A recent large-scale genetic study uncovers 14 new mutations in children.
Congenital anomalies are responsible for the death of more than 300,000 infants worldwide. These anomalies often include developmental disorders, including neural tube defects, heart defects, autism, Down syndrome, or other forms of intellectual disability.
For over 50 percent of these anomalies, researchers do not yet know the cause. They do, however, know that genes play a key role.
There are currently more than 1,000 recognized genetic causes for some of the developmental disorders. However, given that most developmental disorders are very rare, many more pathogenic variants remain unknown.
The Deciphering Developmental Disorders (DDD) study aimed to identify developmental disorders in children, and use genomic technologies to improve diagnosing.
DDD is the largest genetic study of children with previously undiagnosed developmental disorders to date. It involved 200 clinical geneticists from the National Health Service (NHS) in the United Kingdom. They examined more than 20,000 human genes, and included children from around 4,000 families from the U.K. and the Republic of Ireland.
The results have been published in the journal Nature.
Examining new mutations in more than 4,000 children and their families
The DDD study was carried out by researchers from the Wellcome Trust Sanger Institute in Cambridge, U.K., and it was co-led by Dr. Matthew Hurles and Jeremy McRae.
The research involved the exome sequencing of 4,293 families that had at least one member with a severe but undiagnosed developmental disorder.
Exome sequencing is a common and effective way of selectively sequencing the protein-coding regions of the DNA in order to discover genetic variations associated with disorders.
Exons represent approximately 2.5 percent of the human genome, which makes exome sequencing more efficient. This means that a large number of people can be examined in a more cost-effective and less time-consuming manner.
In the sequencing for this study, the team focused on spontaneously arising mutations that occur when the DNA is passed on from parents to children. These mutations - also called de novo or new mutations - are not present in either parent, but appear for the first time in one family member. This is as a result of a variant in the sperm or egg of the parent, or in the fertilized egg itself.
The children in the DDD study were also clinically assessed. Researchers then combined the clinical data with previous analyses of another 3,287 people living with similar disorders.
Study finds 400,000 children born with new mutations each year
The results of the study revealed 94 genes that were particularly likely to have de novo mutations. Of these, 14 genes had not been previously recognized in developmental disorders.
Overall, the authors calculated that 42 percent of the study participants carried a damaging de novo mutation in their protein-coding DNA sequences.
Furthermore, they estimated that developmental disorders caused by new mutations affect, on average, 1 in 300 children in the U.K., which totals around 2,000 children every year.
Overall, depending on the age of the parents, the team report that between 1 in 213 and 1 in 448 children are affected by new mutation-induced developmental disorders. Worldwide, this means that almost 400,000 newly born children are affected by spontaneous mutations.
Dr. Matthew Hurles comments on the significance of the study:
"This study has the largest cohort of such families in the world, and harnesses the power of the NHS, with 200 clinical geneticists and 4,000 patients. The diagnoses we found were only possible because of the great collaborative effort. Finding a diagnosis can be a huge relief for parents and enables them to link up with other families with the same disorder. It lets them access support, plug into social networks and participate in research projects for that specific disorder."
Professor David FitzPatrick - a supervising author based at the MRC Human Genetics Unit at the University of Edinburgh, U.K. - also emphasizes the benefits of the study for potential treatment and prevention. He says:
"Families search for a genetic diagnosis for their children, as this helps them understand the cause of their child's disorder. This can help doctors better manage the child's condition, and gives clues for further research into future therapeutics. In addition to this, a diagnosis can let parents know what the future holds for their child and the risk of any subsequent pregnancies being affected with the same disorder, which can be an enormous help if they want a larger family."