A double hit implicates DIAPH3 as an autism risk gene
Open accessAbstract
Recent studies have shown that more than 10% of autism cases are caused by de novo structural genomic rearrangements. Given that some heritable copy number variants (CNVs) have been observed in patients as well as in healthy controls, to date little attention has been paid to the potential function of these non-de novo CNVs in causing autism. A normally intelligent patient with autism, with non-affected parents, was identified with a maternally inherited 10 Mb deletion at 13q21.2. Sequencing of the genes within the deletion identified a paternally inherited nonsynonymous amino-acid substitution at position 614 of diaphanous homolog 3 (DIAPH3) (proline to threonine; Pro614Thr). This variant, present in a highly conserved domain, was not found in 328 healthy subjects. Experiments showed a transient expression of Diaph3 in the developing murine cerebral cortex, indicating it has a function in brain development. Transfection of Pro614Thr in murine fibroblasts showed a significant reduction in the number of induced filopodia in comparison to the wild-type gene. DIAPH3 is involved in cell migration, axon guidance and neuritogenesis, and is suggested to function downstream of SHANK3. Our findings strongly suggest DIAPH3 as a novel autism susceptibility gene. Moreover, this report of a 'double-hit' compound heterozygote for a large, maternally inherited, genomic deletion and a paternally inherited rare missense mutation shows that not only de novo genomic variants in patients should be taken seriously in further study but that inherited CNVs may also provide valuable information.
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Several studies recently supported the existence of a combination of rare variants in some cases of autism.
“Several studies recently supported the existence of such a combination of rare variants in some cases”
From Autism risk factors: genes, environment, and gene-environment interactions (2012) · cites this paper as [50]
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- Authors
- Vorstman, J. A. S., van Daalen, E., Jalali, G. R., Schmidt, E. R. E., Pasterkamp, R. J., de Jonge, M., Hennekam, E. A. M., Janson, E., Staal, W. G., van der Zwaag, B., Burbach, J. P. H., Kahn, R. S., Emanuel, B. S., van Engeland, H., & Ophoff, R. A.
- Affiliations
- Children's Hospital of Philadelphia (US)
- University Medical Center Utrecht (NL)
- University of California, Los Angeles (US)
- Corresponding author
- Vorstman, J A S
- ORCID
- Venue
- Molecular Psychiatry
- Published
- 2010-03-23
- Volume
- 16
- Issue
- 4
- Pages
- 442-451
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- PMC
- PMC3334288
- OpenAlex
- W2003169554
- Cited by
- 74
- References
- 54
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 1 · 2023: 4 · 2022: 4 · 2021: 6 · 2020: 3 · 2019: 3 · 2018: 1 · 2017: 8 · 2016: 4 · 2015: 4 · 2014: 3 · 2013: 9 · 2012: 11
- FWCI
- 5.22
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion, other-oa)
- Trinity's Access to Research Output (TARA) (Trinity College Dublin) (submittedVersion)
- Funders
- National Cancer Institute (R01CA039926)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Keywords
- DIAPH3, autism spectrum disorder, copy number variation, compound heterozygosity, missense mutations, filopodia, cortical development, SHANK3, autism susceptibility genes
- MeSH terms
- Formins, Adolescent, Animals, Animals, Newborn, Autistic Disorder, Brain, Cell Line, Transformed, Cognition Disorders, Family Health, Genotype, Humans, Male, Transfection, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Adaptor Proteins, Signal Transducing, Mice, Genome-Wide Association Study
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