Due to technical limitations, genetic analysis has historically focused on the exome – the regions of our DNA that encode proteins. A new study, published in the American Journal of Human Genetics, analysing so-called 'junk' or noncoding DNA, has identified seven mutations linked to developmental disorders.
'We found that nearly one-quarter of diagnoses identified in the Deciphering Developmental Disorders (DDD) study in one particular gene are due to noncoding region variants,' said senior author Dr Nicky Whiffin, research group leader at the Wellcome Centre for Human Genetics at the University of Oxford. '[This] suggests that it could be highly beneficial to analyse these regions in patients that remain genetically undiagnosed.'
Developmental disorders usually present in children and can comprise physical, learning, language or behavioural difficulties. These disorders are usually associated with de novo mutations, spontaneous genetic changes that are not inherited from the parents. Although the majority of these mutations are harmless, they can also lead to rare genetic disorders which can be challenging to identify and diagnose.
This paper, led by researchers at the Wellcome Centre for Human Genetics and the University of Exeter, is part of the DDD study, which aims to apply state-of-the-art technologies to improve understanding and advance the clinical genetic practice for children with developmental disorders.
The team investigated the areas of the genome outside the exome – also known as noncoding or untranslated regions – which have include regulatory sequences involved in controlling levels of gene expression.
Through computational and lab-based approaches, the team identified six different mutations in the noncoding region of the gene MEF2C, which leads to developmental disorders in children through three different loss-of-function mechanisms.
The discovery of these gene mutations has enabled the researchers to diagnose multiple families in a clinical context, providing long-sought answers and bringing them a step closer to personalised treatment.
'Receiving a diagnosis can allow patients and their families to access support networks and gain a greater understanding of their condition, which can have a huge impact on their lives, as well as understanding the risk for any future children they might have' said co-author Dr Meena Balasubramanian, consultant clinical geneticist at Sheffield Children's Hospital.