Prevalence, phenotype and architecture of developmental disorders caused by de novo mutation
Jeremy F McRae,
Tomas W Fitzgerald,
Daniel M Barrett,
Wendy D Jones,
Laura E Mason,
Adrian R Tivey,
A Paul Bevan,
David J Bunyan,
Morag N Collinson,
Dylan de Vries,
V.K Ajith Kumar,
Sally A Lynch,
Dominic J McMullan,
Michael J Parker,
Daniela T Pilz,
Ganesh Jawahar Swaminathan,
I. Karen Temple,
Helen V. Firth,
Caroline F. Wright,
David R. FitzPatrick,
Jeffrey C Barrett,
Matthew E Hurles
Posted 20 Apr 2016
bioRxiv DOI: 10.1101/049056
Posted 20 Apr 2016
Individuals with severe, undiagnosed developmental disorders (DDs) are enriched for damaging de novo mutations (DNMs) in developmentally important genes. We exome sequenced 4,293 families with individuals with DDs, and meta-analysed these data with published data on 3,287 individuals with similar disorders. We show that the most significant factors influencing the diagnostic yield of de novo mutations are the sex of the affected individual, the relatedness of their parents and the age of both father and mother. We identified 94 genes enriched for damaging de novo mutation at genome-wide significance (P < 7 x 10-7), including 14 genes for which compelling data for causation was previously lacking. We have characterised the phenotypic diversity among these genetic disorders. We demonstrate that, at current cost differentials, exome sequencing has much greater power than genome sequencing for novel gene discovery in genetically heterogeneous disorders. We estimate that 42% of our cohort carry pathogenic DNMs (single nucleotide variants and indels) in coding sequences, with approximately half operating by a loss-of-function mechanism, and the remainder resulting in altered-function (e.g. activating, dominant negative). We established that most haplo insufficient developmental disorders have already been identified, but that many altered-function disorders remain to be discovered. Extrapolating from the DDD cohort to the general population, we estimate that developmental disorders caused by DNMs have an average birth prevalence of 1 in 213 to 1 in 448 (0.22-0.47% of live births), depending on parental age.
- Downloaded 7,301 times
- Download rankings, all-time:
- Site-wide: 465 out of 100,883
- In genetics: 33 out of 5,020
- Year to date:
- Site-wide: 14,812 out of 100,883
- Since beginning of last month:
- Site-wide: 16,645 out of 100,883
Downloads over time
Distribution of downloads per paper, site-wide
- 20 Oct 2020: Support for sorting preprints using Twitter activity has been removed, at least temporarily, until a new source of social media activity data becomes available.
- 18 Dec 2019: We're pleased to announce PanLingua, a new tool that enables you to search for machine-translated bioRxiv preprints using more than 100 different languages.
- 21 May 2019: PLOS Biology has published a community page about Rxivist.org and its design.
- 10 May 2019: The paper analyzing the Rxivist dataset has been published at eLife.
- 1 Mar 2019: We now have summary statistics about bioRxiv downloads and submissions.
- 8 Feb 2019: Data from Altmetric is now available on the Rxivist details page for every preprint. Look for the "donut" under the download metrics.
- 30 Jan 2019: preLights has featured the Rxivist preprint and written about our findings.
- 22 Jan 2019: Nature just published an article about Rxivist and our data.
- 13 Jan 2019: The Rxivist preprint is live!