Recent advances in genome sequencing technology havefacilitated rapid identification of genetic alterations in genes associated withAutism Spectrum Disorder (ASD). The universal challenge in the field ofgenetics has been to determine whether these mutations will result in autism.
In a study to be published in the May 25th advanced online edition NatureGenetics, researchers at The Hospital for Sick Children (SickKids) andUniversity of Toronto have essentially unraveled the autism code, by creating a“genetic formula” that will enable clinicians to identify genetic mutations thathave the highest and lowest likelihood of causing ASD.
ASD, which has recently been reported to affect one in every 68 children, is aneurodevelopmental disorder characterized by impairments in socialinteraction and communication, as well as repetitive and restrictive behaviors.It is well established that genetics has a major role in the development ofautism, which in itself represents a collection of clinically similar disorders.
“There has been incredible progress finding genetic answers, but these areoften accompanied by puzzling clinical observations. Previous research hasrevealed many conundrums such as mutation carriers who do not exhibitsymptoms of autism,” says Dr. Stephen Scherer, principal author of the studyand senior scientist and director of The Centre for Applied Genomics atSickKids and the University of Toronto McLaughlin Centre. “In our new studywe’ve finally discovered a unifying set of characteristics in the DNA that we canweave into a ‘genetic formula’ that helps us calculate which genetic mutationshave the highest probability of causing autism, and equally important, whichalterations do not have a role.”
Dr. Mohammed Uddin, a postdoctoral fellow on Scherer’s team determinedthat the key to solving the enigma of the autism mutation code, resides inrecognizing small segments (called exons) of genes that are both “highlyconserved” in human evolution and “turned on” during early braindevelopment.
“The timing of this gene activation is an important finding. The fact that thesegenes could be turned on prenatally, gives us a clue as to when autism couldstart to develop,” says Scherer.
Metaphorically, genes are often compared to an orchestra, with the mostimportant exons representing instruments like the violin that crescendo (turnon, or express) at critical times in the developmental symphony.
The Toronto team identified almost four thousand such brain exons in morethan seventeen hundred different genes. In addition, the one hundred or soknown autism susceptibility genes already used for diagnostic testing werefurther validated by the new approach, as were genes involved in otherneurodevelopmental conditions such as intellectual disability, which is often afeature of ASD.
Scherer predicts that many of the novel genes discovered by his group thatbear these newly defined unique characteristics, will eventually be proven byother means to be involved in autism or intellectual disability, or other relatedmedical conditions associated with brain development or cognition.
“This groundbreaking work will have immediate impact on efforts to developmore accurate genetic diagnostic tests aimed at improving earlier detectionand clinical decisions to begin intervention” says Dr. Robert Ring, ChiefScientific Officer of Autism Speaks. “Improvements in our understanding ofmechanisms involved in brain expression of disease mutations will also helpto reveal new biological space worth targeting for the development ofmedicines that benefit individuals with autism and related neurodevelopmentaldisorders.”
This research was supported by grants from the University of TorontoMcLaughlin Centre, NeuroDevNet, Genome Canada and the OntarioGenomics Institute, the Canadian Institutes for Health Research (CIHR), theCanadian Institute for Advanced Research, the Canada Foundation forInnovation, the government of Ontario, the Ontario Brain Institute, AutismSpeaks and SickKids Foundation.
This research has been developed in close collaboration with the IndustryPartnerships and Commercialization Office at SickKids. The technologymentioned above is available for licensing.
About The Hospital for Sick Children
The Hospital for Sick Children (SickKids) is recognized as one of the world’sforemost paediatric health-care institutions and is Canada’s leading centrededicated to advancing children’s health through the integration of patient care,research and education. Founded in 1875 and affiliated with the University ofToronto, SickKids is one of Canada’s most research- intensive hospitals andhas generated discoveries that have helped children globally. Its mission is toprovide the best in complex and specialized family-centred care; pioneerscientific and clinical advancements; share expertise; foster an academicenvironment that nurtures health-care professionals; and champion anaccessible, comprehensive and sustainable child health system. SickKids is proud of its vision for Healthier Children. A Better World. For more information,please visit www.sickkids.ca
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