Mar 29, 2019 SON mutation causes intellectual disability

A gene that encodes a DNA-binding protein causes an intellectual disability syndrome

A computer graphic illustration depicts a point mutation: this type of mutation can range from benign (e.g. a synonymous mutation) to catastrophic (e.g. a frameshift mutation), in terms of protein production, composition, and function

©  Alfred Pasieka / Science Photo Library

Information from four different research groups has linked a non-inherited SON gene mutation with a discernible set of differences in childhood development. Children with the newly identified syndrome experience intellectual disability, congenital heart disease, distinctive facial features, and abnormal growth rates in some body parts. Better understanding of SON mutations will also help to explain how intellectual disability occurs in the rare Braddock-Carey syndrome.

Non-inherited de novo gene mutations can happen in any newborn, but they are not always symptomatic. To establish that a de novo mutation causes certain symptoms, several people with the mutation and the accompanying clinical presentation need to be identified, explains Toshiki Takenouchi of the Center for Medical Genetics, Keio University School of Medicine1.

This type of mutation, called a frameshift mutation, affects the way a gene is ‘read’. Takenouchi identified a patient in whom this mutation led to growth retardation accompanied by a relatively large head and long extremities, intellectual disability, joints that can be hyperextended, cardiac abnormalities and significant delay in motor development.

Zhu Xiaolin of Duke University School of Medicine’s Center for Human Genome Variation, previously reported a single patient with intellectual disability and a SON mutation. But this observation in a single patient was not sufficient to conclude that mutations in SON causes an intellectual disability syndrome. The identification of the second patient by Toshiki Takenouchi provided decisive evidence that this type of mutation in the SON gene leads to an intellectual disability syndrome with recognisable features.

The SON gene is located in the same DNA region that is responsible for Braddock-Carey syndrome, which is characterised by a small number of blood platelets, intellectual disability, distinctive facial features, and a small jaw. Researchers had previously identified a mutation in another gene, called ITSN1, as responsible for developmental delay in these patients. But it has been unclear if other genes in this same region could also contribute to the condition. The findings of Takenouchi and his colleagues suggest that SON plays a significant role in the developmental delay observed in Braddock-Carey syndrome.

Soon after Toshiki Takenouchi’s report, similar patients with SON mutations were reported by two other independent groups from the United States, namely Jung-Hyun Kim2 from University of South Alabama’s Mitchell Cancer Institute, and Mari J. Tokita3 from Baylor College of Medicine’s Department of Molecular and Human Genetics.

This newly identified condition of intellectual disability has been named ZTTK syndrome (OMIM # 617140), which represents Zhu-Takenouchi-Tokita-Kim syndrome.

The program-affiliated researchers contributing to this research are from the Center for Medical Genetics, Keio University School of Medicine.


  1. Takenouchi, T., Miura, K., Uehara, T., Mizuno, S., & Kosaki, K. Establishing SON in 21q22.11 as a cause a new syndromic form of intellectual disability: possible contribution to Braddock-Carey syndrome phenotype. American Journal of Medical Genetics 170, 2587-2590 (2016). | Article
  2. Kim, J.-H., Shinde, D. N., Reijnders, M. R. F., Hauser, N. A., Belmonte, R. L., et al. De novo mutations in SON disrupt RNA splicing of genes essential for brain development and metabolism, causing an intellectual-disability syndrome. American Journal of Human Genetics 99, 711-719 (2016). | Article
  3. Tokita, M. J., Braxton, A. A., Shao, Y., Lewis, A. M., Vincent, M., et al. De novo truncating variants in SON cause intellectual disability, congenital malformations, and failure to thrive.  American Journal of Human Genetics 99, 720-727 (2016). | Article

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