CoChat
Sign Up
Cited by 139Genomic variations and chromosomal abnormalitiesAutism Spectrum Disorder ResearchGenetics and Neurodevelopmental Disorders

Characterization of a family with rare deletions in CNTNAP5 and DOCK4 suggests novel risk loci for autism and dyslexia.

Open access
Pagnamenta, Alistair T., Bacchelli, Elena, de Jonge, Maretha V., Mirza, Ghazala, Scerri, Thomas S., Minopoli, Fiorella, Chiocchetti, Andreas, Ludwig, Kerstin U. +19 more·2010·Biological Psychiatry
DOI 10.1016/j.biopsych.2010.02.002PMC PMC2941017
Open this paper in CoChat — free account

Abstract

BACKGROUND: Autism spectrum disorders (ASDs) are characterized by social, communication, and behavioral deficits and complex genetic etiology. A recent study of 517 ASD families implicated DOCK4 by single nucleotide polymorphism (SNP) association and a microdeletion in an affected sibling pair. METHODS: The DOCK4 microdeletion on 7q31.1 was further characterized in this family using QuantiSNP analysis of 1M SNP array data and reverse transcription polymerase chain reaction. Extended family members were tested by polymerase chain reaction amplification of junction fragments. DOCK4 dosage was measured in additional samples using SNP arrays. Since QuantiSNP analysis identified a novel CNTNAP5 microdeletion in the same affected sibling pair, this gene was sequenced in 143 additional ASD families. Further polymerase chain reaction-restriction fragment length polymorphism analysis included 380 ASD cases and suitable control subjects. RESULTS: The maternally inherited microdeletion encompassed chr7:110,663,978-111,257,682 and led to a DOCK4-IMMP2L fusion transcript. It was also detected in five extended family members with no ASD. However, six of nine individuals with this microdeletion had poor reading ability, which prompted us to screen 606 other dyslexia cases. This led to the identification of a second DOCK4 microdeletion co-segregating with dyslexia. Assessment of genomic background in the original ASD family detected a paternal 2q14.3 microdeletion disrupting CNTNAP5 that was also transmitted to both affected siblings. Analysis of other ASD cohorts revealed four additional rare missense changes in CNTNAP5. No exonic deletions of DOCK4 or CNTNAP5 were seen in 2091 control subjects. CONCLUSIONS: This study highlights two new risk factors for ASD and dyslexia and demonstrates the importance of performing a high-resolution assessment of genomic background, even after detection of a rare and likely damaging microdeletion using a targeted approach.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/j.biopsych.2010.02.002

Cites

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • DOCK4 is one of few genes associated with both autism spectrum disorder (ASD) and dyslexia.

    “DOCK4 (dedicator for cytokinesis 4), a guanine nucleotide exchange factor (GEF) for the small GTPase Rac1, is one of few genes that are associated with both ASD and dyslexia.”

    From Two Autism/Dyslexia Linked Variations of DOCK4 Disrupt the Gene Function on Rac1/Rap1 Activation, Neurite Outgrowth, and Synapse Development (2020) · cites this paper as Pagnamenta et al., 2010

    The Results report DOCK4 deletions in an ASD family and a deletion co-segregating with dyslexia in another family. The Discussion cautions that larger studies are needed to confirm DOCK4’s relevance to reading ability; the paper also does not establish that it is one of only a few genes linked to both conditions. Page numbers are unavailable in our copy. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Two specific DOCK4 variations, Exon27-52 deletion (Dock4-945VS) and rs2074130 missense (Dock4-R853H), are associated with dyslexia and/or ASD with reading difficulties.

    “Two DOCK4 variations, Exon27-52 deletion (protein product: Dock4-945VS) and a missense mutation at rs2074130 (protein product: Dock4-R853H), are associated with dyslexia and/or ASD with reading difficulties.”

    From Two Autism/Dyslexia Linked Variations of DOCK4 Disrupt the Gene Function on Rac1/Rap1 Activation, Neurite Outgrowth, and Synapse Development (2020) · cites this paper as Pagnamenta et al., 2010

    The Results (page unavailable) describe a DOCK4 deletion in an ASD family whose carriers had poor reading ability, and a second deletion that co-segregated with dyslexia. The Discussion cautions that larger studies are needed to confirm DOCK4’s relevance to reading ability. Our copy does not identify the deletion as Exon27–52 or its product as Dock4-945VS, and it does not report the rs2074130/Dock4-R853H missense variant. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • The Exon27-52 deletion in DOCK4 causes a frameshift after amino acid 945, producing Dock4-945VS (1-945 aa + Val + Ser) with a premature stop.

    “This variant leads to the deletion of the DHR2-containing C-terminal coding sequence of DOCK4 (Exons 27-52), which causes a frameshift of Dock4 protein coding after 945 aa; two missense amino acids, namely Valine (Val) and Serine (Ser), is translated after 945 aa, followed by a premature stop codon (Pagnamenta et al., 2010).”

    From Two Autism/Dyslexia Linked Variations of DOCK4 Disrupt the Gene Function on Rac1/Rap1 Activation, Neurite Outgrowth, and Synapse Development (2020) · cites this paper as Pagnamenta et al., 2010

    The Results (page unavailable) report an out-of-frame DOCK4–IMMP2L fusion transcript predicted to translate Valine–Serine followed by a premature stop codon. Our copy does not specify a frameshift after amino acid 945 or identify exons 27–52 as the deleted sequence, so those details are not verified by this source. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Several microdeletions lead to loss of various lengths of the C-terminal portion of Dock4 protein, which is responsible for its Rac1-activating ability.

    “For instance, several microdeletions lead to loss of various lengths of the C-terminal portion of Dock4 protein 19, 21, 26, which is responsible for its Rac1-activating ability 27.”

    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 [19]

    The Results report distinct DOCK4 deletions: a 594-kb IMMP2L–DOCK4 deletion and a 132-kb deletion of DOCK4 exons 38–52. They do not establish that these deletions produce proteins missing different lengths of the C-terminal portion; for the 594-kb deletion, the reported fusion transcript is likely subject to nonsense-mediated decay. The Rac1-activation clause has a separate citation in the citing sentence, although this paper’s Discussion does describe DOCK4 as a Rac1-activating factor. Page numbers were not available in our copy. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • 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 [19]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

The citation lists haven’t been fetched yet

References 45 · Cited by 139

Research works printed but not linked: 33

  1. [4]Jamain S. Quach H. Betancur C. Rastam M. Colineaux C. Gillberg I.C. Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism Nat Genet 34 2003 27 29 12669065 PMC1925054
  2. [6]Sebat J. Lakshmi B. Malhotra D. Troge J. Lese-Martin C. Walsh T. Strong association of de novo copy number mutations with autism Science 316 2007 445 449 17363630 PMC2993504
  3. [7]Szatmari P. Paterson A.D. Zwaigenbaum L. Roberts W. Brian J. Liu X.Q. Mapping autism risk loci using genetic linkage and chromosomal rearrangements Nat Genet 39 2007 319 328 17322880 PMC4867008
  4. [8]Bakkaloglu B. O'Roak B.J. Louvi A. Gupta A.R. Abelson J.F. Morgan T.M. Molecular cytogenetic analysis and resequencing of contactin associated protein-like 2 in autism spectrum disorders Am J Hum Genet 82 2008 165 173 18179895 PMC2253974
  5. [9]Rossi E. Verri A.P. Patricelli M.G. Destefani V. Ricca I. Vetro A. A 12Mb deletion at 7q33-q35 associated with autism spectrum disorders and primary amenorrhea Eur J Med Genet 51 2008 631 638 18675947
  6. [10]Zweier C. de Jong E.K. Zweier M. Orrico A. Ousager L.B. Collins A.L. CNTNAP2 and NRXN1 are mutated in autosomal-recessive Pitt–Hopkins-like mental retardation and determine the level of a common synaptic protein in Drosophila Am J Hum Genet 85 2009 655 666 19896112 PMC2775834
  7. [11]Friedman J.I. Vrijenhoek T. Markx S. Janssen I.M. van der Vliet W.A. Faas B.H. CNTNAP2 gene dosage variation is associated with schizophrenia and epilepsy Mol Psychiatry 13 2008 261 266 17646849
  8. [12]Pagnamenta A.T. Wing K. Akha E.S. Knight S.J. Bolte S. Schmotzer G. A 15q13.3 microdeletion segregating with autism Eur J Hum Genet 17 2009 687 692 19050728 PMC2986268
  9. [15]Stefansson H. Rujescu D. Cichon S. Pietilainen O.P. Ingason A. Steinberg S. Large recurrent microdeletions associated with schizophrenia Nature 455 2008 232 236 18668039 PMC2687075
  10. [16]Walsh T. McClellan J.M. McCarthy S.E. Addington A.M. Pierce S.B. Cooper G.M. Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia Science 320 2008 539 543 18369103
  11. [17]Barrett S. Beck J.C. Bernier R. Bisson E. Braun T.A. Casavant T.L. An autosomal genomic screen for autism: Collaborative linkage study of autism Am J Med Genet 88 1999 609 615 10581478
  12. [18]International Molecular Genetic Study of Autism Consortium A full genome screen for autism with evidence for linkage to a region on chromosome 7q. International Molecular Genetic Study of Autism Consortium Hum Mol Genet 7 1998 571 578 9546821
  13. [20]Shao Y. Wolpert C.M. Raiford K.L. Menold M.M. Donnelly S.L. Ravan S.A. Genomic screen and follow-up analysis for autistic disorder Am J Med Genet 114 2002 99 105 11840513
  14. [21]Badner J.A. Gershon E.S. Regional meta-analysis of published data supports linkage of autism with markers on chromosome 7 Mol Psychiatry 7 2002 56 66 11803446
  15. [22]Trikalinos T.A. Karvouni A. Zintzaras E. Ylisaukko-Oja T. Peltonen L. Jarvela I. Ioannidis J.P. A heterogeneity-based genome search meta-analysis for autism-spectrum disorders Mol Psychiatry 11 2006 29 36 16189507
  16. [23]Maestrini E. Pagnamenta A.T. Lamb J.A. Bacchelli E. Sykes N.H. Sousa I. High-density SNP association study and copy number variation analysis of the AUTS1 and AUTS5 loci implicate the IMMP2L-DOCK4 gene region in autism susceptibility [published online ahead of print April 28] Mol Psychiatry 2009 PMC2934739 19401682
  17. [24]Ueda S. Fujimoto S. Hiramoto K. Negishi M. Katoh H. Dock4 regulates dendritic development in hippocampal neurons J Neurosci Res 86 2008 3052 3061 18615735
  18. [25]Diaz-Anzaldua A. Joober R. Riviere J.B. Dion Y. Lesperance P. Chouinard S. Association between 7q31 markers and Tourette syndrome Am J Med Genet A 127A 2004 17 20 15103711
  19. [26]Petek E. Windpassinger C. Vincent J.B. Cheung J. Boright A.P. Scherer S.W. Disruption of a novel gene (IMMP2L) by a breakpoint in 7q31 associated with Tourette syndrome Am J Hum Genet 68 2001 848 858 11254443 PMC1275638
  20. [27]de Silva M.G. Elliott K. Dahl H.H. Fitzpatrick E. Wilcox S. Delatycki M. Disruption of a novel member of a sodium/hydrogen exchanger family and DOCK3 is associated with an attention deficit hyperactivity disorder-like phenotype J Med Genet 40 2003 733 740 14569117 PMC1735283
  21. [29]Colella S. Yau C. Taylor J.M. Mirza G. Butler H. Clouston P. QuantiSNP: An objective Bayes Hidden-Markov Model to detect and accurately map copy number variation using SNP genotyping data Nucleic Acids Res 35 2007 2013 2025 17341461 PMC1874617
  22. [30]Saugier-Veber P. Goldenberg A. Drouin-Garraud V. de la Rochebrochard C. Layet V. Drouot N. Simple detection of genomic microdeletions and microduplications using QMPSF in patients with idiopathic mental retardation Eur J Hum Genet 14 2006 1009 1017 16773131
  23. [31]Pfaffl M. A new mathematical model for relative quantification in real-time RT-PCR Nucleic Acids Res 29 2001 e45 11328886 PMC55695
  24. [33]Ramensky V. Bork P. Sunyaev S. Human non-synonymous SNPs: Server and survey Nucleic Acids Res 30 2002 3894 3900 12202775 PMC137415
  25. [34]Klauck S.M. Felder B. Kolb-Kokocinski A. Schuster C. Chiocchetti A. Schupp I. Mutations in the ribosomal protein gene RPL10 suggest a novel modulating disease mechanism for autism Mol Psychiatry 11 2006 1073 1084 16940977
  26. [35]Iafrate A.J. Feuk L. Rivera M.N. Listewnik M.L. Donahoe P.K. Qi Y. Detection of large-scale variation in the human genome Nat Genet 36 2004 949 951 15286789
  27. [36]Sherry S.T. Ward M.H. Kholodov M. Baker J. Phan L. Smigielski E.M. Sirotkin K. dbSNP: The NCBI database of genetic variation Nucleic Acids Res 29 2001 308 311 11125122 PMC29783
  28. [37]Hutcheson H.B. Olson L.M. Bradford Y. Folstein S.E. Santangelo S.L. Sutcliffe J.S. Haines J.L. Examination of NRCAM, LRRN3, KIAA0716, and LAMB1 as autism candidate genes BMC Med Genet 5 2004 12 15128462 PMC420465
  29. [38]Elia J. Gai X. Xie H.M. Perin J.C. Geiger E. Glessner J.T. Rare structural variants found in attention-deficit hyperactivity disorder are preferentially associated with neurodevelopmental genes [published online ahead of print June 23] Mol Psychiatry 2009 PMC2877197 19546859
  30. [39]Kaminen N. Hannula-Jouppi K. Kestila M. Lahermo P. Muller K. Kaaranen M. A genome scan for developmental dyslexia confirms linkage to chromosome 2p11 and suggests a new locus on 7q32 J Med Genet 40 2003 340 345 12746395 PMC1735449
  31. [40]Pannekoek W.J. Kooistra M.R. Zwartkruis F.J. Bos J.L. Cell-cell junction formation: The role of Rap1 and Rap1 guanine nucleotide exchange factors Biochim Biophys Acta 1788 2009 790 796 19159611
  32. [42]Weichenhan D. Traut W. Gongrich C. Himmelbauer H. Busch L. Monyer H. Winking H. A mouse translocation associated with Caspr5-2 disruption and perinatal lethality Mamm Genome 19 2008 675 686 18949514
  33. [44]Ballarati L. Recalcati M.P. Bedeschi M.F. Lalatta F. Valtorta C. Bellini M. Cytogenetic, FISH and array-CGH characterization of a complex chromosomal rearrangement carried by a mentally and language impaired patient Eur J Med Genet 52 2009 218 223 19236961

Authors
Pagnamenta, A. T., Bacchelli, E., de Jonge, M. V., Mirza, G., Scerri, T. S., Minopoli, F., Chiocchetti, A., Ludwig, K. U., Hoffmann, P., Paracchini, S., Lowy, E., Harold, D. H., Chapman, J. A., Klauck, S. M., Poustka, F., Houben, R. H., Staal, W. G., Ophoff, R. A., O'Donovan, M. C., Williams, J., Nöthen, M. M., Schulte-Körne, G., Deloukas, P., Ragoussis, J., Bailey, A. J., Maestrini, E., & Monaco, A. P.
Affiliations
  • Centre for Human Genetics (GB)
  • University of Bologna (IT)
  • German Cancer Research Center (DE)
  • University of Bonn (DE)
  • Goethe University Frankfurt (DE)
  • University Medical Center Utrecht (NL)
  • University of California, Los Angeles (US)
  • Wellcome Sanger Institute (GB)
  • Warneford Hospital (GB)
Corresponding author
Monaco, Anthony P.
ORCID
Venue
Biological Psychiatry
Publisher
Elsevier BV
Published
2010-08
Volume
68
Issue
4
Pages
320-328
ISSN
0006-3223 (ISSN-L)
DOI
10.1016/j.biopsych.2010.02.002
PMC
PMC2941017
OpenAlex
W2022575794
Cited by
139
References
45
Citations by year
2026: 2 · 2025: 6 · 2024: 6 · 2023: 11 · 2022: 9 · 2021: 9 · 2020: 8 · 2019: 8 · 2018: 6 · 2017: 7 · 2016: 8 · 2015: 10 · 2014: 15 · 2013: 11 · 2012: 9
FWCI
6.12
Type
journal article
Language
en
Open access
Licence
Locations
  • Biological Psychiatry (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Newcastle University ePrints (Newcastle Univesity)
Funders
  • Nancy Lurie Marks Family Foundation
  • Simons Foundation
  • Wellcome Trust (075491/Z/04, 068545/Z/02)
  • Deutsche Forschungsgemeinschaft
  • European Union in the Sixth Framework Program
  • LifeScienceHealth
  • Dyslexia genes and neurobiological pathways
  • National Institute of Mental Health
  • United Kingdom Medical Research Council (G0000934)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Keywords
autism spectrum disorder, dyslexia, DOCK4, microdeletion, genetic susceptibility loci, missense mutations, genetic background
MeSH terms
Adult, Child, Child Development Disorders, Pervasive, Child, Preschool, DNA, Dyslexia, Female, Gene Expression Regulation, Humans, Male, Middle Aged, Pedigree, Reference Values, Severity of Illness Index, Transcription, Genetic, Cell Adhesion Molecules, Neuronal, Case-Control Studies, Sequence Deletion, Polymorphism, Single Nucleotide, GTPase-Activating Proteins

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review