Clustering autism: using neuroanatomical differences in 26 mouse models to gain insight into the heterogeneity.
Ellegood J., Anagnostou E., Babineau BA., Crawley JN., Lin L., Genestine M., DiCicco-Bloom E., Lai JKY., Foster JA., Peñagarikano O., Geschwind DH., Pacey LK., Hampson DR., Laliberté CL., Mills AA., Tam E., Osborne LR., Kouser M., Espinosa-Becerra F., Xuan Z., Powell CM., Raznahan A., Robins DM., Nakai N., Nakatani J., Takumi T., van Eede MC., Kerr TM., Muller C., Blakely RD., Veenstra-VanderWeele J., Henkelman RM., Lerch JP.
Autism is a heritable disorder, with over 250 associated genes identified to date, yet no single gene accounts for >1-2% of cases. The clinical presentation, behavioural symptoms, imaging and histopathology findings are strikingly heterogeneous. A more complete understanding of autism can be obtained by examining multiple genetic or behavioural mouse models of autism using magnetic resonance imaging (MRI)-based neuroanatomical phenotyping. Twenty-six different mouse models were examined and the consistently found abnormal brain regions across models were parieto-temporal lobe, cerebellar cortex, frontal lobe, hypothalamus and striatum. These models separated into three distinct clusters, two of which can be linked to the under and over-connectivity found in autism. These clusters also identified previously unknown connections between Nrxn1α, En2 and Fmr1; Nlgn3, BTBR and Slc6A4; and also between X monosomy and Mecp2. With no single treatment for autism found, clustering autism using neuroanatomy and identifying these strong connections may prove to be a crucial step in predicting treatment response.