Genomes of patients having severe, undiagnosed developmental disorders are well known to be enriched in damaging de novo mutations (DNMs) in developmentally important genes. The attached paper describes the whole-exome sequencing (WES) of 4,293 families containing individuals with developmental disorders. These results were then combined with data from another 3,287 individuals with similar disorders for one large meta-analysis study.
Authors show herein that the most important factors influencing the diagnostic yield of DNMs are the gender of the affected individual, the relatedness of their parents, whether close relatives are affected, and the parental ages. They identified 94 genes enriched in damaging DNMs, including 14 that had previously lacked compelling evidence of involvement in developmental disorders. Authors have also characterized the phenotypic diversity among these disorders.
They estimate that 42% of their cohort carries pathogenic DNMs in coding sequences –– with approximately half of these DNMs disrupting gene function and the remainder resulting in altered protein function. Authors estimate that developmental disorders caused by DNMs have an average prevalence of 1 in 213 to 1 in 448 births, depending on parental age. Given current global demographics, this equates to almost 400,000 children born with undiagnosed developmental disorders per year.
Nature 23 Feb 2o17; 542: 433–438