Genetics of autism spectrum disorders

Hi. I'm Matt State and I'd like to talk to you today about the genetics of autism spectrum disorders. I am the Donald J. Cohen, Associate professor of Child Psychiatry and Genetics. I co-direct the program on neurogenetics and serve as Deputy Chairman for Research within the Department of Psychiatry at the Yale School of Medicine.

Let me start by reviewing for you the topics I'd like to cover today. First, I'm going to address the challenges that have faced researchers attempting to identify specific genes contributing to idiopathic autism. That is autism. That is not a consequence of a rare genetic syndrome. I'm going to move from there to describe some basic issues in human genetics, and I'm going particularly to focus on the difference between genetic variation that's rare in the population versus genetic variation that's common in the population. That will then serve as a prelude for a review of recent findings in the field. I'm going to particularly highlight the last 3-4 years of research as this has been a particularly productive time for gene discovery in autism and autism spectrum disorders. I'm going to conclude then with a discussion of how these recent findings are beginning to inform the clinical evaluation of children presenting with autism spectrum disorders.

Let me begin by describing for you some of the evidence suggesting that genes are important to look at in autism, that they're playing a significant role in the etiology and pathogenesis of autism spectrum disorders. A strong piece of evidence that this is the case comes from comparing the rate at which monozygotic twins share a diagnosis of autism or autism spectrum disorder versus the rate at which dizygotic twins share such a diagnosis. The key difference between these types of twin pairs is the amount of DNA that they share. Monozygotic twins share all of their DNA exactly alike. and dizygotic twins share only as much genetic material as any sibling pair. The observation that monozygotic twins are much more likely to share a diagnosis of autism or autism spectrum disorders than dizygotic twins suggests that genes are carrying the lion's share of risk for ASD. In fact, this calculation suggests that autism is the most genetic or most heritable of all neuropsychiatric syndromes. In addition to the twin data, we see many families clinically in which there's familial aggregation of autism. There are many multiplex or multiple affected families, but what's also clear is that few families present to clinic in which there's an obvious, simple or Mendelian pattern of transmission from generation to generation. In fact, this observation, along with now several decades of efforts to identify genes contributing to autism, have led to a widespread consensus that writ large as a general proposition autism is not the consequence of a mutation in just a single gene. In fact, what's thought is that autism is a highly genetically heterogeneous disorder, and we can think about heterogeneity in a variety of different ways. One way that geneticists think about heterogeneity is something called locus heterogeneity. What this would mean is that multiple different genes around the genome might all either contribute to or lead to a similar or overlapping phenotype. This is somewhat different than a second related notion called allelic heterogeneity, in which even if there's a single gene that is contributing some risk to autism, there may be many ways in which that gene might vary in terms of its sequence or its structure that may contribute to autism. It is the general conclusion of the field that autism is characterized both by a high degree of locus heterogeneity and allelic heterogeneity. While there is this type of agreement, there is not agreement on precisely how many genes are contributing, both in the sense of an individual, how many different genetic kits, if you will, might be necessary in order to lead someone to have a clinical presentation of autism. Also, then how many genes or how many different spots around the genome might be contributing in the population in general.