Haploinsufficiency of SOX5 at 12p12.1 is associated with developmental delays with prominent language delay, behavior problems, and mild dysmorphic features
Open accessAbstract
SOX5 encodes a transcription factor involved in the regulation of chondrogenesis and the development of the nervous system. Despite its important developmental roles, SOX5 disruption has yet to be associated with human disease. We report one individual with a reciprocal translocation breakpoint within SOX5, eight individuals with intragenic SOX5 deletions (four are apparently de novo and one inherited from an affected parent), and seven individuals with larger 12p12 deletions encompassing SOX5. Common features in these subjects include prominent speech delay, intellectual disability, behavior abnormalities, and dysmorphic features. The phenotypic impact of the deletions may depend on the location of the deletion and, consequently, which of the three major SOX5 protein isoforms are affected. One intragenic deletion, involving only untranslated exons, was present in a more mildly affected subject, was inherited from a healthy parent and grandparent, and is similar to a deletion found in a control cohort. Therefore, some intragenic SOX5 deletions may have minimal phenotypic effect. Based on the location of the deletions in the subjects compared to the controls, the de novo nature of most of these deletions, and the phenotypic similarities among cases, SOX5 appears to be a dosage-sensitive, developmentally important gene.
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SOX5 has a known role in mammalian corticogenesis.
“Among the transcription factors identified, SOX5 was of particular interest because of its known role in mammalian corticogenesis23,24, its sole membership in the ACP set, and its correlation with predicted targets in the brains of control subjects, which is lost in ASD (Fig. 2b–d).”
From Genome-wide changes in lncRNA, splicing, and regional gene expression patterns in autism (2016) · cites this paper as [24]
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“Among the transcription factors identified, SOX5 was of particular interest because of its known role in mammalian corticogenesis 23,24 , its sole membership in the ACP set, and its correlation with predicted targets in the brains of control subjects, which is lost in ASD (Fig.”
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- Authors
- Lamb, A. N., Rosenfeld, J. A., Neill, N. J., Talkowski, M. E., Blumenthal, I., Girirajan, S., Keelean-Fuller, D., Fan, Z., Pouncey, J., Stevens, C., Mackay-Loder, L., Terespolsky, D., Bader, P. I., Rosenbaum, K., Vallee, S. E., Moeschler, J. B., Ladda, R., Sell, S., Martin, J., Ryan, S., Jones, M. C., Moran, R., Shealy, A., Madan-Khetarpal, S., McConnell, J., Surti, U., Delahaye, A., Heron-Longe, B., Pipiras, E., Benzacken, B., Passemard, S., Verloes, A., Isidor, B., Le Caignec, C., Glew, G. M., Opheim, K. E., Descartes, M., Eichler, E. E., Morton, C. C., Gusella, J. F., Schultz, R. A., Ballif, B. C., & Shaffer, L. G.
- Affiliations
- PerkinElmer (United States) (US)
- Broad Institute (US)
- Massachusetts General Hospital (US)
- University of Washington (US)
- University of North Carolina at Chapel Hill (US)
- Credit Valley Hospital (CA)
- Parkview Health (US)
- Children's National (US)
- Dartmouth–Hitchcock Medical Center (US)
- Pennsylvania State University (US)
- Providence Sacred Heart Medical Center (US)
- University of California San Diego (US)
- Cleveland Clinic (US)
- Children's Hospital of Pittsburgh (US)
- University of Pittsburgh (US)
- Inserm (FR)
- Centre Hospitalier Universitaire de Nantes (FR)
- Seattle Children's Hospital (US)
- University of Alabama at Birmingham (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Shaffer, Lisa G.
- ORCID
- Venue
- Human Mutation
- Publisher
- Hindawi Limited
- Published
- 2012-03-12
- Volume
- 33
- Issue
- 4
- Pages
- 728-740
- ISSN
- 1059-7794 (ISSN-L)
- PMC
- PMC3618980
- OpenAlex
- W2098036819
- Cited by
- 107
- References
- 58
- Citations by year
- 2026: 6 · 2025: 9 · 2024: 7 · 2023: 10 · 2022: 8 · 2021: 6 · 2020: 5 · 2019: 11 · 2018: 10 · 2017: 6 · 2016: 7 · 2015: 9 · 2013: 9 · 2012: 4
- FWCI
- 4.23
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Human Mutation (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- Research Explorer (The University of Manchester) (submittedVersion)
- UNC Libraries
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health (GM061354)
- National Institute of Mental Health (R00MH095867, F32MH087123)
- National Institute of General Medical Sciences (GM061354, P01GM061354)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD065286, R21HD065286)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- 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
- SOX5, haploinsufficiency, reciprocal translocation, intragenic deletion, de novo deletion, speech delay, language delay, intellectual disability, behavioral problems, dysmorphic features, transcription factors, dosage-sensitive genes, protein isoforms, chondrogenesis, brain development
- MeSH terms
- Adolescent, Adult, Mental Disorders, Child, Developmental Disabilities, Child, Preschool, Chromosomes, Human, Pair 12, Female, Humans, Language Development Disorders, Male, Case-Control Studies, SOXD Transcription Factors, Body Dysmorphic Disorders, Haploinsufficiency
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