Simons Simplex Collection:
The Key to Findings in Three Major Autism Genetics Studies
Connie Anderson, Ph.D.
IAN Community Scientific Liaison
Kennedy Krieger Institute
Date First Published: January 9, 2012
The June 9, 2011 issue of Neuron featured three groundbreaking studies on autism genetics. Findings in all three were only possible thanks to families participating in the Simons Simplex Collection (SSC), a unique autism initiative that has worked with more than 2,700 families that have just one child with an autism spectrum disorder (ASD).
A Multitude of Small Genetic Changes
Two of the studies took a deeper look than ever before at a vast number of varied genetic “tweaks” present in some children with ASD.1,2 Researchers were looking for a particular kind of genetic change: a copy number variation, or CNV. With CNVs, nothing is wrong with a gene or genes. It is just that genetic material is deleted or duplicated so that instead of the two copies a person is supposed to possess, the person has no, one, or three copies. There may be too much or too little of part of a gene, a whole gene, or a whole set of genes all lying along a strand of DNA. When genes are duplicated or deleted, the processes they control, such as digestion or brain function, are likely to be disrupted.
The children with ASD participating in the SSC are from “simplex” families -- that is, families in which only one child has an ASD.3 Because they and their family members have provided DNA samples, researchers are able to compare the genetic picture for different individuals in the same family. This helps them identify whether genetic changes are being passed down from parent to child, or whether genetic changes exist in the child alone. When a genetic change is found only in the child with ASD and not in his or her parents, it is called a de novo mutation. Because such a change exists only in the child with ASD, but not in his or her unaffected parents or siblings, researchers suspect that the change may be linked to ASD.
Dr. Michael Wigler (at left) of Cold Spring Harbor Laboratory and his team examined genetic information from 887 SSC families, looking specifically for de novo copy number variations.1 They found these in nearly 8% of children with ASD, but in only 2% of their unaffected siblings. Furthermore, a total of 953 genes are involved in the CNVs occurring in the children with ASD, but only 59 genes are “hit” by the CNVs of the siblings. This is especially true of deletions, that is, cases where genetic material is missing. Compared to only 2 genes affected by deletions in siblings, 534 genes are affected by deletions in children with ASD. All of this provides convincing evidence that CNVs, especially those involving missing genetic material, are linked to autism.
Dr. Matthew State (at right) of Yale University and his team also focused on CNVs, this time in 1,124 SSC families.2 They found similar results, with de novo CNVs identified in nearly 6% of children with ASD but in less than 2% of unaffected siblings. The team wrote, “Our data show that large de novo CNVs confer substantial risk for ASD in the SSC.” They also investigated whether having a CNV, and especially one that affects a large amount of genetic material, is linked to more severe autism or greater intellectual disability in the children, but found little evidence of this.
Both studies confirmed that CNVs in specific regions of certain chromosomes, such as the region known as 16p11.2, are strongly associated with ASD. Especially interesting was the finding by both studies that de novo duplications of 7q11.23 are associated with ASD. Why? Because deletions of the same region are associated with Williams-Beuren syndrome, a condition “characterized by precocious verbal ability, avid eye contact, and a highly sociable disposition."1 These features might be considered the opposite of common autistic traits like fleeting eye contact and social disinterest. The fact that too little of some “ingredient” or process controlled by these genes makes a person go into social overdrive, while too much makes a person socially disengaged, provides some evidence that CNVs can play a major role in a person’s development and functioning.
The results of both studies also indicate that girls may require a bigger genetic “hit” to develop ASD, which would explain why boys have ASD so much more often than girls do. Girls are less likely to have ASD in the first place, but of those that do, a higher proportion have de novo CNVs compared to boys with ASD, and the girls’ CNVs involve more genetic material.
Based on these studies, as well as others, it is currently believed that 7-20% of cases of ASD may be linked to CNVs.4
Not Just Autism
The notion that many different, very small genetic mutations can cause disease is not relevant just to autism. As technology progresses, permitting researchers to “see” the tiniest CNVs, those studying other diseases are running into some of the same questions and challenges. For example, cancer researchers at Johns Hopkins University, looking at the genetics picture in breast and colorectal cancer, suggest that the most frequently occurring genetic changes in cancer don’t account for most cases. Instead, many mutations, each occurring very rarely, “dominate the cancer genome landscape.”5
In brief, autism researchers are part of a larger quest to understand how small genetic changes result in diseases or disorders – a quest that takes them to the very edge of current knowledge and technology and galvanizes them to push beyond it.
Many Genetic “Tweaks,” but Common Functions
How can many different CNVs, involving many different genes, all be linked to autism?
To address that question, researchers focused on what functions might be disrupted by the de novo CNVs associated with autism.6 Using the data from Wigler’s SSC study and a novel approach, they showed that the genes involved with these CNVs often play a role in the formation and function of synapses.
Brain cells (called neurons) communicate with each other through a complex electrochemical process. Central to this process is the synapse -- the gap between neurons across which chemicals called neurotransmitters flow. Because this process is so essential to normal brain function, any problem with it will clearly have some very negative effects, and perhaps many negative effects. “Our analysis,” the researchers wrote, “strongly supports the hypothesis that autism is primarily a disease of synaptic and neuronal connectivity malfunction.” This would certainly explain why so many areas of functioning are affected in ASD.
The finding that the vast number of genetic changes associated with ASD result in similar problems at the level of brain function may make it possible to develop therapies that target the common pathway – the problems in brain function – no matter what genetic “tweak” led to it.4
Acknowledging SSC Families
While participating in the SSC, mothers, fathers, children with ASD, and their unaffected siblings took time out of their busy and often stressful lives to travel to university clinics for interviews, evaluations, and blood draws. It is only thanks to them, and the fact that they were willing to share their time, energy, and insight, that these scientific advances were possible. Researchers, as well as families with children on the autism spectrum everywhere, deeply appreciate their contribution.
- Levy, D., Ronemus, M., Yamrom, B., Lee, Y. H., Leotta, A., Kendall, J., et al. (2011). Rare de novo and transmitted copy-number variation in autistic spectrum disorders. Neuron, 70(5), 886-897.
- Sanders, S. J., Ercan-Sencicek, A. G., Hus, V., Luo, R., Murtha, M. T., Moreno-De-Luca, D., et al. (2011). Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism. Neuron, 70(5), 863-885.
- Fischbach, G. D., & Lord, C. (2010). The Simons Simplex Collection: A resource for identification of autism genetic risk factors. Neuron, 68(2), 192-195.
- Schaaf, C. P., & Zoghbi, H. Y. (2011). Solving the autism puzzle a few pieces at a time. Neuron, 70(5), 806-808.
- Wood, L. D., Parsons, D. W., Jones, S., Lin, J., Sjoblom, T., Leary, R. J., et al. (2007). The genomic landscapes of human breast and colorectal cancers. Science, 318(5853), 1108-1113.
- Gilman, S. R., Iossifov, I., Levy, D., Ronemus, M., Wigler, M., & Vitkup, D. (2011). Rare de novo variants associated with autism implicate a large functional network of genes involved in formation and function of synapses. Neuron, 70(5), 898-907.