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“Non-gene” Mutations and Neurodevelopmental Disorders

Every year, thousands of children are born with neurodevelopmental issues. This is not just about lagging intellectual growth or autism: in fact, many of the psychiatric illnesses in later life have been blamed on neurodevelopmental problems. These conditions are more common than most people imagine. One estimate suggests that as many as 15% of people suffer from certain neurological and psychiatric issues that have to do with genetics and neurodevelopmental disorders.

However, at present researchers are unable to explain the cause of many neurodevelopmental disorders based on genetic mutations only. That led them to think that they must be missing something. Advances in genetic sequencing technology have revolutionized our understanding of inherited disorders. This change has been further supported by improvements in computing and big data analysis. Nowadays, researchers have better tools and plentiful data to analyze and uncover the genetic landscape of various neurodevelopmental disorders.

A new understanding of neurodevelopmental disorders

For many years, researchers have primarily focused their attention on ~23,000 so-called protein-coding genes, as most neurodevelopmental disorders are directly or indirectly related to proteinopathies (i.e., defects in proteins encoded by the genes). These genes make up just 2% of our genome. To date, researchers have mostly been calling the remaining 98% of our genome as “junk” (i.e., non-coding), and its role is poorly understood.

Now scientists are uncovering that what they have been dismissing as junk has a significant influence on the way the 2% containing protein-coding genes works. This 98% of the genome participates in activation, deactivation, or changes the expression level of the 2%. Researchers have discovered many mutations in these neglected parts of the genome that influence the other more active part of the genome. Thus, it seems that junk DNA has a vital role to play in multiple genetic disorders, including neurodevelopmental diseases.

However, identifying the link between these non-coding genome regions and the coding genes is not a straightforward task. It requires the use of an enormous amount of data and computing power. Detailed investigations of non-coding regions have become possible due to novel genome projects like the 1000 Genome Project, as these projects provide complete genome information, including information about non-coding regions.

A new study confirms the link between non-coding genes and neurodevelopmental disorders

In one of the most extensive studies of its kind that has been published this year in the journal Nature, genetic data from 8000 families were analyzed. Researchers were able to demonstrate the link between neurodevelopmental disorders and mutations outside of protein-coding genes. This is the first study that was able to provide information regarding neurodevelopmental disease risk in undiagnosed children.

Although thousands of children around the world develop neurodevelopmental illnesses linked to slow intellectual growth, epilepsy, and even heart defects, a large number of them remain undiagnosed until clinical symptoms develop. This delay or missed diagnosis means that valuable time to take prophylactic measures is lost.

The new findings are the result of the Deciphering Developmental Disorders (DDD) study initiated in 2010, aimed at early diagnosis of rare developmental disorders. So far, even in the developed European nations and the US, only a very small percentage of children with developmental disorders are diagnosed in a timely manner. It is expected that these new findings will revolutionize the way these conditions are diagnosed and possibly help in the early identification of the disorders and associated risk factors.

In about one-third of 13,000 children diagnosed with neurodevelopmental disorders, researchers were able to identify the genetic mutations that had been previously found. However, they had no clue as to what mutations or genetic issues were responsible for developmental disorders in the remaining 8000 patients.

Therefore, researchers turned their attention towards the non-coding or junk parts of the genome, which control the inhibition or activation of genes and serve as gene regulators. To their surprise, they discovered that specific mutations in these non-coding areas were strongly related to specific neurodevelopmental disorders. There was a good reason to pay attention to the particular parts of these non-coding genes since they have been highly conserved in various species during evolutionary history. Usually, conserved genetic material plays a critical role in the survival and fitness of living species.

What are the future implications of the findings?

At present, researchers agree that they have limited knowledge about the link between mutations in non-coding genome regions and neurodevelopmental disorders. Nonetheless, they think that things will change for the better, as they are now on the right track. As more data becomes available, we will be able to predict and diagnose rare neurodevelopmental disorders more precisely. Data from new projects like NHS’s 100,000 Genome Project may provide truly rich data for a better understanding of the subject. As more plentiful genome and health-related data become available, the diagnosis of neurodevelopmental disorders will be done with higher precision.

Novel studies have finally opened the doors to new unexplored territory, and eventually, we will be able to get the answers to the questions that were too difficult to deal with for many years. Once we are able to diagnose done in a timely fashion, we will be better equipped to make the best decisions regarding the treatment options.


Hu, W. F., Chahrour, M. H., & Walsh, C. A. (2014). The diverse genetic landscape of neurodevelopmental disorders. Annual Review of Genomics and Human Genetics, 15, 195–213. doi:10.1146/annurev-genom-090413-025600

Khurana, E., Fu, Y., Colonna, V., Mu, X. J., Kang, H. M., Lappalainen, T., … Gerstein, M. (2013). Integrative Annotation of Variants from 1092 Humans: Application to Cancer Genomics. Science, 342(6154), 1235587. doi:10.1126/science.1235587

Plummer, J. T., Gordon, A. J., & Levitt, P. (2016). The Genetic Intersection of Neurodevelopmental Disorders and Shared Medical Comorbidities – Relations that Translate from Bench to Bedside. Frontiers in Psychiatry, 7. doi:10.3389/fpsyt.2016.00142

Short, P. J., McRae, J. F., Gallone, G., Sifrim, A., Won, H., Geschwind, D. H., … Hurles, M. E. (2018). De novo mutations in regulatory elements in neurodevelopmental disorders. Nature, 555(7698), 611–616. doi:10.1038/nature25983

Image via kalhh/Pixabay.

Source: Brain Blogger