Autism spectrum disorders (ASDs) have a complex inheritance pattern. Despite researchers having identified rare variants in synaptic proteins in patients with ASD, little work has been carried out to determine the effect at the synapse and their interactions with other genetic variations ... until now. A European team of researchers has confirmed that synaptic mutations heightens the risk of ASD. The study, presented in the journal PLoS Genetics, was funded in part by the EUHFAUTISM ('European high-functioning autism network: translational research in a phenotypically well characterised sample') project, a Neuron-ERA-NET funded under the EU's Seventh Framework Programme (FP7) to the tune of almost EUR 370 000.
Researchers led by the Institut Pasteur in France combined genetic and neurobiological approaches to determine how ASD risk increases. They also found how modifier genes influence these disorders.
ASDs are a heterogeneous group of neurodevelopmental disorders with a complex inheritance pattern characterised by impairments in social interaction and communication. Repetitive behaviour also restricts them.
According to the researchers, ASDs emerge before the age of three years and affect 1% of children. More boys than girls have a higher risk of being affected by ASD. The researchers say a number of genes that play a role in ASD have been identified in patients with ASD. However, researchers have only recently begun learning about their effects on neuronal functions and their interaction with other genetic variations.
'The genetic causes of ASD are diverse, but the main category of genes associated with the disorder is related to the development and function of neuronal circuits,' the authors write. 'Mutations of genes coding for synaptic cell adhesion molecules and scaffolding proteins, such as neuroligins (NLGNs), neurexins (NRXNs) and SHANK, have been recurrently reported in patients with ASD. These proteins play a crucial role in the formation and stabilisation of synapses, as well as in synaptic homeostasis.
'SHANK2 and SHANK3 code for scaffolding proteins located in the postsynaptic density (PSD) of glutamatergic synapses. Deletions of ProSAP2/SHANK3 at chromosome 22q13 are one of the major genetic abnormalities in neurodevelopmental disorders, and mutations of ProSAP2/SHANK3 have been identified in patients with ASD, intellectual disability (ID) and schizophrenia. Mutations of ProSAP1/SHANK2 have also recently been reported in both ASD and ID. The difference in clinical outcome of mutation carriers has been attributed to the presence of still uncharacterised additional genetic, epigenetic and/or environmental factors.'
Commenting on the significance of the findings, the Institut Pasteur's Thomas Bourgeron says they emphasise the importance of a synaptic gene dysfunction in ASD, and they underline a role for modifier genes confirming 'a multiple hit model for ASD. A better knowledge of these genetic interactions will be necessary to understand the complex inheritance pattern of ASD'.
Experts from Canada, Finland, France, Germany, Italy, the Netherlands, Portugal, Sweden and the United Kingdom contributed to this study.