Article

Rare complete knockouts in humans: population distribution and significant role in autism spectrum disorders.

Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA
Neuron (Impact Factor: 15.98). 01/2013; 77(2):235-42. DOI: 10.1016/j.neuron.2012.12.029
Source: PubMed

ABSTRACT To characterize the role of rare complete human knockouts in autism spectrum disorders (ASDs), we identify genes with homozygous or compound heterozygous loss-of-function (LoF) variants (defined as nonsense and essential splice sites) from exome sequencing of 933 cases and 869 controls. We identify a 2-fold increase in complete knockouts of autosomal genes with low rates of LoF variation (≤5% frequency) in cases and estimate a 3% contribution to ASD risk by these events, confirming this observation in an independent set of 563 probands and 4,605 controls. Outside the pseudoautosomal regions on the X chromosome, we similarly observe a significant 1.5-fold increase in rare hemizygous knockouts in males, contributing to another 2% of ASDs in males. Taken together, these results provide compelling evidence that rare autosomal and X chromosome complete gene knockouts are important inherited risk factors for ASD.

0 Followers
 · 
238 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Pinpointing the small number of causal variants among the abundant naturally occurring genetic variation is a difficult challenge, but a crucial one for understanding precise molecular mechanisms of disease and follow-up functional studies. We propose and investigate two complementary statistical approaches for identification of rare causal variants in sequencing studies: a backward elimination procedure based on groupwise association tests, and a hierarchical approach that can integrate sequencing data with diverse functional and evolutionary conservation annotations for individual variants. Using simulations, we show that incorporation of multiple bioinformatic predictors of deleteriousness, such as PolyPhen-2, SIFT and GERP++ scores, can improve the power to discover truly causal variants. As proof of principle, we apply the proposed methods to VPS13B, a gene mutated in the rare neurodevelopmental disorder called Cohen syndrome, and recently reported with recessive variants in autism. We identify a small set of promising candidates for causal variants, including two loss-of-function variants and a rare, homozygous probably-damaging variant that could contribute to autism risk. Copyright: ß 2014 Ionita-Laza et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability: The authors confirm that all data underlying the findings are fully available without restriction. The data are from dbGaP (dbGaP Study Accession: phs000298.v1.p1) Funding: This work has been supported in part by grants R01MH095797 and MH100233 from the National Institute of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist.
    PLoS Genetics 12/2014; 10(12). DOI:10.1371/journal.pgen.1004729 · 8.17 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Contactins and Contactin-Associated Proteins, and Contactin-Associated Protein-Like 2 (CNTNAP2) in particular, have been widely cited as autism risk genes based on findings from homozygosity mapping, molecular cytogenetics, copy number variation analyses, and both common and rare single nucleotide association studies. However, data specifically with regard to the contribution of heterozygous single nucleotide variants (SNVs) have been inconsistent. In an effort to clarify the role of rare point mutations in CNTNAP2 and related gene families, we have conducted targeted next-generation sequencing and evaluated existing sequence data in cohorts totaling 2704 cases and 2747 controls. We find no evidence for statistically significant association of rare heterozygous mutations in any of the CNTN or CNTNAP genes, including CNTNAP2, placing marked limits on the scale of their plausible contribution to risk.
    PLoS Genetics 01/2015; 11(1):e1004852. DOI:10.1371/journal.pgen.1004852 · 8.17 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Autism spectrum disorder (ASD) is defined by impaired social interaction and communication accompanied by stereotyped behaviors and restricted interests. Although ASD is common, its genetic and clinical features are highly heterogeneous. A number of recent breakthroughs have dramatically advanced our understanding of ASD from the standpoint of human genetics and neuropathology. These studies highlight the period of fetal development and the processes of chromatin structure, synaptic function, and neuron-glial signaling. The initial efforts to systematically integrate findings of multiple levels of genomic data and studies of mouse models have yielded new clues regarding ASD pathophysiology. This early work points to an emerging convergence of disease mechanisms in this complex and etiologically heterogeneous disorder.

Full-text

Download
21 Downloads
Available from
May 21, 2014