Neuroanatomical Abnormalities Are Shared By Males with Autism and Their Unaffected Brothers

Background: Autism is a highly heritable neurodevelopmental disorder, yet the search for genes with a definitive role in its etiology has remained elusive. Deconstructing the disorder with endophenotypic approach, where the variance is thought to be associated with a fewer number of genes, should boost the statistical power of molecular genetic studies and clarify the pathophysiology of autism.

Objectives: We aimed to test for neuroanatomical endophenotypes in a group of males with autism, their unaffected brothers, and typically developing control (TDC) males.  

Methods: The 94 participants (aged 9-19 years) consist of 20 males with autism (mean age, 13.3 ± 2.5 years; mean full-scale IQ, 103.8 ± 17.8), 20 unaffected brothers (mean age, 14.4 ± 3.1 years; mean full-scale IQ, 112.0 ± 10.4), and 54 TDC males (mean age, 12.8 ± 2.6 years; mean full-scale IQ, 112.5 ± 11.6) received clinical and neuropsychological assessments and undertook structural magnetic resonance imaging scans. Voxel-based morphometry using DARTEL approach was performed to obtain regional gray and white matter volumes. General linear analyses of the volumes of brain regions, adjusting for age, full-scale IQ and tissue specific volume, were used to compare the three groups. Conjunction analysis for global differences was done at a cluster level (clusters surviving familywise error p<0.05, with cluster-forming threshold at p < 0.005).  

Results: There were no differences in global gray matter, white matter, and total brain volumes among three groups. We found abnormal neuroanatomy in gray matter volume in the mid-cingulate cortex, precentral cortex, alongside rolandic operculum, and white matter volume in the bilateral superior corona radiata and hippocampus portion of the cingulum bundle were shared between males with autism and their unaffected brothers as compared to the TDC males.

Conclusions: The present study had limitations of relatively small sample size and caveat of generalization to other subgroups on the autism spectrum conditions. Nonetheless, our findings suggest that atypical neuroanatomy in the brain regions related to motor, language, and memory processing may be an endophenotypic marker for autism. Functional implications for these shared neuroanatomical abnormality warrants further investigation.