Sequencing and analysis of the exomes, protein-coding regions of the DNA, of more than 4,000 individuals with severe, undiagnosed developmental disorders has identified 14 novel genes that underlie the risk of developing these disorders. The findings, published online in Nature this week, could help to improve the diagnosis of developmental disorders and aid the development of potential therapeutic strategies.
Around 2-5% of children are born with major birth defects and/or exhibit severe neurodevelopmental disorders during childhood. Although various mechanisms underlie such disorders, damaging genetic variation in developmentally important genes makes a substantial contribution. However, because individual developmental disorders can be rare and exhibit variable symptoms, their genetic diagnosis remains challenging.
As part of the Deciphering Developmental Disorders Study, Matthew Hurles, Jeremy McRae and colleagues studied 4,293 individuals with a severe, undiagnosed developmental disorder and their families. Combining these data with previously published analyses of a further 3,287 individuals with similar disorders, the authors identified 94 genes that were particularly likely to contain damaging de novo mutations not present in either parent. Fourteen of these genes had not been previously implicated in developmental disorders. The authors estimate that 42% of the individuals studied carry a pathogenic de novo mutation in protein-coding DNA sequences, resulting in disrupted or altered gene function. They also calculate that developmental disorders caused by de novo mutations are present in 1 in 213 to 1 in 448 children, depending on the ages of the parents; globally, this equates to almost 400,000 children born per year.