Unexplained autism is frequently associated with low-level mosaic aneuploidy

Autism is a common childhood neurodevelopmental disorder with a possible 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. This study aimed to investigate a hypothesis suggesting autism to be associated with subtle genomic imbalances presenting as low-level chromosomal mosaicism.

We surveyed stochastic (background) aneuploidy in children with/without autism by interphase three-colour fluorescence in situ hybridisation. The rate of chromosome loss and gain involving six arbitrarily selected autosomes and the sex chromosomes was assessed in the peripheral blood cells of 60 unaffected children and 120 children with autism.

Of 120 analysed boys with autism, 4 (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; and 46,XY,r(22)(p11q13)) were excluded from further molecular cytogenetic analysis. Studying <420 000 cells in 60 controls and 116 children with idiopathic autism, we determined the mean frequency of stochastic aneuploidy in control and autism: (1) autosome loss 0.58% (95% CI 0.42 to 0.75%) and 0.60% (95% CI 0.37 to 0.83%), respectively, p = 0.83; (2) autosome gain 0.15% (95% CI 0.09 to 0.21%) and 0.22% (95% CI 0.14 to 0.30%), respectively, p = 0.39; and (3) chromosome X gain 1.11% (95% CI 0.90 to 1.31%) and 1.01% (95% CI 0.85 to 1.17%), respectively, p = 0.30. A frequency of mosaic aneuploidy greater the background level was found in 19 (16%) of 116 children with idiopathic autism, whereas outlier values were not found in controls (p = 0.0019).

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.