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Cited by 299Autism Spectrum Disorder ResearchGenetics and Neurodevelopmental DisordersGenomics and Rare Diseases

Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder

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Lim, Elaine T, Uddin, Mohammed, De Rubeis, Silvia, Chan, Yingleong, Kamumbu, Anne S, Zhang, Xiaochang, D'Gama, Alissa M, Kim, Sonia N +22 more·2017·Nature Neuroscience
DOI 10.1038/nn.4598PMC PMC5672813
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Abstract

We systematically analyzed postzygotic mutations (PZMs) in whole-exome sequences from the largest collection of trios (5,947) with autism spectrum disorder (ASD) available, including 282 unpublished trios, and performed resequencing using multiple independent technologies. We identified 7.5% of de novo mutations as PZMs, 83.3% of which were not described in previous studies. Damaging, nonsynonymous PZMs within critical exons of prenatally expressed genes were more common in ASD probands than controls (P < 1 × 10-6), and genes carrying these PZMs were enriched for expression in the amygdala (P = 5.4 × 10-3). Two genes (KLF16 and MSANTD2) were significantly enriched for PZMs genome-wide, and other PZMs involved genes (SCN2A, HNRNPU and SMARCA4) whose mutation is known to cause ASD or other neurodevelopmental disorders. PZMs constitute a significant proportion of de novo mutations and contribute importantly to ASD risk.

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  • Recent studies have identified DOCK4 variations associated with ASD, including single nucleotide variations and chromosome microdeletions or duplications.

    “Recent studies have identified a number of DOCK4 variations associated with ASD, including both single nucleotide variations (SNVs) and chromosome microdeletions or duplications (Supplementary Table 1) 18–26.”

    From Autism-like social deficit generated by Dock4 deficiency is rescued by restoration of Rac1 activity and NMDA receptor function. (2021) · cites this paper as [25]

    The Introduction discusses copy-number variants and point mutations associated with ASD generally, but does not identify DOCK4. Searches of our copy for DOCK4 and DOCK4-associated SNVs, microdeletions, and duplications returned no passage addressing the gene-specific claim. No page numbers were supplied for these passages. (LLM, conf=0.76)

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  • In humans, mutations in MAPK3 and TAOK2 but not in KCTD13 have been found in ASD cases.

    “In humans, mutations in MAPK3 [92] and TAOK2 [93, 94] but not in KCTD13 [85, 95] have been found in ASD cases.”

    From 16p11.2 Copy Number Variations and Neurodevelopmental Disorders (2020) · cites this paper as [93]

  • LoF variants in TAOK2 are identified in ASD probands, however it is not a top-ranking ASD risk factor by large genetic screening.

    “LoF variants in TAOK2 are identified in ASD probands [93, 94], however it is not a top-ranking ASD risk factor by large genetic screening [85].”

    From 16p11.2 Copy Number Variations and Neurodevelopmental Disorders (2020) · cites this paper as [93]

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References 53 · Cited by 299

Research works printed but not linked: 38

  1. [1]Gaugler T Most genetic risk for autism resides with common variation Nature genetics 46 881 885 10.1038/ng.3039 2014 25038753 PMC4137411 · DOI · Paper page
  2. [2]Sanders SJ Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci Neuron 87 1215 1233 10.1016/j.neuron.2015.09.016 2015 26402605 PMC4624267 · DOI · Paper page
  3. [5]Iossifov I The contribution of de novo coding mutations to autism spectrum disorder Nature 515 216 221 10.1038/nature13908 2014 25363768 PMC4313871 · DOI · Paper page
  4. [6]Yu TW Using whole-exome sequencing to identify inherited causes of autism Neuron 77 259 273 10.1016/j.neuron.2012.11.002 2013 23352163 PMC3694430 · DOI · Paper page
  5. [7]Lim ET Rare complete knockouts in humans: population distribution and significant role in autism spectrum disorders Neuron 77 235 242 10.1016/j.neuron.2012.12.029 2013 23352160 PMC3613849 · DOI · Paper page
  6. [9]Poduri A Evrony GD Cai X Walsh CA Somatic mutation, genomic variation, and neurological disease Science 341 1237758 10.1126/science.1237758 2013 23828942 PMC3909954 · DOI · Paper page
  7. [10]Genovese G Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence The New England journal of medicine 371 2477 2487 10.1056/NEJMoa1409405 2014 25426838 PMC4290021 · DOI · Paper page
  8. [13]Prendergast JG Semple CA Widespread signatures of recent selection linked to nucleosome positioning in the human lineage Genome research 21 1777 1787 10.1101/gr.122275.111 2011 21903742 PMC3205563 · DOI
  9. [14]Cotney J The autism-associated chromatin modifier CHD8 regulates other autism risk genes during human neurodevelopment Nature communications 6 6404 10.1038/ncomms7404 2015 PMC4355952 25752243 · DOI · Paper page
  10. [15]Koren A Differential relationship of DNA replication timing to different forms of human mutation and variation American journal of human genetics 91 1033 1040 10.1016/j.ajhg.2012.10.018 2012 23176822 PMC3516607 · DOI
  11. [16]Woo YH Li WH DNA replication timing and selection shape the landscape of nucleotide variation in cancer genomes Nature communications 3 1004 10.1038/ncomms1982 2012 22893128 · DOI
  12. [17]Adzhubei I Jordan DM Sunyaev SR Predicting functional effect of human missense mutations using PolyPhen-2 Current protocols in human genetics / editorial board, Jonathan L. Haines … [et al.] Chapter 7 Unit7 20 10.1002/0471142905.hg0720s76 2013 PMC4480630 23315928 · DOI · Paper page
  13. [18]Kumar P Henikoff S Ng PC Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm Nature protocols 4 1073 1081 10.1038/nprot.2009.86 2009 19561590 · DOI · Paper page
  14. [19]Kircher M A general framework for estimating the relative pathogenicity of human genetic variants Nature genetics 46 310 315 10.1038/ng.2892 2014 24487276 PMC3992975 · DOI · Paper page
  15. [21]Carvill GL Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1 Nature genetics 45 825 830 10.1038/ng.2646 2013 23708187 PMC3704157 · DOI · Paper page
  16. [23]Jelinic P Recurrent SMARCA4 mutations in small cell carcinoma of the ovary Nature genetics 46 424 426 10.1038/ng.2922 2014 24658004 PMC5699446 · DOI
  17. [24]Kosho T Okamoto N Coffin-Siris Syndrome International, C Genotype-phenotype correlation of Coffin-Siris syndrome caused by mutations in SMARCB1, SMARCA4, SMARCE1, and ARID1A American journal of medical genetics Part C, Seminars in medical genetics 166C 262 275 10.1002/ajmg.c.31407 2014 25168959 · DOI
  18. [25]Forbes SA COSMIC: exploring the world's knowledge of somatic mutations in human cancer Nucleic acids research 43 D805 811 10.1093/nar/gku1075 2015 25355519 PMC4383913 · DOI
  19. [26]Pugh TJ Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations Nature 488 106 110 10.1038/nature11329 2012 22820256 PMC3413789 · DOI · Paper page
  20. [27]Qiu Z Ghosh A A calcium-dependent switch in a CREST-BRG1 complex regulates activity-dependent gene expression Neuron 60 775 787 10.1016/j.neuron.2008.09.040 2008 19081374 PMC2615455 · DOI
  21. [28]Acuna-Hidalgo R Post-zygotic Point Mutations Are an Underrecognized Source of De Novo Genomic Variation American journal of human genetics 97 67 74 10.1016/j.ajhg.2015.05.008 2015 26054435 PMC4571017 · DOI
  22. [29]Freed D Pevsner J The Contribution of Mosaic Variants to Autism Spectrum Disorder PLoS genetics 12 e1006245 10.1371/journal.pgen.1006245 2016 27632392 PMC5024993 · DOI
  23. [32]Baron-Cohen S The amygdala theory of autism Neuroscience and biobehavioral reviews 24 355 364 2000 10781695
  24. [33]Rutishauser U Single-neuron correlates of atypical face processing in autism Neuron 80 887 899 10.1016/j.neuron.2013.08.029 2013 24267649 PMC3934412 · DOI
  25. [34]Xu X Modular genetic control of sexually dimorphic behaviors Cell 148 596 607 10.1016/j.cell.2011.12.018 2012 22304924 PMC3326403 · DOI
  26. [36]Campbell IM Parental somatic mosaicism is underrecognized and influences recurrence risk of genomic disorders American journal of human genetics 95 173 182 10.1016/j.ajhg.2014.07.003 2014 25087610 PMC4129404 · DOI
  27. [37]O'Roak BJ Recurrent de novo mutations implicate novel genes underlying simplex autism risk Nature communications 5 5595 10.1038/ncomms6595 2014 PMC4249945 25418537 · DOI · Paper page
  28. [38]Lindhurst MJ A mosaic activating mutation in AKT1 associated with the Proteus syndrome The New England journal of medicine 365 611 619 10.1056/NEJMoa1104017 2011 21793738 PMC3170413 · DOI
  29. [39]Weiss LA Association between microdeletion and microduplication at 16p11.2 and autism The New England journal of medicine 358 667 675 10.1056/NEJMoa075974 2008 18184952 · DOI · Paper page
  30. [40]Sebat J Strong association of de novo copy number mutations with autism Science 316 445 449 10.1126/science.1138659 2007 17363630 PMC2993504 · DOI · Paper page
  31. [41]DePristo MA A framework for variation discovery and genotyping using next-generation DNA sequencing data Nature genetics 43 491 498 10.1038/ng.806 2011 21478889 PMC3083463 · DOI
  32. [42]Cingolani P A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3 Fly 6 80 92 10.4161/fly.19695 2012 22728672 PMC3679285 · DOI · Paper page
  33. [44]Kang HJ Spatio-temporal transcriptome of the human brain Nature 478 483 489 10.1038/nature10523 2011 22031440 PMC3566780 · DOI · Paper page
  34. [46]Iossifov I De novo gene disruptions in children on the autistic spectrum Neuron 74 285 299 10.1016/j.neuron.2012.04.009 2012 22542183 PMC3619976 · DOI · Paper page
  35. [47]Fromer M De novo mutations in schizophrenia implicate synaptic networks Nature 506 179 184 10.1038/nature12929 2014 24463507 PMC4237002 · DOI · Paper page
  36. [48]Ramos P Small cell carcinoma of the ovary, hypercalcemic type, displays frequent inactivating germline and somatic mutations in SMARCA4 Nature genetics 46 427 429 10.1038/ng.2928 2014 24658001 PMC4332808 · DOI
  37. [49]Le Loarer F SMARCA4 inactivation defines a group of undifferentiated thoracic malignancies transcriptionally related to BAF-deficient sarcomas Nature genetics 47 1200 1205 10.1038/ng.3399 2015 26343384 · DOI
  38. [50]Tsurusaki Y Mutations affecting components of the SWI/SNF complex cause Coffin-Siris syndrome Nature genetics 44 376 378 10.1038/ng.2219 2012 22426308 · DOI

Authors
Lim, E. T., Uddin, M., De Rubeis, S., Chan, Y., Kamumbu, A. S., Zhang, X., D'Gama, A. M., Kim, S. N., Hill, R. S., Goldberg, A. P., Poultney, C., Minshew, N. J., Kushima, I., Aleksic, B., Ozaki, N., Parellada, M., Arango, C., Penzol, M. J., Carracedo, A., Kolevzon, A., Hultman, C. M., Weiss, L. A., Fromer, M., Chiocchetti, A. G., Freitag, C. M., Autism Sequencing Consortium, Church, G. M., Scherer, S. W., Buxbaum, J. D., & Walsh, C. A.
Affiliations
  • Broad Institute (US)
  • Mohammed Bin Rashid University of Medicine and Health Sciences (AE)
  • Icahn School of Medicine at Mount Sinai (US)
  • University of Pittsburgh (US)
  • Nagoya University (JP)
  • Universidad Complutense de Madrid (ES)
  • Karolinska Institutet (SE)
  • University of California, San Francisco (US)
  • Goethe University Frankfurt (DE)
  • University of Toronto (CA)
Corresponding author
  • Lim, Elaine T
  • Walsh, Christopher A
ORCID
Venue
Nature Neuroscience
Publisher
Springer Science and Business Media LLC
Published
2017-07-17
Volume
20
Issue
9
Pages
1217-1224
ISSN
  • 1097-6256 (ISSN-L)
  • 1546-1726
DOI
10.1038/nn.4598
PMC
PMC5672813
OpenAlex
W2734527849
Cited by
299
References
53
Citations by year
2026: 23 · 2025: 19 · 2024: 31 · 2023: 29 · 2022: 42 · 2021: 40 · 2020: 47 · 2019: 34 · 2018: 26 · 2017: 8
FWCI
18.20
Type
journal article
Language
en
Update notices
correction (2020-07-14)
Open access
Licence
Locations
  • Nature Neuroscience (publishedVersion)
  • PubMed (publishedVersion)
  • ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • HAL (submittedVersion, other-oa)
  • Institutional Research Information System University of Turin (University of Turin) (submittedVersion, other-oa)
  • Use Siena air (University of Siena) (submittedVersion, other-oa)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
  • LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, other-oa)
  • eScholarship (California Digital Library) (submittedVersion)
  • IRIS UNIMORE (University of Modena and Reggio Emilia) (submittedVersion, cc-by)
Funders
  • Howard Hughes Medical Institute
  • Autism Speaks
  • Amgen
  • AstraZeneca
  • GlaxoSmithKline
  • Fundación Alicia Koplowitz
  • Genome Canada
  • Japan Agency for Medical Research and Development
  • Simons Foundation Autism Research Initiative
  • Fundación María José Jove
  • Ministerio de Economía y Competitividad (PI13/01136)
  • University of Toronto
  • Hospital for Sick Children
  • Centro de Investigación Biomédica en Red de Salud Mental
  • National Institutes of Health (1s10od018522-01, 5rc2mh089952-02, PI13/01136, 1rc2hl103010-01, 1s10rr028832-01)
  • Instituto de Salud Carlos III (PI13/01136)
  • National Heart, Lung, and Blood Institute (HL 102923, RC2HL102925, HL-102924, HL-102925, RC2HL102926, RC2HL102923, UC2HL102924, RC2HL-103010, UC2HL102925, HL 103010, UC2HL102923, UC2HL103010, RC2HL102924, UC2HL102926, HL-102926)
  • National Institute of Mental Health (U01MH100209, R21MH106888, R01MH083565, U01MH111661, U01MH100229, R01MH097849, RC2-MH089952, U01MH106883, U01MH100239, R01MH106910, U01MH111662, R01MH113362, R01MH095797, U01MH100233)
  • National Human Genome Research Institute (P50HG005550, RM1HG008525)
  • National Institute of General Medical Sciences (T32GM007753, T32GM007226)
  • National Institute of Neurological Disorders and Stroke (R01NS032457)
  • National Center for Research Resources (S10 RR028832, 1S10RR028832, 1S10RR028832-01)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD090255)
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
Keywords
autism spectrum disorder, de novo mutations, germline mutations, trios, amygdala, SMARCA4, KLF16, SCN2A, HNRNPU, neurodevelopmental disorders, mutation rate
MeSH terms
Autism Spectrum Disorder, Humans, Mosaicism, Genetic Variation, Zygote, Genetic Predisposition to Disease, Mutation, Missense, Databases, Genetic

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