large CNVs detected by microarray or to correlate deletions with pLI, 37,38 no gene-level metrics comparable to pLI exist for SVs at WGS resolution. To gain insight into this problem, we estimated the number of rare SVs expected per gene while adjusting for gene length, exon-intron structure, and genomic context.…”

Section: Relevance To Disease Association and Clinical Geneticsmentioning

confidence: 99%

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An open resource of structural variation for medical and population genetics

Team¹

2019

Preprint

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Structural variants (SVs) rearrange large segments of the genome and can have profound consequences for evolution and human diseases. As national biobanks, disease association studies, and clinical genetic testing grow increasingly reliant on genome sequencing, population references such as the Genome Aggregation Database (gnomAD) have become integral for interpreting genetic variation.To date, no large-scale reference maps of SVs exist from high-coverage sequencing comparable to those available for point mutations in protein-coding genes. Here, we constructed a reference atlas of SVs across 14,891 genomes from diverse global populations (54% non-European) as a component of gnomAD. We discovered a rich landscape of 433,371 distinct SVs, including 5,295 multi-breakpoint complex SVs across 11 mutational subclasses, and examples of localized chromosome shattering, as in chromothripsis. The average individual harbored 7,439 SVs, which accounted for 25-29% of all rare protein-truncating events per genome. We found strong correlations between constraint against damaging point mutations and rare SVs that both disrupt and duplicate protein-coding sequence, suggesting intolerance to reciprocal dosage alterations for a subset of tightly regulated genes. We also uncovered modest selection against noncoding SVs in cis-regulatory elements, although selection against protein-truncating SVs was stronger than any effect on noncoding SVs. Finally, we benchmarked carrier rates for medically relevant SVs, finding very large (≥1Mb) rare SVs in 3.8% of genomes (~1:26 individuals) and clinically reportable incidental SVs in 0.18% of genomes (~1:556 individuals). These data have been integrated directly into the gnomAD browser (https://gnomad.broadinstitute. org) and will have broad utility for population genetics, disease association, and diagnostic screening.

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Section: Discussionmentioning

confidence: 99%

Section: Relevance To Disease Association and Clinical Geneticsmentioning

confidence: 99%

An open resource of structural variation for medical and population genetics

Team¹

2019

Preprint

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“…The homozygous FEZF2 allele may possibly impact on cis elements involving deregulation of the FEZF2 gene. Such cis-regulatory structural variants associated with autism have been recently described (53). FEZF2 is also part of a developing human brain gene co-expression network enriched for neurodevelopmental disorder risk genes that includes ASD high-risk genes such as TBR1, CTTNBP2, and DSCAM (44).…”

Section: Discussionmentioning

confidence: 98%

Multi-hit autism genomic architecture evidenced from consanguineous families with involvement of FEZF2 and mutations in high-risk genes

Bensaid

Loe-Mie

Lepagnol-Bestel

et al. 2019

Preprint

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words)Autism Spectrum Disorders (ASDs) are a heterogeneous collection of neurodevelopmental disorders with a strong genetic basis. Recent studies identified that a single hit of either a de novo or transmitted gene-disrupting, or likely gene-disrupting, mutation in a subset of 65 strongly associated genes can be sufficient to generate an ASD phenotype. We took advantage of consanguineous families with an ASD proband to evaluate this model. By a genome-wide homozygosity mapping of ten families with eleven children displaying ASD, we identified a linkage region of 133 kb in five families at the 3p14.2 locus that includes FEZF2 with a LOD score of 5.8 suggesting a founder effect. Sequencing FEZF2 revealed a common deletion of four codons. However, the damaging FEZF2 mutation did not appear to be sufficient to induce the disease as non-affected parents also carry the mutation and, similarly, Fezf2 knockout mouse embryos electroporated with the mutant human FEZF2 construct did not display any obvious defects in the corticospinal tract, a pathway whose development depends on FEZF2. We extended the genetic analysis of these five FEZF2-linked families versus five FEZF2 non-linked families by studying de novo and transmitted copy number variation (CNV) and performing Whole Exome Sequencing (WES). We identified damaging mutations in the subset of 65 genes strongly associated with ASD whose co-expression analysis suggests an impact on the prefrontal cortex during the mid-fetal periods. From these results, we propose that both FEZF2 deletion and multiple hits in the repertoire of these 65 genes are necessary to generate an ASD phenotype. Significance Statement (120 words)The human neocortex is a highly organized laminar structure with neuron positioning and identity of deep-layer cortical neurons that depend on key transcription factors, such as FEZF2, SATB2, TSHZ3 and TBR1. These genes have a specific spatio-temporal pattern of expression in human midfetal deep cortical projection neurons and display mutations in patients with Autism Spectrum Disorder (ASD). Here, we identified a linkage region involving FEZF2 gene in five consanguineous families with an ASD proband. For these FEZF2-allele linked probands, we identified a four-codon deletion in FEZF2 and damaging mutations in other high-risk ASD genes, that exhibit regional and cell type-specific convergence in neocortical deep-layer excitatory neurons, suggesting a multi-hit genomic architecture of ASD in these consanguineous families.

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“…Besides the above‐described studies analyzing WGS data with an emphasis on de novo SNV and short indels, another large‐scale WGS study primarily focusing on structural variants (SV; e.g., large deletion, insertion, inversion, and mobile element insertions) was recently reported . In this study, the authors first selected SV categories that showed depletion in the real data when compared with a simulated dataset generated by randomly distributing SV in the genome.…”

Section: Rapidly Expanding Knowledge On Functional Non‐coding Elementsmentioning

confidence: 99%

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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Paternally inherited cis-regulatory structural variants are associated with autism

Cited by 172 publications

References 33 publications

An open resource of structural variation for medical and population genetics

An open resource of structural variation for medical and population genetics

Multi-hit autism genomic architecture evidenced from consanguineous families with involvement of FEZF2 and mutations in high-risk genes

Estimating contribution of rare non‐coding variants to neuropsychiatric disorders

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