De novo insertions and deletions of predominantly paternal origin are associated with autism spectrum disorder

Dong, S and Walker, MF and Carriero, NJ and DiCola, M and Willsey, AJ and Ye, AY and Waqar, Z and Gonzalez, LE and Overton, JD and Frahm, S and Keaney, JF and Teran, NA and Dea, J and Mandell, JD and HusBal, V and Sullivan, CA and DiLullo, NM and Khalil, RO and Gockley, J and Yuksel, Z and Sertel, SM and Ercan-Sencicek, AG and Gupta, AR and Mane, SM and Sheldon, M and Brooks, AI and Roeder, K and Devlin, B and State, MW and Wei, L and Sanders, SJ (2014) De novo insertions and deletions of predominantly paternal origin are associated with autism spectrum disorder. Cell Reports, 9 (1). 16 - 23.

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Abstract

Whole-exome sequencing (WES) studies have demonstrated the contribution of de novo loss-of-function single-nucleotide variants (SNVs) to autism spectrum disorder (ASD). However, challenges in the reliable detection of de novo insertions and deletions (indels) have limited inclusion of these variants in prior analyses. By applying a robust indel detection method to WES data from 787 ASD families (2,963 individuals), we demonstrate that de novo frameshift indels contribute to ASD risk (OR= 1.6; 95% CI= 1.0-2.7; p= 0.03), are more common in female probands (p= 0.02), are enriched among genes encoding FMRP targets (p= 6× 10-9), and arise predominantly on the paternal chromosome (p< 0.001). On the basis of mutation rates in probands versus unaffected siblings, we conclude that de novo frameshift indels contribute to risk in approximately 3% of individuals with ASD. Finally, by observing clustering of mutations in unrelated probands, we uncover two ASD-associated genes: KMT2E (MLL5), a chromatin regulator, and RIMS1, a regulator of synaptic vesicle release.

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Details

Item Type:	Article
Status:	Published
Creators/Authors:	Creators Email Pitt Username ORCID Dong, S Walker, MF Carriero, NJ DiCola, M Willsey, AJ Ye, AY Waqar, Z Gonzalez, LE Overton, JD Frahm, S Keaney, JF Teran, NA Dea, J Mandell, JD HusBal, V Sullivan, CA DiLullo, NM Khalil, RO Gockley, J Yuksel, Z Sertel, SM Ercan-Sencicek, AG Gupta, AR Mane, SM Sheldon, M Brooks, AI Roeder, K Devlin, B devlinbj@pitt.edu DEVLINBJ State, MW Wei, L Sanders, SJ
Date:	9 October 2014
Date Type:	Publication
Journal or Publication Title:	Cell Reports
Volume:	9
Number:	1
Page Range:	16 - 23
DOI or Unique Handle:	10.1016/j.celrep.2014.08.068
Schools and Programs:	School of Medicine > Psychiatry
Refereed:	Yes
Date Deposited:	22 May 2015 21:52
Last Modified:	07 Dec 2021 13:55
URI:	http://d-scholarship.pitt.edu/id/eprint/24720

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