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Prevalence and architecture of de novo mutations in developmental disorders

Lookup NU author(s): Dr David Bourn, Professor Sir John BurnORCiD, Dr Richard Fisher, Professor Judith Goodship, Alexander Henderson, Dr Tara Montgomery, Linda Sneddon, Dr Miranda Splitt, Professor Volker StraubORCiD, Dr Michael Wright, Dr Laura Yates



This is the authors' accepted manuscript of an article that has been published in its final definitive form by Nature Publishing Group, 2017.

For re-use rights please refer to the publisher's terms and conditions.


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 disorderscaused 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.

Publication metadata

Author(s): Deciphering Developmental Disorders Study, Study authors include, Bourn D, Burn J, Fisher R, Goodship J, Hellens S, Henderson A, Montgomery T, Sneddon L, Splitt M, Straub V, Wright M, Yates L

Publication type: Article

Publication status: Published

Journal: Nature

Year: 2017

Volume: 542

Pages: 433-438

Print publication date: 23/02/2017

Online publication date: 25/01/2017

Acceptance date: 15/12/2016

Date deposited: 07/06/2018

ISSN (print): 0028-0836

ISSN (electronic): 1476-4687

Publisher: Nature Publishing Group


DOI: 10.1038/nature21062

PubMed id: 28135719


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