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De Novo Gene Disruptions in Children on the Autistic Spectrum

Authors :
Anthony Leotta
Steven Marks
Ivan Iossifov
Lucinda Fulton
Kith Pradhan
Peter Andrews
Linda Rodgers
Michael Wigler
Beicong Ma
Richard W. McCombie
Jennifer Troge
Elena Ghiban
Ryan Demeter
Robert S. Fulton
Julie Rosenbaum
Asya Stepansky
Vincent Magrini
Yoon-ha Lee
Kenny Ye
Jennifer Parla
Richard K. Wilson
Robert B. Darnell
Boris Yamrom
Inessa Hakker
Jennifer C. Darnell
Michael Ronemus
Michael C. Schatz
Dan Levy
Elaine R. Mardis
Zihua Wang
Giuseppe Narzisi
Melissa Kramer
Jude Kendall
Mitchell A. Bekritsky
Ewa A. Grabowska
Source :
Neuron. 74(2):285-299
Publication Year :
2012
Publisher :
Elsevier BV, 2012.

Abstract

SummaryExome 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.

Details

ISSN :
08966273
Volume :
74
Issue :
2
Database :
OpenAIRE
Journal :
Neuron
Accession number :
edsair.doi.dedup.....436dac00dfb388b306cc1884918b76cf
Full Text :
https://doi.org/10.1016/j.neuron.2012.04.009