Unexplained autism is frequently associated with low-level mosaic aneuploidy

Background: Autism is a common childhood neurodevelopmental disorder with suggested genetic background. About 5-10% of autism cases are associated with chromosomal abnormalities or monogenic disorders. However, the role of subtle genomic imbalances in autism has not been delineated. Here, we have tested a hypothesis suggesting autism to be associated with subtle genomic imbalances manifested as low-level chromosomal mosaicism. Methods: We surveyed stochastic (background) aneuploidy in children with/without autism by interphase three-colour fluorescence in situ hybridization (FISH). The rate of chromosome loss and gain involving six arbitrarily selected autosomes and sex chromosomes was assessed in peripheral blood cells of 60 unaffected children and 120 children with autism. Results: Four autistic boys from 120 analyzed (3.3%) with rare structural chromosomal abnormalities: 46,XY,t(1;6)(q42.1;q27); 46,XY,inv(2)(p11q13); 46,XY,der(6),ins(6;1)(q21;p13.3p22,1)pat; 46,XY,r(22)(p11q13) were excluded from further molecular cytogenetic analysis. Studying over 420,000 cells in 60 controls and 116 children with idiopathic autism, we have determined the mean frequency of stochastic aneuploidy in control and autism: (i) autosome loss - 0.58% (95% CI 0.42-0.75%) and 0.60% (95% CI 0.37-0.83%), respectively, p=0.83; (ii) autosome gain - 0.15% (95% CI 0.09-0.21%) and 0.22% (95% CI 0.14-0.30%), respectively, p=0.39; (iii) chromosome X gain - 1.11% (95% CI 0.90-1.31%) and 1.01% (95% CI 0.85-1.17%), respectively, p=0.30. The frequency of mosaic aneuploidy over the background level was found in 19 (16%) of 116 children with idiopathic autism, while outlier values were not found in controls (p=0.0019). Conclusions: Our findings identify low-level aneuploidy as a new genetic risk factor for autism. Therefore, molecular cytogenetic analysis of somatic mosaicism is warranted in children with unexplained autism.