title: De novo insertions and deletions of predominantly paternal origin are associated with autism spectrum disorder.
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.
authors.affiliation: 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.
authors.forename: Shan
authors.initials: S
authors.lastname: Dong
authors.affiliation: Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Walker
authors.affiliation: Biomedical High Performance Computing Center, W.M. Keck Biotechnology Resource Laboratory, Department of Computer Science, Yale University, New Haven, CT 06520, USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Carriero
authors.affiliation: Bionomics Research and Technology, Environmental and Occupational Health Sciences Institute, Rutgers University, 170 Frelinghuysen Road, Piscataway, NJ 08854, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: DiCola
authors.affiliation: 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.
authors.forename: A Jeremy
authors.initials: AJ
authors.lastname: Willsey
authors.affiliation: 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.
authors.forename: Adam Y
authors.initials: AY
authors.lastname: Ye
authors.affiliation: Child Study Center, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Zainulabedin
authors.initials: Z
authors.lastname: Waqar
authors.affiliation: Child Study Center, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Luis E
authors.initials: LE
authors.lastname: Gonzalez
authors.affiliation: 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.
authors.forename: John D
authors.initials: JD
authors.lastname: Overton
authors.affiliation: Bionomics Research and Technology, Environmental and Occupational Health Sciences Institute, Rutgers University, 170 Frelinghuysen Road, Piscataway, NJ 08854, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Frahm
authors.affiliation: Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT 06520, USA.
authors.forename: John F
authors.initials: JF
authors.lastname: Keaney
authors.affiliation: Child Study Center, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Teran
authors.affiliation: Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Jeanselle
authors.initials: J
authors.lastname: Dea
authors.affiliation: Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Mandell
authors.affiliation: Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Hus Bal
authors.affiliation: Child Study Center, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Sullivan
authors.affiliation: Child Study Center, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: DiLullo
authors.affiliation: 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.
authors.forename: Rehab O
authors.initials: RO
authors.lastname: Khalil
authors.affiliation: Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Jake
authors.initials: J
authors.lastname: Gockley
authors.affiliation: Department of Medical Genetics, Gulhane Military Medical Academy, Ankara 06010, Turkey.
authors.forename: Zafer
authors.initials: Z
authors.lastname: Yuksel
authors.affiliation: Department of Molecular Biology and Genetics, Bilkent University, Ankara 06800, Turkey.
authors.forename: Sinem M
authors.initials: SM
authors.lastname: Sertel
authors.affiliation: Department of Neurosurgery, Yale Neurogenetics Program, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: A Gulhan
authors.initials: AG
authors.lastname: Ercan-Sencicek
authors.affiliation: 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.
authors.forename: Abha R
authors.initials: AR
authors.lastname: Gupta
authors.affiliation: Yale Center for Genomic Analysis, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Shrikant M
authors.initials: SM
authors.lastname: Mane
authors.affiliation: Department of Genetics and the Human Genetics Institute, Rutgers University, 145 Bevier Road, Room 136, Piscataway, NJ 08854, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Sheldon
authors.affiliation: Bionomics Research and Technology, Environmental and Occupational Health Sciences Institute, Rutgers University, 170 Frelinghuysen Road, Piscataway, NJ 08854, USA.
authors.forename: Andrew I
authors.initials: AI
authors.lastname: Brooks
authors.affiliation: 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.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Roeder
authors.affiliation: Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
authors.forename: Bernie
authors.initials: B
authors.lastname: Devlin
authors.affiliation: 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.
authors.forename: Matthew W
authors.initials: MW
authors.lastname: State
authors.affiliation: 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.
authors.forename: Liping
authors.initials: L
authors.lastname: Wei
authors.affiliation: 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.
authors.forename: Stephan J
authors.initials: SJ
authors.lastname: Sanders
mesh_terms: D002648:Child; D002659:Child Development Disorders, Pervasive / Q000097:blood / Q000175:diagnosis / Q000235:genetics*; D004247:DNA / Q000097:blood / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics; D016368:Frameshift Mutation; D019204:GTP-Binding Proteins / Q000235:genetics; D006801:Humans; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D017384:Sequence Deletion; D012737:Sex Factors
chemical_list: D004247:DNA; D004268:DNA-Binding Proteins; D051860:Fragile X Messenger Ribonucleoprotein 1; D019204:GTP-Binding Proteins; D009419:Nerve Tissue Proteins; C497683:FMR1 protein, human; C460660:KMT2E protein, human; C491492:RIMS1 protein, human