De Novo Gene Disruptions in Children on the Autistic Spectrum

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• 作者：Ivan Iossifov¹ ; ⁶ ; Michael Ronemus¹ ; ⁶ ; Dan Levy¹ ; Zihua Wang¹ ; Inessa Hakker¹ ; Julie Rosenbaum¹ ; Boris Yamrom¹ ; Yoon-ha Lee¹ ; Giuseppe Narzisi¹ ; Anthony Leotta¹ ; Jude Kendall¹ ; Ewa Grabowska¹ ; Beicong Ma¹ ; Steven Marks¹ ; Linda Rodgers¹ ; Asya Stepansky¹ ; Jennifer Troge¹ ; Peter Andrews¹ ; Mitchell Bekritsky¹ ; Kith Pradhan¹ ; Elena Ghiban¹ ; Melissa Kramer¹ ; Jennifer Parla¹ ; Ryan Demeter² ; Lucinda  ; L. Fulton² ; Robert  ; S. Fulton² ; Vincent  ; J. Magrini² ; Kenny Ye³ ; Jennifer  ; C. Darnell⁴ ; Robert  ; B. Darnell⁴ ; ⁵ ; Elaine  ; R. Mardis² ; Richard  ; K. Wilson² ; Michael  ; C. Schatz¹ ; W.  ; Richard McCombie¹ ; Michael Wigler¹ ; ^{wigler@cshl.edu}
• 刊名：Neuron
• 出版年：2012
• 期刊代码：45_08966273
• 类别：neu
• 出版时间：26 April, 2012
• 卷：74
• 期：2
• 页码：285-299
• 文件大小：449 K

摘要

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Summary

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聽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.