Multiple genes contribute to the clinical phenotype of autism and other neurodevelopmental disorders. The effects of these genes may be modified by environmental factors. Genes contributing to neurodevelopmental disorders are usually thought of as acting in the affected individual, i.e., the child or adult with the neurodevelopmental disorder. Here, an additional class of genes is considered, maternal genes that act in the mother to contribute to the phenotype of her affected offspring, i.e., maternally acting gene alleles. These alleles act in the mother most likely during pregnancy to alter development of the embryo or fetus, e.g., brain development in the affected children. These maternal genes may interact with fetal genes and with environmental factors. A number of maternally acting gene alleles have been identified in autism and other disorders, mostly neurodevelopmental disorders.
Objectives:
To determine whether maternally-acting genes fall into many unrelated categories or whether there are a smaller number of unifying mechanisms. Any unifying mechanisms identified could have relevance for the pathogenesis of autism and could be targets for developing treatment for autism.
Methods:
We identified reports of maternal genetic effects and excluded those that resulted from: maternal environmental effects on the fetus; maternal environmental effects interacting with a fetal genotype; mitochondrial genes, since they do not segregate; microchimerism; or genomic imprinting. We included maternally-acting gene alleles that affected the phenotype of the embryo or fetus. We determined possible mechanisms of action, understanding that genes may have more than one mechanism and considering the possibility of ascertainment bias.
Results:
Among 44 reports of maternally-acting gene alleles: 15 involved folate-related genes, 12 involved detoxification genes, 12 involved immune-related genes, 3 involved lipoprotein genes; 2 did not fit these categories. 5 reports involved maternally acting gene alleles in autism.
Conclusions:
Among 44 reports of maternally-acting gene alleles, nearly all involved neurodevelopmental disorders. 15 involved folate-related genes. 24 involved genes that could contribute to oxidative stress, raising the question of whether oxidative stress of maternal origin during gestation might be a significant contributor, along with folate-related mechanisms, to the phenotype of neurodevelopmental disorders, including autism.
We expected to find that the reports of maternally-acting alleles would implicate a large number of unrelated mechanisms, but to the contrary the results so far could potentially be grouped into two major mechanisms, both with implications for treatment.
All 5 reports so far of maternally acting gene alleles in autism have involved genes that can contribute to oxidative stress. No study of maternally acting folate-related gene alleles has yet been reported for autism – this area appears to be understudied.
Thus, since maternally acting gene alleles in oxidative stress pathways have been linked to autism, they may be targets for treatment of autism during gestation. If maternally acting gene alleles in folate-related pathways could be linked to autism, these could also be targets for treatment of autism during gestation.