Prevalence and architecture of de novo mutations in developmental disorders

Deciphering Developmental Disorders Study

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853 Citations (Scopus)


The genomes of individuals with severe, undiagnosed developmental disorders are enriched in damaging de novo mutations (DNMs) in developmentally important genes. Here we have sequenced the exomes of 4,293 families containing individuals with developmental disorders, and meta-analysed these data with data from another 3,287 individuals with similar disorders. We show that the most important 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 the parental ages. We identified 94 genes enriched in damaging DNMs, including 14 that previously lacked compelling evidence of involvement in developmental disorders. We have also characterized the phenotypic diversity among these disorders. We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function. We 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 per year.

Original languageEnglish
Pages (from-to)433-438
Number of pages6
Issue number7642
Early online date25 Jan 2017
Publication statusPublished - 23 Feb 2017

Bibliographical note

We thank the families for their participation and patience. We are grateful to the Exome Aggregation Consortium for making their data available. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the UK Department of Health, and the Wellcome Trust Sanger Institute (grant WT098051). The views expressed in this publication are those of the author(s) and not necessarily those of the Wellcome Trust or the UK Department of Health. The study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South Research Ethics Committee and GEN/284/12, granted by the Republic of Ireland Research Ethics Committee). The research team acknowledges the support of the National Institutes for Health Research, through the Comprehensive Clinical Research Network. We thank the Sanger Human Genome Informatics team, the Sample Management team, the Illumina High-Throughput team, the New Pipeline Group team, the DNA pipelines team and the Core Sequencing team for their support in generating and processing the data. D.R.F. is funded through an MRC Human Genetics Unit program grant to the University of Edinburgh. Finally we acknowledge the contribution of two esteemed DDD clinical collaborators, J. Tolmie and L. Brueton, who died during the course of the study.


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