title: Targeted DNA Sequencing from Autism Spectrum Disorder Brains Implicates Multiple Genetic Mechanisms.
abstract: Single nucleotide variants (SNVs), particularly loss-of-function mutations, are significant contributors to autism spectrum disorder (ASD) risk. Here we report the first systematic deep sequencing study of 55 postmortem ASD brains for SNVs in 78 known ASD candidate genes. Remarkably, even without parental samples, we find more ASD brains with mutations that are protein-altering (26/55 cases versus 12/50 controls, p = 0.015), deleterious (16/55 versus 5/50, p = 0.016), or loss-of-function (6/55 versus 0/50, p = 0.028) compared to controls, with recurrent deleterious mutations in ARID1B, SCN1A, SCN2A, and SETD2, suggesting these mutations contribute to ASD risk. In several cases, the identified mutations and medical records suggest syndromic ASD diagnoses. Two ASD and one Fragile X premutation case showed deleterious somatic mutations, providing evidence that somatic mutations occur in ASD cases, and supporting a model in which a combination of germline and/or somatic mutations may contribute to ASD risk on a case-by-case basis.
authors.affiliation: Division of Genetics and Genomics, Manton Center for Orphan Disease, and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA; Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Alissa M
authors.initials: AM
authors.lastname: D'Gama
authors.affiliation: Departments of Neuroscience, Genetics, and Psychiatry, and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA.
authors.forename: Sirisha
authors.initials: S
authors.lastname: Pochareddy
authors.affiliation: Departments of Neuroscience, Genetics, and Psychiatry, and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA.
authors.forename: Mingfeng
authors.initials: M
authors.lastname: Li
authors.affiliation: Division of Genetics and Genomics, Manton Center for Orphan Disease, and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA; Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Paediatrics, KK Women's and Children's Hospital, Singapore; Paediatrics Academic Clinical Programme, Duke-NUS Graduate School of Medicine, Singapore.
authors.forename: Saumya S
authors.initials: SS
authors.lastname: Jamuar
authors.affiliation: Division of Genetics and Genomics, Manton Center for Orphan Disease, and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA; Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Reiff
authors.affiliation: Division of Genetics and Genomics, Manton Center for Orphan Disease, and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA; Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Anh-Thu N
authors.initials: AN
authors.lastname: Lam
authors.affiliation: Departments of Neuroscience, Genetics, and Psychiatry, and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA.
authors.forename: Nenad
authors.initials: N
authors.lastname: Sestan
authors.affiliation: Division of Genetics and Genomics, Manton Center for Orphan Disease, and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA; Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: christopher.walsh@childrens.harvard.edu.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Walsh
mesh_terms: D000293:Adolescent; D000067877:Autism Spectrum Disorder / Q000235:genetics* / Q000473:pathology*; D001921:Brain / Q000473:pathology*; D002648:Child; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D062550:NAV1.1 Voltage-Gated Sodium Channel / Q000235:genetics*; D062551:NAV1.2 Voltage-Gated Sodium Channel / Q000235:genetics*; D017422:Sequence Analysis, DNA / Q000379:methods; D014157:Transcription Factors / Q000235:genetics*
chemical_list: C497837:ARID1B protein, human; D004268:DNA-Binding Proteins; D062550:NAV1.1 Voltage-Gated Sodium Channel; D062551:NAV1.2 Voltage-Gated Sodium Channel; C568242:SCN1A protein, human; C568251:SCN2A protein, human; D014157:Transcription Factors; D011495:Histone-Lysine N-Methyltransferase; C521636:SETD2 protein, human