Seven Variants Linked to Developmental Disorders

Non-coding regions of DNA could hold the key to diagnosing developmental disorders in children, new research suggests.

The study, by researchers at the Wellcome Sanger Institute, the Wellcome Centre for Human Genetics at the University of Oxford, the University of Exeter, National Center for Cardiovascular Research (CNIC) in Madrid, and Imperial College London, found mutations in the non-coding regions of DNA that cause developmental disorders in children, giving 10 families a named diagnosis.

The paper, published in the American Journal of Human Genetics, identified seven variants that were previously unknown that cause developmental disorders, and six of these impacted the gene MEF2C. By also identifying two of these variants in other patient groups, the researchers were able to give a diagnosis to multiple families, ending the ‘diagnostic odyssey’ that many patients and their families face.

Globally, around 400,000 babies are born every year with new, spontaneous DNA changes – known as de novo mutations – that interfere with their development. These developmental disorders can lead to conditions such as intellectual disability, epilepsy or heart defects.

De novo mutations in genes that create proteins are a well-established cause of developmental disorders, but to date many of the genes linked to these disorders remain unknown. Every person is born with around 60 de novo mutations on average, though the vast majority do not lead to health problems.

It is a huge advantage to a patient and their family to know the genetic cause of their disorder. Not only does it provide answers, but it also allows risk prediction for other family members and potentially a gateway into personalised treatment. Given this, the majority of patients with developmental disorders will undergo genetic testing as part of their clinical care, however, this leads to a genetic diagnosis in fewer than half of cases. This genetic testing normally identifies any variants that occur in the parts of the genome that code directly for proteins.

Ongoing initiatives, such as the Deciphering Developmental Disorders (DDD) study, have discovered associated genes by looking for patterns in the genomes of children with these disorders and comparing these to their parents’ genomes.

In this study, which is part of the wider DDD study, the teams looked in regions of the genome that are immediately adjacent to protein-coding regions, known as untranslated regions, or UTRs.

These regions are not coded into the final protein, but instead regulate processes; such as controlling how much protein is made, when it stops and where the protein ends up in the cell.

Through computational and lab-based methods, researchers identified six variants in the UTRs that impacted the gene MEF2C, either by changing the levels of gene expression, reducing the amount of protein produced or disrupting the function of the MEF2C protein.

By identifying further genetic links to developmental disorders, it is possible to give more people a diagnosis and an understanding of their condition, which can help family planning, as well as potentially opening up new treatment plans and support. This study has highlighted how important it is to look into UTRs and to possibly include them in routine clinical screening. It could also encourage more researchers to have another look at their existing data, possibly finding more important genetic variants in previously unanalysed UTRs.

Reference: Wright CF, Quaife NM, Ramos-Hernández L, et al. Non-coding region variants upstream of MEF2C cause severe developmental disorder through three distinct loss-of-function mechanisms. Am. J. Hum. Genet. 2021;0(0). doi: 10.1016/j.ajhg.2021.04.025

This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source.