New genetic variants lead to diagnoses for children with developmental disorders


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By analyzing parts of the genome that do not encode proteins, researchers have identified seven variants related to developmental disorders.

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

The study, conducted by researchers from the Wellcome Sanger Institute, the Wellcome Center for Human Genetics at Oxford University, the University of Exeter, the National Center for Cardiovascular Research (CNIC) in Madrid and Imperial College of London, found mutations in countries not regions coding DNA that cause developmental disorders in children, giving 10 families a diagnosis called.

The document, published in American Journal of Human Genetics, identified seven previously unknown variants that caused developmental disorders, and six of these affected the MEF2C gene. Also identifying two of these variants in another , the researchers were able to give a diagnosis to several families, ending the “diagnostic odyssey” facing many patients and their families.

Worldwide, about 400,000 babies are born each year with new spontaneous DNA changes, known as —That they interfere with their development. These developmental disorders can cause conditions such as intellectual disability, epilepsy, or heart defects.

De novo mutations in protein-creating genes are a well-established cause of developmental disorders, but to date many of the genes related to these disorders are unknown. All people are born with an average of 60 de novo mutations, although the vast majority do not have health problems.

It is a great advantage for a patient and theirs know the genetic cause of your disorder. Not only does it provide answers, but it also allows you to predict risks for other family members and potentially a gateway to personalized treatment. With this in mind, most patients with developmental disorders will undergo genetic testing as part of their clinical care, however, this leads to a genetic diagnosis in less than half of the cases. That it usually identifies the variants that occur in the parts of the genome that directly encode proteins.

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

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

These regions are not encoded in the final protein, but regulate processes; how to control how much protein is made, when it stops, and where the protein ends up in the cell.

Using computational and laboratory-based methods, the researchers identified six variants in the UTRs that affected the MEF2C gene, either by changing gene expression levels, reducing the amount of protein produced, or altering MEF2C protein function.

“Looking at the parts of the genome that are next to it coding regions, we have been able to identify multiple variants that cause developmental disorders that would have been lost with current clinical screening. In fact, we found that nearly a quarter of the diagnoses identified in the study of Deciphering Developmental Disorders in a Specific Gene are due to non-coding. variants. While this does not mean that a quarter of all diagnoses of developmental diseases are due to variants in uncoded regions, it suggests that it might be very beneficial to analyze these regions in patients who remain genetically undiagnosed, “says Dr. Nicky. Whiffin, lead author of the leading study and research group at the Wellcome Center for Human Genetics, Oxford University.

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

“It’s great to see that this genetic research translates directly into being able to give patients and families the diagnosis they expected. Receiving a diagnosis can allow patients and their families to access support networks and better understand their condition, which they can have. a big impact on their lives, as well as understanding the risk to future children they may have, ”says Dr. Meena Balasubramanian,
study author and clinical genetic consultant for the Sheffield Children’s NHS Foundation Trust.

“In recent years, dramatic advances in genomic analysis have put an end to the agonizing diagnostic odyssey that so many developing children and their families have endured. However, for many others, genetic diagnosis has been difficult to use. This crucial research, through which some children are motivated they have been identified through the analysis of untranslated regions of the genome, bringing hope and comfort to some families so that their diagnostic odyssey can also come to an end and can help more in the future. Receiving a genetic diagnosis offers families the opportunity to inform, support and find other people with a similar disorder, in order to alleviate their isolation and despair, “says Dr. Beverly Searle, CEO of Unique – the Rare Chromosome & Gene Disorder Support Group.

“Understanding more about the genetic cause of disease is incredibly important, especially when it can have such a big impact on a child’s life and the lives of his or her family. This research shows that although many regions of the world DNAs do not directly encode proteins, these regions still contain vital clues and information that can help many patients and their families get the answers they seek, ”adds Professor Matthew Hurles, co-author of the study and leader in the Deciphering Developmental project. Disorders of the Wellcome Sanger Institute.

Study linking 28 genes with developmental disorders to mean diagnoses for about 500 families

More information:
Caroline F. Wright et al, Non-coding region variants upstream of MEF2C cause severe developmental disorder through three different mechanisms of loss of function, The American Journal of Human Genetics (2021). DOI: 10.1016 / j.ajhg.2021.04.025

Citation: New genetic variants lead to diagnoses for children with developmental disorders (2021, June 3) retrieved June 3, 2021 at developmental-disorders.html

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