Autism spectrum disorders (ASD) are believed to have genetic and environmental origins, yet in only a modest fraction of individuals can specific causes be identified1,2. To identify further genetic risk factors, we assess the role of de novo mutations in ASD by sequencing the exomes of ASD cases and their parents (n= 175 trios). Fewer than half of the cases (46.3%) carry a missense or nonsense de novo variant and the overall rate of mutation is only modestly higher than the expected rate. In contrast, there is significantly enriched connectivity among the proteins encoded by genes harboring de novo missense or nonsense mutations, and excess connectivity to prior ASD genes of major effect, suggesting a subset of observed events are relevant to ASD risk. The small increase in rate of de novo events, when taken together with the connections among the proteins themselves and to ASD, are consistent with an important but limited role for de novo point mutations, similar to that documented for de novo copy number variants. Genetic models incorporating these data suggest that the majority of observed de novo events are unconnected to ASD, those that do confer risk are distributed across many genes and are incompletely penetrant (i.e., not necessarily causal). Our results support polygenic models in which spontaneous coding mutations in any of a large number of genes increases risk by 5 to 20-fold. Despite the challenge posed by such models, results from de novo events and a large parallel case-control study provide strong evidence in favor of CHD8 and KATNAL2 as genuine autism risk factors.

Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease with no effective treatment. Here we report the results of a moderate-scale sequencing study aimed at identifying new genes contributing to predisposition for ALS. We performed whole exome sequencing of 2,874 ALS patients and compared them to 6,405 controls. Several known ALS genes were found to be associated, and the non-canonical IκB kinase family TANK-Binding Kinase 1 (TBK1) was identified as an ALS gene. TBK1 is known to bind to and phosphorylate a number of proteins involved in innate immunity and autophagy, including optineurin (OPTN) and p62 (SQSTM1/sequestosome), both of which have also been implicated in ALS. These observations reveal a key role of the autophagic pathway in ALS and suggest specific targets for therapeutic intervention.

To evaluate evidence for de novo etiologies in schizophrenia, we sequenced at high coverage the exomes of families recruited from two populations with distinct demographic structure and history. We sequenced a total of 795 exomes from 231 parent-proband trios enriched for sporadic schizophrenia cases, as well as 34 unaffected trios. We observed in cases an excess of non-synonymous single nucleotide variants as well as a higher prevalence of gene-disruptive de novo mutations. We found four genes (LAMA2, DPYD, TRRAP and VPS39) affected by recurrent de novo events within or across the two populations, a finding unlikely to have occurred by chance. We show that de novo mutations affect genes with diverse functions and developmental profiles but we also find a substantial contribution of mutations in genes with higher expression in early fetal life. Our results help define the pattern of genomic and neural architecture of schizophrenia.

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.

Despite high heritability, a large fraction of cases with schizophrenia do not have a family history of the disease (sporadic cases). Here, we examine the possibility that rare de novo protein-altering mutations contribute to the genetic component of schizophrenia by sequencing the exome of 53 sporadic cases, 22 unaffected controls and their parents. We identified 40 de novo mutations in 27 patients affecting 40 genes including a potentially disruptive mutation in DGCR2, a gene removed Users may view, print, copy, download and text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms * Correspondence should be addressed to Maria Karayiorgou (mk2758@columbia.edu) or Joseph A. Gogos (jag90@columbia.edu). URLs: Picard (http://picard.sourceforge.net/) SAM tools (http://samtools.sourceforge.net/) PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) UCSC Table Browser (http://genome.ucsc.edu/cgi-bin/hgTables) The Human Splicing Finder (HSF, Version 2.4.1) software (http://www.umd.be/HSF/) R (www.r-project.org/) dbSNP v132 (ftp://ftp.ncbi.nlm.nih.gov/snp/organisms/human_9606/VCF/v4.0/00-All.vcf.gz) GATK VCF annotation file for hg19 (ftp://gatk-ftp:PH5UH7Pa@ftp.broadinstitute.org/refGene/refGene-big-table-hg19.txt.gz) Accession codes: Reference sequences are available from NCBI under the following accession codes: PLCL2, NM_001144382; WDR11, NM_018117; DPYD, NM_000110; OR4C46, NM_001004703; UGT1A3, NM_019093; FAM3D, NM_138805; KLF12, NM_007249; ADCY7, NM_001114; GPR153, NM_207370; PML, NM_002675; SLC26A8, NM_052961; CCDC108, NM_152389; TRAK1, NM_001042646; FASTKD5, NM_021826; DGCR2, NM_005137; ACOT6, NM_001037162; PITPNM1, NM_001130848; NPRL2, NM_006545; MAGEC1, NM_005462; TRRAP, NM_003496; COL3A1, NM_000090; GIF, NM_005142; TEKT5, NM_144674; THBS1, NM_003246; PAG1, NM_018440; RGS12, NM_002926; SAP30BP, NM_013260; ZNF530, NM_020880; MTOR, NM_004958; INPP5A, NM_005539; EDEM2, NM_001145025; CELF2, NM_001083591; SLC26A7, NM_134266; VPS35, NM_018206; ADAMTS3, NM_014243; GPR115, NM_153838; SPATA5, NM_145207; RB1CC1, NM_014781; LAMA2, NM_000426; ESAM, NM_138961 AUTHOR CONTRIBUTIONS BX, JAG and MK designed the study, interpreted the data and prepared the manuscript; BX developed the analysis pipeline and had the primary role in analysis and validation of sequence data; JLR collected the samples and was the primary clinician on the project; SL and BP performed exome library construction, capture and sequencing; PD contributed to the analysis of the data; BB contributed to the primary sequence data analysis; SL supervised the sequencing project at HudsonAlpha Institute and contributed to the manuscript. COMPETING FINANCIAL INTERESTSThe authors declare no competing financial interests. 8,9 . Pilot studies in patients with SCZ focusing on specific synaptic genes identified a small number of putative de novo mutations 10 . However, the full contribution of rare de novo SNVs and in/d...