[Dr. Neale is currently an Assistant in Genetics in the Analytic and Translational Genetics Unit at Massachusetts General Hospital and Harvard Medical School and an affiliate of the Broad Institute of Harvard and MIT. Dr. Neale’s research centers on statistical genetics and how to apply those methods to complex traits, with a particular focus on childhood psychiatric illness such as autism and ADHD.]
Today, in Nature, three letters (1, 2, 3) were published on the role of de novo coding mutations in the development of autism. I am lead author on one of these manuscripts, working in collaboration with the ARRA Autism Consortium. In this post, I’ll describe the main findings of our work as they relate to autism and how we approached the interpretation of de novo mutations. In essence, de novo point mutation is likely relevant to autism in ~10% of cases, but a single de novo event is not likely to be sufficient to cause autism. Underscoring this is that fewer than half of the cases had an obviously functional point mutation in the exome. However, three genes, SCN2A, KATNAL2 and CHD8 have emerged as likely candidates for contributing to autism pathogenesis.
De novo is Latin for “from the beginning,” and when describing genetic variation or mutation means that the variant has spontaneously arisen and was not inherited from either parent. In autism, de novo copy number variants are among the earliest clearly identified genetic risk factors (see Sanders et al. and Pinto et al. for reviews). Given that these events are novel, natural selection has not acted on them, except for instances where the point mutation is lethal in early life. With next generation sequencing (NGS), we now have the opportunity to identify these events directly.
In this study we explored the impact of de novo mutations on autism by performing targeted sequencing of the protein-coding regions of the genome (known collectively as the exome, and comprising just 1.5% of the genome as a whole) in 175 mother-father-child trios in which the child was diagnosed as autistic. Having sequence from all three members of each family allowed us to find mutations that had arisen spontaneously in a patient’s genome, rather than being inherited from their parents.
We have made a pre-formatted version of our manuscript available here. In this post I just wanted to highlight some of the key lessons emerging from our study.
Continue reading ‘Guest post by Ben Neale: Evaluating the impact of de novo coding mutation in autism’