Disease and treatment

Researchers discover genetic link to impaired language among children with autism

An international research group has discovered an association between how genes are expressed in blood and impaired language development among children with autism. The discovery may pave the way for a blood test that can diagnose children with autism at birth.

Autism clearly has a genetic and hereditary component, and researchers now understand this better after studying immune cells in the blood.

More precisely, researchers from the United States, Cyprus and elsewhere have discovered that they can use the gene coexpression in white blood cells to determine whether children with autism have genetic traits that imply impaired language development related to autism spectrum disorder.

In the long term, this discovery may assist in developing a blood test that will enable doctors and parents to determine whether a child might, or might not have autism – at a much earlier stage than today.

“Today, autism is diagnosed based on mental characteristics. However, the tests are usually not effective until a child is older than 3 years. Knowing the hereditary component of autism will enable us to identify this in a blood sample from children so that we can diagnose them and intervene with supportive treatment much earlier than we can today,” explains a researcher that participated in the new study, Nathan Lewis, Associate Professor of Pediatrics and Bioengineering, University of California, San Diego, USA.

The study was recently published in Nature Neuroscience.

Researchers cannot identify autism genetically in most cases

The hereditary nature of autism is undeniable and accounts for 80% of the risk of developing it. Nevertheless, researchers have extreme difficulty in identifying autism by examining genes. Hundreds of genetic mutations and variants have been identified that predispose a person to developing autism. However, each of these can explain less than 1% of the risk of developing autism.

Even when researchers combine all these small differences, they cannot explain more than 5–10% of the risk of developing autism.

Evidence therefore indicates that the hereditary component of autism cannot be identified through differences in the genes for many people, but rather in differences in how the genes are expressed, or in a cocktail effect, in which combinations of commonly occurring genetic variants make people more likely to develop autism than they would based on the sum of the individual genetic variants.

“Epigenetics may cause the development of autism. This means that we cannot examine the genes in isolation to determine whether one child will develop autism while another will not. Their DNA will be similar, but the way the body’s cells decode the DNA differs, and that may cause autism,” explains Nathan Lewis.

Only some children with autism develop language late

This situation is further complicated by the fact that autism is a spectrum disorder, which means that it takes many different forms and probably originates from many different neurobiological backgrounds.

Some children with autism are intellectually impaired; others are genuinely brilliant. Some are very sensitive to food; others are not. Some develop language very late in childhood; others develop language normally.

One great challenge in understanding the neurobiological background of autism is to understand its different manifestations.

In this study, researchers from San Diego and Cyprus investigated differences in gene coexpression in the blood among children with autism and late language development versus normal language development.

Many children with autism develop language very late, which is a sign psychologists use to diagnose these children. For other children with autism, their language development does not indicate whether they have autism.

“Our goal was to look for groups of genes that collectively express themselves differently between the two groups. These genes may help explain the changes in the brain among children with autism who have late language development,” says Nathan Lewis.

Finding signs of autism in the blood

The researchers collected blood samples from 118 infants with autism. Then they examined how the white blood cells expressed messenger RNA (mRNA), which is a marker for the overall activity of the genes and contains results from genetic mutations and variants, epigenetics and so on.

The researchers examined white blood cells because they are constantly being recreated. This means that the same steps that occur as the fetus develops, including the brain, are continually repeated in the white blood cells. This can provide researchers a window into the time when things may go wrong during fetal development and the foundations of autism are laid.

The results showed a clear difference in gene coexpression among children with autism with normal language development versus late language development. One group of children expressed several types of mRNA that were not expressed to the same extent in the other group.

The researchers examined the genes closely, and many were specific to humans and linked to language development. The genes are expressed in many different tissues, including the brain and the white blood cells, and have also been identified as influencing the development of autism.

This is interesting. Many of these genes play a role in brain development in the first trimester of pregnancy. Our findings show neurobiological differences among children with autism who have late language development versus those who do not and that these differences are already present before the children develop their language difficulties,” explains Nathan Lewis.

Discovery can be used for diagnosing autism

The new results give researchers greater insight into autism and its various subtypes. In addition, the results provide insight into developing diagnostic tests that can determine whether a child has autism or not.

Language problems are an early sign of the development of autism, and the fact that researchers can show a measurable neurobiological association with language difficulties enables language support and other actions to be implemented much earlier to help the child develop as normally as possible.

“Although we may not be able to find specific genetic mutations to explain the development of autism, we can pinpoint the genes that are involved and expressed in changes in brain development in the early fetal development stage among children with autism. We have finally begun to understand the neurobiological background for the development of autism. This knowledge will likely make it possible to more effectively treat people with autism in the future,” says Nathan Lewis.

Large-scale associations between the leukocyte transcriptome and BOLD responses to speech differ in autism early language outcome subtypes” has been published in Nature Neuroscience. Nathan Lewis is Associate Professor, Systems Biology and Cell Engineering and Novo Nordisk Foundation Center for Biosustainability, University of California, San Diego, USA.

Nathan E. Lewis
Associate Professor of Pediatrics and Bioengineering
No molecule in a living organism exists in a vacuum. Indeed, each interacts with thousands of other molecules, and the functions associated with each gene product are influenced by surrounding proteins, metabolites, and other molecules. The existence of complex pathways governing phenotypes poses a substantial challenge in efforts to diagnose complex diseases, unravel their causes, and to develop effective therapeutics. In our lab, we use systems biology approaches to make sense of these complex pathways to develop network-based diagnostics for childhood disorders (Autran, Gut, 2017; Courchesne, Mol Psychiatry, 2018; Gazestani, bioRxiv 2018) and to understand the regulation and activity of complex pathways, such as metabolism (Hefzi, Cell Systems, 2016; Richelle, PLoS Comp Bio, 2019; Brunk, PNAS 2018), protein synthesis/secretion (Gutierrez, bioRxiv, 2018), and glycosylation (Spahn, Met Eng, 2016). Insights are also used to guide synthetic biology efforts to engineer mammalian cells for biotherapeutic purposes (Richelle, Curr Opin in Sys Bio, 2017; Kuo, Curr Opin in Biotech, 2018; Hefzi, submitted; Chiang, bioRxiv, 2018)