Hundreds of rare genetic variants may cause a common autism phenotype
By Brant Hamel
Catalina Betancur, M.D., Ph.D., visited NIEHS Nov. 30 as a part of the Keystone Science Lecture Seminar Series. She delivered a presentation titled “Deconstructing ‘idiopathic’ autism: One behavioral syndrome, hundreds of genes,” which illustrated how rare defects in many different genes could give rise to a common phenotype diagnosed as autism. The presentation was hosted by Cindy Lawler, Ph.D., a scientific program administrator in the Division of Extramural Research and Training at NIEHS.
Betancur is an investigator for INSERM (the French National Institute of Health and Medical Research) at the Université Pierre et Marie Curie in Paris. Her research focuses on understanding the genetic underpinnings of autism with a focus on the heterogeneous mutations that give rise to common behavioral symptoms, possibly through gene-gene and gene-environment interactions.
Autism is not a single disorder
Betancur explained that autism spectrum disorder is not a single disorder, but rather is a set of behavioral manifestations that may arise from any one of hundreds of individual genetic defects. Although autistic patients have common behavioral symptoms, such as decreased social interaction, the etiology of the disease may be vastly different between patients. In the majority of the cases, the cause of autism is not known. Betancur has been able to pinpoint the rare genetic mutations that have given rise to about 20 percent of autistic cases and makes a persuasive argument that, with more screening and enhanced technologies, many more cases of idiopathic autism, or autism of unknown cause, would likely be diagnosed as resulting from diverse and rare genetic defects.
Betancur explained that autism is much like intellectual disability and epilepsy, which also result from a plethora of independent genetic mutations, yet produce a common phenotype. Interestingly, many of the genes known to be involved in autism are also linked to other disorders, such as intellectual disability, epilepsy, and schizophrenia. Betancur said that out of 91 X-linked genes associated with intellectual disability, 45 of them also were linked to autism. It is not yet clear why in some cases the same mutation may result in intellectual disability and in others autism, but it may depend on other genetic, environmental, or chance factors.
Searching for rare variants to understand etiology of autism
Betancur described her work with the Paris Autism Research International SibpairStudy, which looked at 677 families with autism spectrum disorder from France and Sweden. With metabolic screening and a search for microdeletions and microduplications, her team was able to determine genetic causes for 20 percent of cases that had no previous molecular diagnosis. Most of the causes were extremely rare genetic defects that would not be commonly screened for.
As Betancur observed, one of the difficulties in showing that a genetic defect is involved in autism arises from the concepts of variable expressivity and incomplete penetrance. As an example of incomplete penetrance, Betancur pointed to cases of autism caused by DiGeorge syndrome, a deletion of a portion of chromosome 22 inherited from parents who do not have any signs of autism. In other cases variable expressivity occurs where the same genetic defect gives rise to different behavioral effects, as in the case of a family with mutations in neuroligin 4. One brother with the mutation had a severe case of autism, while the other brother with the identical mutation had a milder case of Asperger’s syndrome.
Betancur concluded that more systematic molecular screening is necessary to diagnose the many rare genetic defects that contribute to the common behavioral manifestation known as autism. She argued that a paradigm shift was necessary, so that physicians and researchers would stop thinking about autism as a single disease with a common cause or set of common causes, but rather as a heterogeneous mix of many rare defects with variable clinical outcomes.
(Brant Hamel, Ph.D., is a postdoctoral fellow in the NIEHS Molecular Endocrinology Group.)
New genes involved in autism
Betancur’s work has led to the discovery of new genes and signaling pathways involved in some cases of autism. Mutations in both neurexins, which reside on presynaptic neurons, and neuroligins, which reside on postsynaptic neurons and interact with neurexins, are linked to autism.
Betancur and her colleagues have been able to show that the intracellular protein SHANK3, downstream of this signaling pathway, is also involved in the etiology of autism. SHANK3 defects were found in three independent families including a 22q13 deletion in one family, also known as Phelan-McDermid syndrome; a frameshift mutation in another; and, interestingly, a third family where the son had a duplication of SHANK3 resulting in Asperger’s, while the daughter had a deletion of SHANK3 resulting in autism.
Betancur estimated that SHANK3 might be involved in about 0.5 percent of global autism cases. She said that although that sounds like a small number, it would actually make it one of the most common causes of autism that can be traced to a specific genetic mutation.