De Novo Gene Disruptions in Children on the Autistic Spectrum

Iossifov, I., Ronemus, M., Levy, D., Wang, Z. H., Hakker, I., Rosenbaum, J., Yamrom, B., Lee, Y. H., Narzisi, G., Leotta, A., Kendall, J., Grabowska, E., Ma, B. C., Marks, S., Rodgers, L., Stepansky, A., Troge, J., Andrews, P., Bekritsky, M., Pradhan, K., Ghiban, E., Kramer, M., Parla, J., Demeter, R., Fulton, L. L., Fulton, R. S., Magrini, V. J., Ye, K., Darnell, J. C., Darnell, R. B., Mardis, E. R., Wilson, R. K., Schatz, M. C., McCombie, W. R., Wigler, M. (2012) De Novo Gene Disruptions in Children on the Autistic Spectrum. Neuron, 74 (2). pp. 285-299. ISSN 0896-6273

URL: http://www.ncbi.nlm.nih.gov/pubmed/22542183
DOI: 10.1016/j.neuron.2012.04.009

Abstract

Exome sequencing of 343 families, each with a single child on the autism spectrum and at least one unaffected sibling, reveal de novo small indels and point substitutions, which come mostly from the paternal line in an age-dependent manner. We do not see significantly greater numbers of de novo missense mutations in affected versus unaffected children, but gene-disrupting mutations (nonsense, splice site, and frame shifts) are twice as frequent, 59 to 28. Based on this differential and the number of recurrent and total targets of gene disruption found in our and similar studies, we estimate between 350 and 400 autism susceptibility genes. Many of the disrupted genes in these studies are associated with the fragile X protein, FMRP, reinforcing links between autism and synaptic plasticity. We find FMRP-associated genes are under greater purifying selection than the remainder of genes and suggest they are especially dosage-sensitive targets of cognitive disorders.

Item Type: Paper
Uncontrolled Keywords: copy-number variation mental-retardation active zone disorders identification rim1-alpha mutations dyrk1a region paradigm
Subjects: bioinformatics
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification
diseases & disorders
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics
diseases & disorders > mental disorders
diseases & disorders > mental disorders > personality disorders
diseases & disorders > mental disorders > personality disorders > autism
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function
CSHL Authors:
Communities: CSHL Post Doctoral Fellows
CSHL labs > McCombie lab
CSHL labs > Schatz lab
CSHL labs > Wigler lab
Watson School > Publications
CSHL Cancer Center Shared Resources > DNA Sequencing Service
CSHL Cancer Center Shared Resources > Flow Cytometry Service
CSHL Cancer Center Shared Resources > Instrumentation Service
Depositing User: Matt Covey
Date Deposited: 30 Jan 2013 18:01
Last Modified: 07 Apr 2015 16:34
PMCID: PMC3619976
Related URLs:
URI: http://repository.cshl.edu/id/eprint/26968

Actions (login required)

Administrator's edit/view item Administrator's edit/view item
CSHL HomeAbout CSHLResearchEducationNews & FeaturesCampus & Public EventsCareersGiving