Details

Autor(en) / Beteiligte

• Iossifov, Ivan
• Ronemus, Michael
• Levy, Dan
• Wang, Zihua
• Hakker, Inessa
• Rosenbaum, Julie
• Yamrom, Boris
• Lee, Yoon-ha
• Narzisi, Giuseppe
• Leotta, Anthony
• Kendall, Jude
• Grabowska, Ewa
• Ma, Beicong
• Marks, Steven
• Rodgers, Linda
• Stepansky, Asya
• Troge, Jennifer
• Andrews, Peter
• Bekritsky, Mitchell
• Pradhan, Kith
• Ghiban, Elena
• Kramer, Melissa
• Parla, Jennifer
• Demeter, Ryan
• Fulton, Lucinda L.
• Fulton, Robert S.
• Magrini, Vincent J.
• Ye, Kenny
• Darnell, Jennifer C.
• Darnell, Robert B.
• Mardis, Elaine R.
• Wilson, Richard K.
• Schatz, Michael C.
• McCombie, W. Richard
• Wigler, Michael

Titel

De Novo Gene Disruptions in Children on the Autistic Spectrum

Ist Teil von

• Neuron (Cambridge, Mass.), 2012-04, Vol.74 (2), p.285-299

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2012

Quelle

ScienceDirect

Beschreibungen/Notizen

• 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. ► De novo mutations derive mainly from the paternal line in an age-dependent manner ► Mutations disrupting genes are twice as frequent in affected as unaffected siblings ► Many disrupted genes are associated with the fragile X protein, FMRP ► FMRP-associated genes are under unexpectedly strong purifying selection Iossifov et al. use exome sequencing of 343 autistic families to identify de novo gene mutations associated with autism. Many of the mutated genes are associated with the fragile X protein FMRP, indicating new links between autism and synaptic plasticity.