De Novo Gene Disruptions in Children on the Autistic Spectrum

被引：1075

作者：

Iossifov, Ivan ^{[1
]}

Ronemus, Michael ^{[1
]}

Levy, Dan ^{[1
]}

Wang, Zihua ^{[1
]}

Hakker, Inessa ^{[1
]}

Rosenbaum, Julie ^{[1
]}

Yamrom, Boris ^{[1
]}

Lee, Yoon-ha ^{[1
]}

Narzisi, Giuseppe ^{[1
]}

Leotta, Anthony ^{[1
]}

Kendall, Jude ^{[1
]}

Grabowska, Ewa ^{[1
]}

Ma, Beicong ^{[1
]}

Marks, Steven ^{[1
]}

Rodgers, Linda ^{[1
]}

Stepansky, Asya ^{[1
]}

Troge, Jennifer ^{[1
]}

Andrews, Peter ^{[1
]}

Bekritsky, Mitchell ^{[1
]}

Pradhan, Kith ^{[1
]}

Ghiban, Elena ^{[1
]}

Kramer, Melissa ^{[1
]}

Parla, Jennifer ^{[1
]}

Demeter, Ryan ^{[2
]}

Fulton, Lucinda L. ^{[2
]}

Fulton, Robert S. ^{[2
]}

Magrini, Vincent J. ^{[2
]}

Ye, Kenny ^{[3
]}

Darnell, Jennifer C. ^{[4
]}

Darnell, Robert B. ^{[4
,5
]}

Mardis, Elaine R. ^{[2
]}

Wilson, Richard K. ^{[2
]}

Schatz, Michael C. ^{[1
]}

McCombie, W. Richard ^{[1
]}

Wigler, Michael ^{[1
]}

机构：

[1] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA

[2] Washington Univ, Sch Med, Genome Inst, St Louis, MO 63108 USA

[3] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10461 USA

[4] Rockefeller Univ, Mol Neurooncol Lab, New York, NY 10065 USA

[5] Rockefeller Univ, Howard Hughes Med Inst, New York, NY 10065 USA

来源：

NEURON | 2012年 / 74卷 / 02期

关键词：

COPY-NUMBER VARIATION; IDENTIFICATION; RIM1-ALPHA; DYRK1A; REGION; PARADIGM; RESOURCE; NETWORK;

D O I：

10.1016/j.neuron.2012.04.009

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

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.

引用

页码：285 / 299

页数：15

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