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Cell Rep. 2014 Oct 9;9(1):16-23. doi: 10.1016/j.celrep.2014.08.068. Epub 2014 Oct 2.

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

Author information

1
Center for Bioinformatics, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, People's Republic of China; Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA.
2
Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94158, USA.
3
Biomedical High Performance Computing Center, W.M. Keck Biotechnology Resource Laboratory, Department of Computer Science, Yale University, New Haven, CT 06520, USA.
4
Bionomics Research and Technology, Environmental and Occupational Health Sciences Institute, Rutgers University, 170 Frelinghuysen Road, Piscataway, NJ 08854, USA.
5
Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94158, USA.
6
Center for Bioinformatics, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, People's Republic of China; National Institute of Biological Sciences, Beijing 102206, People's Republic of China.
7
Child Study Center, Yale University School of Medicine, New Haven, CT 06520, USA.
8
Yale Center for Genomic Analysis, Yale University School of Medicine, New Haven, CT 06520, USA; Regeneron Genetics Center, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA.
9
Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT 06520, USA.
10
Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Research on Children with Special Needs, National Research Center, Cairo 11787, Egypt.
11
Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA.
12
Department of Medical Genetics, Gulhane Military Medical Academy, Ankara 06010, Turkey.
13
Department of Molecular Biology and Genetics, Bilkent University, Ankara 06800, Turkey.
14
Department of Neurosurgery, Yale Neurogenetics Program, Yale University School of Medicine, New Haven, CT 06520, USA.
15
Child Study Center, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Pediatrics, Yale University School of Medicine, New Haven, CT 06520, USA.
16
Yale Center for Genomic Analysis, Yale University School of Medicine, New Haven, CT 06520, USA.
17
Department of Genetics and the Human Genetics Institute, Rutgers University, 145 Bevier Road, Room 136, Piscataway, NJ 08854, USA.
18
Department of Statistics, Carnegie Mellon University, Pittsburgh, PA 15213, USA; Ray and Stephanie Lane Center for Computational Biology, Carnegie Mellon University, Pittsburgh, PA 15213, USA.
19
Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
20
Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94158, USA; Child Study Center, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: matthew.state@ucsf.edu.
21
Center for Bioinformatics, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, People's Republic of China; National Institute of Biological Sciences, Beijing 102206, People's Republic of China. Electronic address: weilp@mail.cbi.pku.edu.cn.
22
Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: stephan.sanders@ucsf.edu.

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.

PMID:
25284784
PMCID:
PMC4194132
DOI:
10.1016/j.celrep.2014.08.068
[Indexed for MEDLINE]
Free PMC Article

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