A quarterly publication of the Autism Research Institute
Winter, 2017 | Number 1, Volume 31
Genetic mutations occurring after conception may play a significant role in autism spectrum disorders (ASD), a new study reports.
Many cases of autism involve de novo (spontaneous, non-inherited) mutations that occur in a parent’s sperm or egg or arise after fertilization. Mutations that occur after fertilization are called post-zygotic mutations, or PZMs. The later PZMs occur during development, the fewer cells carry them, and the more difficult they are to detect.
Using previously analyzed gene sequencing data collected from nearly 6,000 families, Elaine Lim and colleagues resequenced some of the DNA using three separate sequencing technologies in parallel. The researchers classified 7.5% of de novo mutations in individuals with ASD as PZMs. Of these, they report, 83% were not identifi ed in the original analysis.
Some of the PZMs detected by the researchers affected genes known to be associated with autism or other neurodevelopmental disorders, while others affected genes known to be active in brain development but not previously associated with ASD. While some mutations reduced the effects of genes, others increased these effects.
Comparing their sequencing data to gene expression data from brain autopsies, the researchers found that PZMs in individuals with ASD occur disproportionately in genes expressed in the amygdala. Lim says, “This was exciting to us, in that the amygdala has been proposed as an important region of the brain in autism.”
Senior study author Christopher Walsh adds, “We have known that PZMs are an important cause of epilepsy, but this work provides the best evidence so far that they are relevant to autism as well.”
“Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder,” Elaine T. Lim, Mohammed Uddin, Silvia De Rubeis, Yingleong Chan, Anne S. Kamumbu, Xiaochang Zhang, Alissa M. D’Gama, Sonia N. Kim, Robert Sean Hill, Arthur P. Goldberg, Christopher Poultney, Nancy J. Minshew, Itaru Kushima, Branko Aleksic, Norio Ozaki, Mara Parellada, Celso Arango, Maria J. Penzol, Angel Carracedo, Alexander Kolevzon, Christina M. Hultman, Lauren A. Weiss, Menachem Fromer, Andreas G. Chiocchetti, Christine M. Freitag, Autism Sequencing Consortium, George M. Church, Stephen W. Scherer, Joseph D. Buxbaum, and Christopher A. Walsh, Nature Neuroscience, July 17, 2017 (online). Address: Elaine T. Lim, Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children’s Hospital, Boston, MA 02115.
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“Late-breaking mutations may play an important role in autism,” news release, Boston Children’s Hospital, July 17, 2017
