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Cited by 114Autism Spectrum Disorder ResearchGenetics and Neurodevelopmental DisordersGenomics and Rare Diseases

Exome sequencing in multiplex autism families suggests a major role for heterozygous truncating mutations

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Toma, C, Torrico, B, Hervás, A, Valdés-Mas, R, Tristán-Noguero, A, Padillo, V, Maristany, M, Salgado, M +4 more·2014·Molecular Psychiatry
DOI 10.1038/mp.2013.106
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Abstract

Autism is a severe neurodevelopmental disorder, the aetiology of which remains mainly unknown. Family and twin studies provide strong evidence that genetic factors have a major role in the aetiology of this disease. Recently, whole exome sequencing (WES) efforts have focused mainly on rare de novo variants in singleton families. Although these studies have provided pioneering insights, de novo variants probably explain only a small proportion of the autism risk variance. In this study, we performed exome sequencing of 10 autism multiplex families with the aim of investigating the role of rare variants that are coinherited in the affected sibs. The pool of variants selected in our study is enriched with genes involved in neuronal functions or previously reported in psychiatric disorders, as shown by Gene Ontology analysis and by browsing the Neurocarta database. Our data suggest that rare truncating heterozygous variants have a predominant role in the aetiology of autism. Using a multiple linear regression model, we found that the burden of truncating mutations correlates with a lower non-verbal intelligence quotient (NVIQ). Also, the number of truncating mutations that were transmitted to the affected sibs was significantly higher (twofold) than those not transmitted. Protein-protein interaction analysis performed with our list of mutated genes revealed that the postsynaptic YWHAZ is the most interconnected node of the network. Among the genes found disrupted in our study, there is evidence suggesting that YWHAZ and also the X-linked DRP2 may be considered as novel autism candidate genes.

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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 [22]

    The Results section lists inherited copy-number variants in several genes, but not DOCK4. A search of our copy for DOCK4 and for DOCK4 deletions, duplications, and single-nucleotide variants found no passage addressing DOCK4 variation in ASD (page numbers unavailable). (LLM, conf=0.75)

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Authors
Toma, C., Torrico, B., Hervás, A., Valdés-Mas, R., Tristán-Noguero, A., Padillo, V, Maristany, M., Salgado, M., Arenas, C., Puente, X. S., Bayés, M., & Cormand, B.
Affiliations
  • Centre for Biomedical Network Research on Rare Diseases (ES)
  • Hospital Sant Joan de Déu Barcelona (ES)
  • University Hospital Mútua de Terrassa (ES)
  • Universitat de Barcelona (ES)
  • Universidad de Oviedo (ES)
  • Centro Nacional de Análisis Genómico (ES)
Corresponding author
Cormand, B
ORCID
Venue
Molecular Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2013-09-03
Volume
19
Issue
7
Pages
784-790
ISSN
  • 1359-4184 (ISSN-L)
  • 1476-5578
DOI
10.1038/mp.2013.106
OpenAlex
W2162475253
Cited by
114
References
5
Citations by year
2026: 1 · 2025: 3 · 2024: 9 · 2023: 8 · 2022: 7 · 2021: 8 · 2020: 12 · 2019: 10 · 2018: 9 · 2017: 13 · 2016: 12 · 2015: 17 · 2014: 3 · 2013: 1
FWCI
6.02
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
  • DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, other-oa)
  • Consultation of the Doctoral Thesis Database (TESEO) (Ministerio de Educación, Cultura y Deporte) (submittedVersion, cc-by-nc-nd)
Funders
  • Fundación Alicia Koplowitz
  • Fundació la Marató de TV3 (092010)
  • European Commission (254930)
  • Ministerio de Economía y Competitividad (SAF2012-33484, SAF2012)
  • Agència de Gestió d'Ajuts Universitaris i de Recerca
  • National Heart, Lung, and Blood Institute
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, multiplex families, truncating mutations, heterozygous mutation, rare variants, nonverbal intelligence, 14-3-3ζ, postsynaptic proteins, protein-protein interaction network, autism candidate genes, genetic aetiology
MeSH terms
Autistic Disorder, Child, Child, Preschool, Female, Heterozygote, Humans, Intelligence, Male, Mutation, Nerve Tissue Proteins, Genetic Predisposition to Disease, Databases, Genetic, Intercellular Signaling Peptides and Proteins, 14-3-3 Proteins, Young Adult, Exome, Protein Interaction Maps

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