Prevalence and architecture of de novo mutations in developmental disorders

Journal article

Individuals with severe, undiagnosed developmental disorders (DDs) are enriched for damaging de novomutations (DNMs) in developmentally important genes. We exome sequenced 4,293 families with individuals with DDs, and meta-analysed these data with another 3,287 individuals with similar disorders. We show that the most significant factors influencing the diagnostic yield of DNMs are the sex of the affected individual, the relatedness of their parents, whether close relatives are affected and parental ages. We identified 94 genes enriched for damaging DNMs, including 14 without previous compelling evidence. We have characterised the phenotypic diversity among these disorders. We estimate that42% of our cohort carry pathogenic DNMs in coding sequences, and approximately half disruptgene function, with the remainder resulting in altered-function. We estimate that developmental disorders caused by DNMs have an average birth prevalence of 1 in 213 to 1 in 448, depending on parental age. Given current global demographics, this equates to almost 400,000 children born per year.

Authors: Parker, M; The Deciphering Developmental Disorders Study,

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Nature Publishing Group
• Journal: Nature
• Publication date: 2017-01-01
• Acceptance date: 2016-12-15
• DOI: 10.1038/nature21062
• EISSN: 1476-4687
• ISSN: 0028-0836
• Keywords: Average Faces; De novo mutation; Developmental Disease; Intellectual Disability; Seizures; PhenIcons